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Angeler, PhD</a><span class="mx-1">,</span></span><span class="text-md mr-2"><a class="text-author text-gray-500 hover:text-primary underline hover:no-underline decoration-gray-400" href="/authors/robert-m-lundin-bsc-mbbch">Robert M. Lundin, BSc, MBBCh</a></span></div><button class="text-xs text-gray-500 flex items-center mt-2 xs:mt-0 xs:ml-2">+16 More<span class="ml-1"><svg stroke="currentColor" fill="currentColor" stroke-width="0" viewBox="0 0 512 512" height="1em" width="1em" xmlns="http://www.w3.org/2000/svg"><path d="M256 294.1L383 167c9.4-9.4 24.6-9.4 33.9 0s9.3 24.6 0 34L273 345c-9.1 9.1-23.7 9.3-33.1.7L95 201.1c-4.7-4.7-7-10.9-7-17s2.3-12.3 7-17c9.4-9.4 24.6-9.4 33.9 0l127.1 127z"></path></svg></span></button></div></div><div class="max-w-full"><div class="flex flex-wrap sm:flex-nowrap items-center w-fit my-2"></div><div class="w-full flex flex-col sm:flex-row justify-between mt-2"><div class="block md:hidden "><div class="mt-2 flex items-center max-w-fit"><button title="Building Brain Resilience: A Multi-Level Systems Approach" aria-label="facebook" class="react-share__ShareButton" style="background-color:transparent;border:none;padding:0;font:inherit;color:inherit;cursor:pointer"><svg viewBox="0 0 64 64" 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fill="white"></path></svg></button><button aria-label="email" class="react-share__ShareButton" style="background-color:transparent;border:none;padding:0;font:inherit;color:inherit;cursor:pointer"><svg viewBox="0 0 64 64" width="32" height="32"><circle cx="32" cy="32" r="31" fill="#7f7f7f"></circle><path d="M17,22v20h30V22H17z M41.1,25L32,32.1L22.9,25H41.1z M20,39V26.6l12,9.3l12-9.3V39H20z" fill="white"></path></svg></button><a class="print-wrap flex justify-center items-center cursor-pointer"><svg id="print" xmlns="http://www.w3.org/2000/svg" width="24" height="24" fill="currentColor" class="print bi bi-printer" viewBox="0 0 16 16"> <path d="M2.5 8a.5.5 0 1 0 0-1 .5.5 0 0 0 0 1z"></path> <path d="M5 1a2 2 0 0 0-2 2v2H2a2 2 0 0 0-2 2v3a2 2 0 0 0 2 2h1v1a2 2 0 0 0 2 2h6a2 2 0 0 0 2-2v-1h1a2 2 0 0 0 2-2V7a2 2 0 0 0-2-2h-1V3a2 2 0 0 0-2-2H5zM4 3a1 1 0 0 1 1-1h6a1 1 0 0 1 1 1v2H4V3zm1 5a2 2 0 0 0-2 2v1H2a1 1 0 0 1-1-1V7a1 1 0 0 1 1-1h12a1 1 0 0 1 1 1v3a1 1 0 0 1-1 1h-1v-1a2 2 0 0 0-2-2H5zm7 2v3a1 1 0 0 1-1 1H5a1 1 0 0 1-1-1v-3a1 1 0 0 1 1-1h6a1 1 0 0 1 1 1z"></path></svg></a></div><style> .print-wrap { width: 32px; height: 32px; background: #7F7F7F; border-radius: 100%; } .print { background: #7F7F7F; color: white; padding: 2px; border-radius: 100%; } </style></div></div></div></div><div class=" lg:w-full flex flex-col lg:flex-row lg:items-center lg:justify-end"></div><p class="py-2 mb-2 text-sm italic text-gray-600">Beyond the COVID-19-driven shock, we must develop a resilient future in an increasingly uncertain world. </p><div class="py-2"><div class="blockText_blockContent__TbCXh"><div class=""><div style="width:80%;float:center;max-width:525px;margin:0 auto 1rem;clear:both;cursor:" class=" figure"><div class="flex-none relative text-center"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%271000%27%20height=%27422%27/%3e"/></span><img alt="kras99_AdobeStock" title="kras99_AdobeStock" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain"/><noscript><img alt="kras99_AdobeStock" title="kras99_AdobeStock" srcSet="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F972990255d4a55fab15b6cc6ddc7a18b0fdffa6e-1000x422.jpg%3Ffit%3Dcrop%26auto%3Dformat&w=1080&q=75 1x, /_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F972990255d4a55fab15b6cc6ddc7a18b0fdffa6e-1000x422.jpg%3Ffit%3Dcrop%26auto%3Dformat&w=2048&q=75 2x" src="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F972990255d4a55fab15b6cc6ddc7a18b0fdffa6e-1000x422.jpg%3Ffit%3Dcrop%26auto%3Dformat&w=2048&q=75" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain" loading="lazy"/></noscript></span></div><div id="image-caption" class="text-gray-500 italic"><div class="blockText_blockContent__TbCXh"><p class="pb-2">kras99_AdobeStock</p></div></div><div class="top-[-100%] block w-[1px] transition-opacity duration-500 ease-in-out opacity-0 overflow-hidden"><img class="m-auto absolute inset-0 max-w-[0%] max-h-[0%] border-[3px] border-solid border-white shadow-[0px_0px_8px_rgba(0,0,0,0.3)] box-border transition ease-in-out duration-500" src="https://cdn.sanity.io/images/0vv8moc6/psychtimes/972990255d4a55fab15b6cc6ddc7a18b0fdffa6e-1000x422.jpg?fit=crop&auto=format"/></div></div><style> #image-caption p{ font-size: 12px; max-width: 525px; margin: 0 auto; text-align: center; } </style></div><p class="pb-2">Societies need to be better prepared for rapid changes in economics, politics, and climate. This will depend on our ability to cope with complexity. We propose a new framework based on neuroscience for understanding resilience at multiple levels. This framework considers adaptation, transformation, and the hierarchical structure from brain cells and physiological stress systems to organizations, communities, cultures, and countries. We also discuss how resilience can be managed through transdisciplinary and collaborative approaches, creating a resilient neuroscience system to withstand potentially catastrophic changes to social-ecological systems.</p><p class="pb-2">The COVID-19 pandemic has clarified that resilience is a complex and multi-tiered phenomenon. Medical specialties have commonly focused on the individual brain systems for resilience, but attention to subcellular, epigenetic, brain connectivity, and organ system factors has been growing. These are embedded in social, environmental, and developmental contexts that play a determinative role in the ability of humans to navigate major challenges successfully. Our proposed multi-level systems neuroscience of resilience framework is based on an ecological conceptualization of resilience.<sup class="text-inherit">1</sup></p><p class="pb-2">A collaborative approach using concepts of transdisciplinary (known as convergence) science is needed to prepare individuals and societies for the complex social-ecological challenges that lay ahead.<sup class="text-inherit">2</sup> Increasing evidence shows how perturbations negatively affect mental health and sustainable development.<sup class="text-inherit">3-5</sup> However, the potential direct and indirect effects of disturbances on mental health, such as those arising from climate change, likely add more complexity by exacerbating the effects evident in a single shock such as COVID-19.<sup class="text-inherit">4,6</sup> Siloed approaches studying mental health disorders or resilience across the lifespan are inadequate for assessing this complexity. Although this work is meritorious, it needs to be integrated with a holistic perspective. Thus, our framework emphasizes that cognition cannot be properly understood or supported without attention to multiple factors and levels of influence.<sup class="text-inherit">7</sup></p><p class="pb-2">We envision a multi-level neuroscience system as an <em>emergent property</em> or phenomenon that arises from dynamic, nonstationary, multi-scale, hierarchical interaction (for a definition of terms in italics see <a rel="nofollow noreferrer noopener" target="_blank" href="https://cdn.sanity.io/images/0vv8moc6/psychtimes/9aad5fd33d94ac510373d3ff150afa04df959735-726x1472.png/Eyre%20Table%201.png?w=1500&fit=max&auto=format"><strong>Table 1</strong></a><sup class="text-inherit">8</sup>). </p><div class=""><div style="width:50%;float:right;max-width:525px;margin:0 0 1.5rem 1.5rem;clear:both;cursor:" class=" figure"><div class="flex-none relative text-center"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%27726%27%20height=%271472%27/%3e"/></span><img alt="Table 1. Definitions of Selected Resilience Terms" title="Table 1. Definitions of Selected Resilience Terms" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain"/><noscript><img alt="Table 1. Definitions of Selected Resilience Terms" title="Table 1. Definitions of Selected Resilience Terms" srcSet="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F9aad5fd33d94ac510373d3ff150afa04df959735-726x1472.png%3Ffit%3Dcrop%26auto%3Dformat&w=750&q=75 1x, /_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F9aad5fd33d94ac510373d3ff150afa04df959735-726x1472.png%3Ffit%3Dcrop%26auto%3Dformat&w=1920&q=75 2x" src="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F9aad5fd33d94ac510373d3ff150afa04df959735-726x1472.png%3Ffit%3Dcrop%26auto%3Dformat&w=1920&q=75" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain" loading="lazy"/></noscript></span></div><div id="image-caption" class="text-gray-500 italic"><div class="blockText_blockContent__TbCXh"><p class="pb-2"><strong>Table 1.</strong> Definitions of Selected Resilience Terms<sup class="text-inherit">8</sup></p></div></div><div class="top-[-100%] block w-[1px] transition-opacity duration-500 ease-in-out opacity-0 overflow-hidden"><img class="m-auto absolute inset-0 max-w-[0%] max-h-[0%] border-[3px] border-solid border-white shadow-[0px_0px_8px_rgba(0,0,0,0.3)] box-border transition ease-in-out duration-500" src="https://cdn.sanity.io/images/0vv8moc6/psychtimes/9aad5fd33d94ac510373d3ff150afa04df959735-726x1472.png?fit=crop&auto=format"/></div></div><style> #image-caption p{ font-size: 12px; max-width: 525px; margin: 0 auto; text-align: center; } </style></div><p class="pb-2">This covers internal factors such as genetics, stress, neurobiology, plasticity, and external forces such as close and extended social supports, positive and adaptive organization, economics, and individual environments. These are the life history factors and trajectories that influence our reactions and capacity to act (<em>adaptive capacity</em>) in the present moment (Table 1<sup class="text-inherit">8</sup>).</p><p class="pb-2"></p><p class="pb-2"><strong>Complex Adaptive Systems</strong></p><p class="pb-2">This complexity is accounted for in <em>ecological resilience</em>, which we use as the framework scaffold. Ecological resilience emphasizes the emergent property of all complex adaptive systems (such as ecosystems and the human brain), which extends beyond models used in other domains like <em>resilience in health care</em> and <em>disaster resilience</em>.<sup class="text-inherit">1,9</sup> These disciplines focus on adaptation, <em>recovery</em>, and coping with stressful events. As such, features are individual manifestations of patterns and processes integrated and subsumed within adaptive capacity as in the allosteric model<em>.</em><sup class="text-inherit">10</sup></p><p class="pb-2">At an individual level, adaptive capacity is often predicated on prior adaptation and mastery of challenges. However, at a systemic level, the function is to maintain equilibrium and contribute to the stationary dynamics of specific system regimes as outlined in <a rel="nofollow noreferrer noopener" target="_blank" href="https://cdn.sanity.io/images/0vv8moc6/psychtimes/69ea5b65bc2bc5c61f0b5ee99f837bd2d8f185ad-426x516.png/Figure%201.png?w=1500&fit=max&auto=format"><strong>Figure 1</strong></a>.<sup class="text-inherit">8</sup> </p><div class=""><div style="width:50%;float:right;max-width:525px;margin:0 0 1.5rem 1.5rem;clear:both;cursor:" class=" figure"><div class="flex-none relative text-center"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%27426%27%20height=%27516%27/%3e"/></span><img alt="Figure 1. Ecological Resilience Model Showing the Transformation of Resilience Over Time Following Erosion of Adaptive Capacity Until a Shift to a Novel Regime Can Occur" title="Figure 1. Ecological Resilience Model Showing the Transformation of Resilience Over Time Following Erosion of Adaptive Capacity Until a Shift to a Novel Regime Can Occur" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain"/><noscript><img alt="Figure 1. Ecological Resilience Model Showing the Transformation of Resilience Over Time Following Erosion of Adaptive Capacity Until a Shift to a Novel Regime Can Occur" title="Figure 1. Ecological Resilience Model Showing the Transformation of Resilience Over Time Following Erosion of Adaptive Capacity Until a Shift to a Novel Regime Can Occur" srcSet="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F69ea5b65bc2bc5c61f0b5ee99f837bd2d8f185ad-426x516.png%3Ffit%3Dcrop%26auto%3Dformat&w=640&q=75 1x, /_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F69ea5b65bc2bc5c61f0b5ee99f837bd2d8f185ad-426x516.png%3Ffit%3Dcrop%26auto%3Dformat&w=1080&q=75 2x" src="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F69ea5b65bc2bc5c61f0b5ee99f837bd2d8f185ad-426x516.png%3Ffit%3Dcrop%26auto%3Dformat&w=1080&q=75" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain" loading="lazy"/></noscript></span></div><div id="image-caption" class="text-gray-500 italic"><div class="blockText_blockContent__TbCXh"><p class="pb-2"><strong>Figure 1. </strong>Ecological Resilience Model Showing the Transformation of Resilience Over Time Following Erosion of Adaptive Capacity Until a Shift to a Novel Regime Can Occur</p></div></div><div class="top-[-100%] block w-[1px] transition-opacity duration-500 ease-in-out opacity-0 overflow-hidden"><img class="m-auto absolute inset-0 max-w-[0%] max-h-[0%] border-[3px] border-solid border-white shadow-[0px_0px_8px_rgba(0,0,0,0.3)] box-border transition ease-in-out duration-500" src="https://cdn.sanity.io/images/0vv8moc6/psychtimes/69ea5b65bc2bc5c61f0b5ee99f837bd2d8f185ad-426x516.png?fit=crop&auto=format"/></div></div><style> #image-caption p{ font-size: 12px; max-width: 525px; margin: 0 auto; text-align: center; } </style></div><p class="pb-2">The adaptive capacity, therefore, allows the complex system (individual or ecosystem) to return to the predisturbance conditions after disruptions. In a practical setting, this can be boosted by additional management interventions such as psychotherapy and preventative fitness interventions. Adaptive capacity is thus a system component that is nested in ecological resilience.<sup class="text-inherit">11</sup></p><p class="pb-2">An important caveat is that complex adaptive systems cannot infinitely cope with disturbances. They operate within defined bounds of system dynamics that are at least partly learned from prior appropriate adaptations to environmental demands.<sup class="text-inherit">12,13</sup> Once adaptive capacity is exhausted, a critical disturbance threshold is passed, and the system flips into a novel, <em>alternative regime</em> with different system dynamics (Figure 1). Such fundamental, often abrupt, nonlinear system change is inherent in ecological resilience. It highlights the ability of complex systems to undergo a <em>nonstationary</em> transformation and to exist in regimes with each of their structures, processes, <em>feedbacks</em>, and adaptive capacity.</p><p class="pb-2">Consider a democracy shifting to an authoritarian regime, rainforests turning into deserts and healthy individuals and populations developing chronic diseases. Once complex systems are “degraded,” such as individuals and communities living with persistent health problems, resilience-based management allows for purposefully eroding the adaptive capacity of an impaired, suboptimal regime to make it prone to transformation into a more “desired” regime that would allow fostering of improved health.<sup class="text-inherit">14</sup> Alternative regimes may lose critical functions, such as food rationing, energy, and communication, relative to previous social-ecological systems regimes. Degraded regimes often need constant costly management to force desired functions artificially. In such <em>coerced regimes</em> functions can no longer be sustained by the system itself.<sup class="text-inherit">15</sup></p><p class="pb-2">Management of adaptive capacity does not necessarily achieve recovery to a previous regime or the creation of a novel one, and it is often limited to mitigating the effects of disturbances. This is due to previous coping regimes having become maladaptive or obsolete, leading to deeply entrenched feedbacks that stabilize the novel, alternative, or degraded regime (Figure 1). This can be exemplified in therapeutic interventions that merely mitigate mental illness without recovering patients to a symptomless regime where further therapy or medication is unnecessary.<sup class="text-inherit">16</sup> Similarly, biological and technological solutions often only mitigate turbid, nutrient-enriched lakes with toxic algal blooms and fail to create a clear-water regime with abundant plants and good water quality.<sup class="text-inherit">17</sup></p><p class="pb-2">Alternative regimes underscore the importance of accounting for transformation in theory and practice because adaptation and transformation both need to be considered when managing resilient multi-level systems. However, transformative management is plagued by high uncertainty. Despite developing early warning scores for impending system transitions used in psychiatry, these often have limited predictability within ecosystems.<sup class="text-inherit">18-23</sup> This uncertainty is exemplified by the increased mental health challenges associated with the COVID-19 pandemic, where the future trajectory is impossible to predict.<sup class="text-inherit">24</sup> As such, it is currently not possible to ascertain whether the global mental health crisis is a mirror image of social-ecological systems having already flipped into novel regimes, possibly triggered by the pandemic and social media, or whether regime shifts will likely occur in the future.</p><p class="pb-2">Consider the Russian invasion of Ukraine, which has had international ramifications through military rearmament, inflation, mass migration, and supply of resources. All these considerations must be accounted for if the transformation goal is to create desirable, resilient, and <em>self-organizing</em> multi-level systems of neuroscience, and ultimately meet the United Nations Sustainable Development goals for health and resilience of social-ecological systems.</p><p class="pb-2">Despite this complexity, transformative management can be informed by planning competing scenarios using science-based predictive models, including simulations and group scenarios with stakeholders. Such scenarios can envision different social, environmental, technological, and economic realities that can be reiteratively tested as we move toward an uncertain future.<sup class="text-inherit">25</sup> There are, however, many challenges that need to be accounted for in scenario planning and transformation, which may be informed by interdisciplinary research, exemplified by the cross-pollination of economics and physics.<sup class="text-inherit">26</sup> Relevant factors range from the levels of neurons to societies, resilience by design, intervention in health care logistics, responsible governance, economic and energetic transformation, and media communication.<sup class="text-inherit">27</sup></p><p class="pb-2"></p><p class="pb-2"><strong>Demonstrating a Multi-Level Neuroscience System of Resilience</strong></p><p class="pb-2">The complexity that crystalizes the resilience of <em>multi-level</em> neuroscience systems initially requires a simplified conceptualization as seen in <a rel="nofollow noreferrer noopener" target="_blank" href="https://cdn.sanity.io/images/0vv8moc6/psychtimes/4614fb162293aec2a3dfba113fdd17014bfbbff5-816x348.png/Figure%202.png?w=1500&fit=max&auto=format"><strong>Figure 2</strong></a>. </p><div class=""><div style="width:50%;float:right;max-width:525px;margin:0 0 1.5rem 1.5rem;clear:both;cursor:" class=" figure"><div class="flex-none relative text-center"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%27816%27%20height=%27348%27/%3e"/></span><img alt="Figure 2. Simplified Conceptualization of the Multi-Level Systems Neuroscience of Resilience" title="Figure 2. Simplified Conceptualization of the Multi-Level Systems Neuroscience of Resilience" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain"/><noscript><img alt="Figure 2. Simplified Conceptualization of the Multi-Level Systems Neuroscience of Resilience" title="Figure 2. Simplified Conceptualization of the Multi-Level Systems Neuroscience of Resilience" srcSet="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F4614fb162293aec2a3dfba113fdd17014bfbbff5-816x348.png%3Ffit%3Dcrop%26auto%3Dformat&w=828&q=75 1x, /_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F4614fb162293aec2a3dfba113fdd17014bfbbff5-816x348.png%3Ffit%3Dcrop%26auto%3Dformat&w=1920&q=75 2x" src="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F4614fb162293aec2a3dfba113fdd17014bfbbff5-816x348.png%3Ffit%3Dcrop%26auto%3Dformat&w=1920&q=75" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain" loading="lazy"/></noscript></span></div><div id="image-caption" class="text-gray-500 italic"><div class="blockText_blockContent__TbCXh"><p class="pb-2"><strong>Figure 2. </strong>Simplified Conceptualization of the Multi-Level Systems Neuroscience of Resilience</p></div></div><div class="top-[-100%] block w-[1px] transition-opacity duration-500 ease-in-out opacity-0 overflow-hidden"><img class="m-auto absolute inset-0 max-w-[0%] max-h-[0%] border-[3px] border-solid border-white shadow-[0px_0px_8px_rgba(0,0,0,0.3)] box-border transition ease-in-out duration-500" src="https://cdn.sanity.io/images/0vv8moc6/psychtimes/4614fb162293aec2a3dfba113fdd17014bfbbff5-816x348.png?fit=crop&auto=format"/></div></div><style> #image-caption p{ font-size: 12px; max-width: 525px; margin: 0 auto; text-align: center; } </style></div><p class="pb-2">A scaffold for a conceptual model for multi-level neuroscience systems resilience can be built through research that increasingly unravels its inherent complexity, including the connectivity and “information flow” across system levels, through a constant iterative learning process.</p><p class="pb-2">One example would be how genetic susceptibility to mental illness at the brain level can trigger disorders following stressful life events. This transforms a healthy regime with fragile resilience into a potentially dysfunctional, highly resistant regime that may need constant health care management to mitigate symptom expressions.<sup class="text-inherit">16</sup> The brain-level changes resulting from transformation influence the next system level: the individual. At this scale, symptoms affect psychological, physiological, and behavioral functioning that may need to be managed therapeutically. At the population level, it becomes necessary to implement systems that manage patients and other related brain problems for multiple individuals experiencing the same problem. These treatments have economic repercussions at the societal level through loss of productivity and cost of health care.</p><p class="pb-2">This chain of events demonstrates a clear “bottom-up” component in transmitting information in a multi-level neuroscience system. However, “top-down” events also further influence system processes and feedbacks. For instance, public illiteracy about mental illness and stigma, limited resources for managing mental health, and ineffective policies foster the negative societal repercussions of mental illness as well as reinforce stressful environments for patients. Bottom-up and top-down factors combined form negative feedbacks to maintain this demonstrated neuroscience system in a resilient undesired regime. However, they also identify scales in the system where management can be leveraged to create a more desirable regime through transformation.</p><p class="pb-2"></p><p class="pb-2"><strong>Leveraging System Management for Multi-Level Neuroscience Systems of Resilience</strong></p><p class="pb-2">There is a wide range of system management possibilities that may contribute to creating a resilient, multi-level neuroscience system. Management options may likely encompass a wide spectrum of molecular, clinical, technological, educational, economic, and ecological tools and approaches as outlined in <a rel="nofollow noreferrer noopener" target="_blank" href="https://cdn.sanity.io/images/0vv8moc6/psychtimes/9555a92c140c2877467e730f1b1fc874a6023109-928x1002.png/Eyre%20Table%202.png?w=1500&fit=max&auto=format"><strong>Table 2</strong></a>. </p><div class=""><div style="width:50%;float:right;max-width:525px;margin:0 0 1.5rem 1.5rem;clear:both;cursor:" class=" figure"><div class="flex-none relative text-center"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%27928%27%20height=%271002%27/%3e"/></span><img alt="Table 2. Examples of Adaptive and Transformative Approaches Across Scales as Crucial Components of Multi-Level Systems Neuroscience of Resilience" title="Table 2. Examples of Adaptive and Transformative Approaches Across Scales as Crucial Components of Multi-Level Systems Neuroscience of Resilience" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain"/><noscript><img alt="Table 2. Examples of Adaptive and Transformative Approaches Across Scales as Crucial Components of Multi-Level Systems Neuroscience of Resilience" title="Table 2. Examples of Adaptive and Transformative Approaches Across Scales as Crucial Components of Multi-Level Systems Neuroscience of Resilience" srcSet="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F9555a92c140c2877467e730f1b1fc874a6023109-928x1002.png%3Ffit%3Dcrop%26auto%3Dformat&w=1080&q=75 1x, /_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F9555a92c140c2877467e730f1b1fc874a6023109-928x1002.png%3Ffit%3Dcrop%26auto%3Dformat&w=1920&q=75 2x" src="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F9555a92c140c2877467e730f1b1fc874a6023109-928x1002.png%3Ffit%3Dcrop%26auto%3Dformat&w=1920&q=75" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain" loading="lazy"/></noscript></span></div><div id="image-caption" class="text-gray-500 italic"><div class="blockText_blockContent__TbCXh"><p class="pb-2"><strong>Table 2. </strong>Examples of Adaptive and Transformative Approaches Across Scales as Crucial Components of Multi-Level Systems Neuroscience of Resilience</p></div></div><div class="top-[-100%] block w-[1px] transition-opacity duration-500 ease-in-out opacity-0 overflow-hidden"><img class="m-auto absolute inset-0 max-w-[0%] max-h-[0%] border-[3px] border-solid border-white shadow-[0px_0px_8px_rgba(0,0,0,0.3)] box-border transition ease-in-out duration-500" src="https://cdn.sanity.io/images/0vv8moc6/psychtimes/9555a92c140c2877467e730f1b1fc874a6023109-928x1002.png?fit=crop&auto=format"/></div></div><style> #image-caption p{ font-size: 12px; max-width: 525px; margin: 0 auto; text-align: center; } </style></div><p class="pb-2">These options can be exploited for adaptive and transformative management, but specific approaches may be most suitable for only a few specific hierarchical levels that comprise such a system. For instance, at the brain level, the development of nanotechnology may provide opportunities to create nanoparticle-based drugs that improve psychotherapeutic approaches.<sup class="text-inherit">28</sup> Similarly, experimental data corroborate that mesenchymal stem cell therapy could be a potential treatment for depression based on anti-inflammatory and neurotrophic properties.<sup class="text-inherit">29</sup></p><p class="pb-2">An example of a novel therapeutic approach is the addition of cytokine markers to antidepressants that provide a protective effect on executive functioning and treatment response in older adults with depression.<sup class="text-inherit">30,31</sup> Pharmacogenetic innovations could transform the clinical space and complement or refine current adaptive treatment approaches based on medication adjustment for brain disorders. This allows adaptive and transformative management options to target neurocircuits and developmental processes at the next higher scale: the brain.</p><p class="pb-2">The ability of a few interventions to target more than 1 scale in a multi-level neuroscience system has implications for resilience. Specifically, medications currently used to treat disorders include redundant management options that target neuronal molecular structures and physiology and structures at the brain level. Creating redundant management interventions within scales or across them can foster resilience in multi-level neuroscience systems like those proposed for climate change mitigation.<sup class="text-inherit">32</sup> Brain-level management options cannot directly be used to manage higher hierarchical scales. For example, at the scale of individuals, management targeting suicide rates may build on current clinical tools such as individually adjusted therapy through adaptation. Novel self-reflexive approaches, such as mental health apps monitoring mood states, could provide improved insight through transformation.<sup class="text-inherit">27</sup></p><p class="pb-2">We acknowledge that our examples focus broadly on factors that directly affect the multi-level neuroscience systems of resilience like the genetic proclivity of mental illness. However, other issues affecting these systems indirectly, like the mental health impact of sickle cell anemia, need to be accounted for. Success in rewiring the brain toward the best possible health can reduce the burden on mental health care systems and associated economic costs. Meanwhile, creating equal and fair access to health care can cascade down to lower levels and contribute to reinforcing improved brain health.</p><p class="pb-2">Within-scale and cross-scale redundancy of management options at the individual and societal level shows the interconnectedness of hierarchical scales that ultimately influences its resilience through the flow of information from the lowest to the highest hierarchical scale in the system and vice versa. It will also be essential to identify additional levels not noted in the previously outlined model, such as organizational levels in which maintaining values and promoting growth at the individual level will nurture desirable behaviors at the society level. Companies, schools, volunteer agencies, and clubs play an important role in shaping adaptive and maladaptive behavior. A toxic or unethical organizational climate can have ill effects that spread to the wider levels, but a positive one may be transformative for a multi-level system.</p><p class="pb-2"></p><p class="pb-2"><strong>Creating and Managing Resilient Multi-Level Neuroscience Systems</strong></p><p class="pb-2">A major goal of management is to create self-organizing systems that need minimal intervention in providing necessary goods and services. These can range from food, clean water, and financial security to brain health, sustainable workload, and access to health care. This complexity leads to a multi-level neuroscience system as pictured in <a rel="nofollow noreferrer noopener" target="_blank" href="https://cdn.sanity.io/images/0vv8moc6/psychtimes/2376da87c2cd6dda6384f62095ed31be9de3044c-358x604.png/Figure%203.png?w=1500&fit=max&auto=format"><strong>Figure 3A</strong></a>. </p><div class=""><div style="width:50%;float:right;max-width:525px;margin:0 0 1.5rem 1.5rem;clear:both;cursor:" class=" figure"><div class="flex-none relative text-center"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%27358%27%20height=%27604%27/%3e"/></span><img alt="Figure 3 A-C. Model Scenarios of Desired and Undesired Social-Ecological Regimes of Multi-Level Neuroscience Systems" title="Figure 3 A-C. Model Scenarios of Desired and Undesired Social-Ecological Regimes of Multi-Level Neuroscience Systems" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain"/><noscript><img alt="Figure 3 A-C. Model Scenarios of Desired and Undesired Social-Ecological Regimes of Multi-Level Neuroscience Systems" title="Figure 3 A-C. Model Scenarios of Desired and Undesired Social-Ecological Regimes of Multi-Level Neuroscience Systems" srcSet="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F2376da87c2cd6dda6384f62095ed31be9de3044c-358x604.png%3Ffit%3Dcrop%26auto%3Dformat&w=384&q=75 1x, /_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F2376da87c2cd6dda6384f62095ed31be9de3044c-358x604.png%3Ffit%3Dcrop%26auto%3Dformat&w=750&q=75 2x" src="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F2376da87c2cd6dda6384f62095ed31be9de3044c-358x604.png%3Ffit%3Dcrop%26auto%3Dformat&w=750&q=75" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain" loading="lazy"/></noscript></span></div><div id="image-caption" class="text-gray-500 italic"><div class="blockText_blockContent__TbCXh"><p class="pb-2"><strong>Figure 3 A-C. </strong>Model Scenarios of Desired and Undesired Social-Ecological Regimes of Multi-Level Neuroscience Systems</p><p class="pb-2"></p><p class="pb-2"><em>Desired social-ecological regimes of multi-level neuroscience systems are in green, and undesired social-ecological regimes are in red. The ball and blue arrow indicate system trajectories that can lead to (A) self-organizing systems in a desirable regime, (B) coerced regime approximating the desired scenario, or (C) a failure to reach one despite coercion.</em></p></div></div><div class="top-[-100%] block w-[1px] transition-opacity duration-500 ease-in-out opacity-0 overflow-hidden"><img class="m-auto absolute inset-0 max-w-[0%] max-h-[0%] border-[3px] border-solid border-white shadow-[0px_0px_8px_rgba(0,0,0,0.3)] box-border transition ease-in-out duration-500" src="https://cdn.sanity.io/images/0vv8moc6/psychtimes/2376da87c2cd6dda6384f62095ed31be9de3044c-358x604.png?fit=crop&auto=format"/></div></div><style> #image-caption p{ font-size: 12px; max-width: 525px; margin: 0 auto; text-align: center; } </style></div><p class="pb-2">Despite comprising an apparent individual entity, such a system must be understood as an integral part of broader social-ecological systems.<sup class="text-inherit">27</sup> Therefore, the evolution of multi-level neuroscience systems is likely developed in tandem with the dynamics and change of socio-ecological systems and their underlying economic, social, technological, and ecological drivers.</p><p class="pb-2">The increasing global mental health crisis is projected to incur substantial economic and societal costs. This suggests that creating self-organizing, desirable, and resilient multi-level neuroscience systems will likely be impossible.<sup class="text-inherit">33</sup> Thus, substantial and incrementally intensifying management will be needed to coerce multi-level neuroscience systems into a regime that artificially maintains the desired functioning. There may be contrasting scenarios in which management will either succeed in emulating multi-level neuroscience systems conditions that approximate those of a resilient desired regime (<strong>Figure 3B</strong>) or fail to do so (<strong>Figure 3C</strong>).</p><p class="pb-2"></p><p class="pb-2"><strong>A Way Forward</strong></p><p class="pb-2">We have suggested scenarios comprising opposites between best-case and worst-case outcomes of managing coerced multi-level neuroscience systems of resilience. Although scenario planning is a useful tool to suggest how management may be geared for creating best-possible multi-level neuroscience systems of resilience, benchmarked against the worst-case, scenarios must not be seen as static endpoints. They rather need to be refined and recalibrated iteratively. They also can be informed by machine learning to accommodate the unforeseen change that may result from technological, economic, and societal innovation. At the same time, there is a pervasive inability to abate many of the crises that have challenged sustainable development.<sup class="text-inherit">25,34</sup> The “unforeseeable” is an essential part of the high uncertainty inherent in the dynamics of complex systems of individuals and nature. This means that in addition to known unknowns, we need to account for unknown unknowns.<sup class="text-inherit">35</sup> Addressing the unknown unknowns comprises a dilemma because defining social-ecological, including brain health, challenges that we do not know to comprise is an absurd contradiction.<sup class="text-inherit">36</sup></p><p class="pb-2">Compartmentalization across spheres of society is ill-suited to deal with the unknown unknowns. Fundamental changes in academia are needed to move away from models emphasizing isolation and metric fulfillment. More room needs to be created for intuitive thinking and collaborative work that allows for novelty and innovation, which arises at the intersection between, rather than within, distinctly different knowledge domains and life experiences.<sup class="text-inherit">37</sup> Such collaborations will need to be truly transdisciplinary and include cooperation across all spheres of society. Such partnerships can be inspired by a creative, alternative, provocative, and unorthodox dialog at the intersection of the arts, sciences, philosophy, and spirituality. Such collaborations may ultimately facilitate the planning of scenarios that may provide management targets for creating the best-possible resilient multi-level neuroscience systems desirable for human societies.</p><p class="pb-2"></p><p class="pb-2"><strong>Dr Angeler </strong><em>is a transdisciplinary researcher at the Swedish University of Agricultural Sciences, adjunct professor at the University of Nebraska-Lincoln, collaborator at the PRODEO Institute and honorary fellow at the Institute for Mental and Physical Health and Clinical Translation (IMPACT) at Deakin University. </em><strong>Dr Lundin </strong><em>is a psychiatry registrar with Barwon Health, an affiliate lecturer with IMPACT, and a PhD candidate with the University of Auckland. </em><strong>Dr Hunter </strong><em>is assistant professor of psychology in the College of Liberal Arts at The University of Massachusetts at Boston</em>.<strong>Ms Smith</strong><em> is an Atlantic Fellow for Equity in Brain Health at the Global Brain Health Institute, a Thiel Fellow at Stanford University, and a Steering Committee member for the OECD Neuroscience-inspired Policy Initiative. </em><strong>Dr Wister</strong> <em>is director of the Gerontology Research Centre and a professor in the Department of Gerontology at Simon Fraser University. </em><strong>Dr Hynes</strong> <em>is an associate fellow at the Johns Hopkins School of Advanced International Studies.</em> <strong>Dr Berk</strong> <em>is the director of IMPACT at Deakin University. </em><strong>Dr Lavretsky</strong> <em>is a professor in residence in the Department of Psychiatry at UCLA in Los Angeles, California. Her work on geriatric depression and integrative mental health using mind-body interventions has received national attention, and she has won numerous grants supporting that work. She is the president-elect of the American Association for Geriatric Psychiatry, a distinguished fellow of the American Psychiatric Association and of the American Association for Geriatric Psychiatry, and a fellow of the American College of Neuropsychopharmacology. She is also on the board of Psychiatric Times™. </em><strong>Dr Trump</strong> <em>is senior research social scientist at U.S. Army Engineer Research and Development Center (ERDC). </em><strong>Dr Linkov </strong><em>is senior scientific and technical manager at the US Army Engineer Research and Development Center, where he manages crisis response and resilience project portfolio. </em><strong>Dr Benight</strong> <em>is professor, executive director of the Lyda Hill Institute of Human Resilience, University of Colorado at Colorado Springs. </em><strong>Ms Estafany</strong><em> is an associate with The PRODEO Institute </em><strong>Dr Winter</strong> <em>is a physician-scientist, social entrepreneur, and health policy analyst. Besides training in neurology at the Charité University Hospital and Berlin Institute of Health, Germany, he is a postdoctoral researcher at the Massachusetts General Hospital at Harvard Medical School, Boston, USA. </em><strong>Mr Edmonds </strong><em>is research associate professor and Master of Humanities & Master of Social Science Programs at The University of Colorado at Denver. </em><strong>Mr Lister </strong><em>is senior clinical system analyst at Stanford Health Care. </em><strong>Dr Storch</strong> <em>is professor, vice chair, and McIngvale Presidential Endowed Chair in the Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine. </em><strong>Dr Matthews</strong> <em>is professor of engineering psychology, United States Military Academy (West Point). </em><strong>Dr Eyre</strong><em> is lead of the Brain Capital Alliance, co-lead of the OECD Neuroscience-inspired Policy Initiative, senior fellow for Brain Capital with the Meadows Mental Health Policy Institute and advisor to the Euro-Mediterranean Economists Association.</em></p><p class="pb-2"></p><p class="pb-2"><em>Dr Lavretsky was supported by an AT009198 NIH grant. 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Johansson F. <a rel="nofollow noreferrer noopener" target="_blank" href="https://store.hbr.org/product/the-medici-effect-with-a-new-preface-and-discussion-guide-what-elephants-and-epidemics-can-teach-us-about-innovation/10129"><em>The Medici Effect, With a New Preface and Discussion Guide: What Elephants and Epidemics Can Teach Us About Innovation</em></a>. 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Griesbach, PhD</a></div><div class="jsx-ad50481d5ee26850 article-summary"><a class="jsx-ad50481d5ee26850" href="/view/traumatic-brain-injury-s-impact-on-normal-aging-and-neurodegenerative-diseases?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent"></a></div></div></div><div style="border-bottom:1px solid #CCCCCC" class="jsx-ad50481d5ee26850"></div></div><div class="jsx-ad50481d5ee26850 w-full h-full"><div class="jsx-ad50481d5ee26850 flex flex-col sm:flex-row justify-between my-4 gap-x-4"><a class="jsx-ad50481d5ee26850" href="/view/neurosyphilis-when-an-antipsychotic-is-not-enough?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent"><img src="https://cdn.sanity.io/images/0vv8moc6/psychtimes/bd9f138da69aadd1781819ac9441411821ed3966-5824x3264.jpg?fit=crop&auto=format" alt="brain" width="288" class="jsx-ad50481d5ee26850 lg:w-[110px] lg:h-[100px] xl:w-[135px] xl:h-[125px] xs:w-[288px] "/></a><div class="jsx-ad50481d5ee26850 article-detail flex flex-col gap-[0.2rem] w-full xl:w-[70%]"><span class="jsx-ad50481d5ee26850 article-publish-date block italic text-sm text-gray-500 mt-[1rem] sm:mt-0">September 9th 2024</span><p class="jsx-ad50481d5ee26850 article-title font-bold text-[1rem]"><a class="jsx-ad50481d5ee26850" href="/view/neurosyphilis-when-an-antipsychotic-is-not-enough?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent">Neurosyphilis: When an Antipsychotic Is Not Enough </a></p><div class="jsx-ad50481d5ee26850 authors flex-row wrap gap-[0.2rem]"><a class="jsx-ad50481d5ee26850 text-[#00ADEF] underline text-sm italic" href="/authors/william-hendricks">William Hendricks, MBE</a><span class="jsx-ad50481d5ee26850 mr-1 ml-[1px]"> </span><a class="jsx-ad50481d5ee26850 text-[#00ADEF] underline text-sm italic" href="/authors/reza-safavi-md">Reza Safavi, MD </a></div><div class="jsx-ad50481d5ee26850 article-summary"><a class="jsx-ad50481d5ee26850" href="/view/neurosyphilis-when-an-antipsychotic-is-not-enough?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent"></a></div></div></div><div style="border-bottom:1px solid #CCCCCC" class="jsx-ad50481d5ee26850"></div></div></div></div></div><div class="pb-24"></div></div><script type="application/ld+json">{"@context":"https://schema.org","@type":"NewsArticle","headline":"Building Brain Resilience: A Multi-Level Systems Approach","datePublished":"2022-10-26T20:00:25.822Z","dateModified":"2024-02-20T17:09:08Z","inLanguage":"en-US","image":"https://cdn.sanity.io/images/0vv8moc6/psychtimes/972990255d4a55fab15b6cc6ddc7a18b0fdffa6e-1000x422.jpg?fit=crop&auto=format","mainEntityOfPage":{"@type":"WebPage","@id":"https://www.psychiatrictimes.com/view/building-brain-resilience-a-multi-level-systems-approach"},"publisher":{"@type":"Organization","name":"Psychiatric Times","logo":{"@type":"ImageObject","url":"https://www.psychiatrictimes.com/PsychiatricTimesLogo.png"}},"articleBody":"\n\nSocieties need to be better prepared for rapid changes in economics, politics, and climate. This will depend on our ability to cope with complexity. We propose a new framework based on neuroscience for understanding resilience at multiple levels. This framework considers adaptation, transformation, and the hierarchical structure from brain cells and physiological stress systems to organizations, communities, cultures, and countries. We also discuss how resilience can be managed through transdisciplinary and collaborative approaches, creating a resilient neuroscience system to withstand potentially catastrophic changes to social-ecological systems.\n\nThe COVID-19 pandemic has clarified that resilience is a complex and multi-tiered phenomenon. Medical specialties have commonly focused on the individual brain systems for resilience, but attention to subcellular, epigenetic, brain connectivity, and organ system factors has been growing. These are embedded in social, environmental, and developmental contexts that play a determinative role in the ability of humans to navigate major challenges successfully. Our proposed multi-level systems neuroscience of resilience framework is based on an ecological conceptualization of resilience.1\n\nA collaborative approach using concepts of transdisciplinary (known as convergence) science is needed to prepare individuals and societies for the complex social-ecological challenges that lay ahead.2 Increasing evidence shows how perturbations negatively affect mental health and sustainable development.3-5 However, the potential direct and indirect effects of disturbances on mental health, such as those arising from climate change, likely add more complexity by exacerbating the effects evident in a single shock such as COVID-19.4,6 Siloed approaches studying mental health disorders or resilience across the lifespan are inadequate for assessing this complexity. Although this work is meritorious, it needs to be integrated with a holistic perspective. Thus, our framework emphasizes that cognition cannot be properly understood or supported without attention to multiple factors and levels of influence.7\n\nWe envision a multi-level neuroscience system as an emergent property or phenomenon that arises from dynamic, nonstationary, multi-scale, hierarchical interaction (for a definition of terms in italics see Table 18). \n\n\n\nThis covers internal factors such as genetics, stress, neurobiology, plasticity, and external forces such as close and extended social supports, positive and adaptive organization, economics, and individual environments. These are the life history factors and trajectories that influence our reactions and capacity to act (adaptive capacity) in the present moment (Table 18).\n\n\n\nComplex Adaptive Systems\n\nThis complexity is accounted for in ecological resilience, which we use as the framework scaffold. Ecological resilience emphasizes the emergent property of all complex adaptive systems (such as ecosystems and the human brain), which extends beyond models used in other domains like resilience in health care and disaster resilience.1,9 These disciplines focus on adaptation, recovery, and coping with stressful events. As such, features are individual manifestations of patterns and processes integrated and subsumed within adaptive capacity as in the allosteric model.10\n\nAt an individual level, adaptive capacity is often predicated on prior adaptation and mastery of challenges. However, at a systemic level, the function is to maintain equilibrium and contribute to the stationary dynamics of specific system regimes as outlined in Figure 1.8 \n\n\n\nThe adaptive capacity, therefore, allows the complex system (individual or ecosystem) to return to the predisturbance conditions after disruptions. In a practical setting, this can be boosted by additional management interventions such as psychotherapy and preventative fitness interventions. Adaptive capacity is thus a system component that is nested in ecological resilience.11\n\nAn important caveat is that complex adaptive systems cannot infinitely cope with disturbances. They operate within defined bounds of system dynamics that are at least partly learned from prior appropriate adaptations to environmental demands.12,13 Once adaptive capacity is exhausted, a critical disturbance threshold is passed, and the system flips into a novel, alternative regime with different system dynamics (Figure 1). Such fundamental, often abrupt, nonlinear system change is inherent in ecological resilience. It highlights the ability of complex systems to undergo a nonstationary transformation and to exist in regimes with each of their structures, processes, feedbacks, and adaptive capacity.\n\nConsider a democracy shifting to an authoritarian regime, rainforests turning into deserts and healthy individuals and populations developing chronic diseases. Once complex systems are “degraded,” such as individuals and communities living with persistent health problems, resilience-based management allows for purposefully eroding the adaptive capacity of an impaired, suboptimal regime to make it prone to transformation into a more “desired” regime that would allow fostering of improved health.14 Alternative regimes may lose critical functions, such as food rationing, energy, and communication, relative to previous social-ecological systems regimes. Degraded regimes often need constant costly management to force desired functions artificially. In such coerced regimes functions can no longer be sustained by the system itself.15\n\nManagement of adaptive capacity does not necessarily achieve recovery to a previous regime or the creation of a novel one, and it is often limited to mitigating the effects of disturbances. This is due to previous coping regimes having become maladaptive or obsolete, leading to deeply entrenched feedbacks that stabilize the novel, alternative, or degraded regime (Figure 1). This can be exemplified in therapeutic interventions that merely mitigate mental illness without recovering patients to a symptomless regime where further therapy or medication is unnecessary.16 Similarly, biological and technological solutions often only mitigate turbid, nutrient-enriched lakes with toxic algal blooms and fail to create a clear-water regime with abundant plants and good water quality.17\n\nAlternative regimes underscore the importance of accounting for transformation in theory and practice because adaptation and transformation both need to be considered when managing resilient multi-level systems. However, transformative management is plagued by high uncertainty. Despite developing early warning scores for impending system transitions used in psychiatry, these often have limited predictability within ecosystems.18-23 This uncertainty is exemplified by the increased mental health challenges associated with the COVID-19 pandemic, where the future trajectory is impossible to predict.24 As such, it is currently not possible to ascertain whether the global mental health crisis is a mirror image of social-ecological systems having already flipped into novel regimes, possibly triggered by the pandemic and social media, or whether regime shifts will likely occur in the future.\n\nConsider the Russian invasion of Ukraine, which has had international ramifications through military rearmament, inflation, mass migration, and supply of resources. All these considerations must be accounted for if the transformation goal is to create desirable, resilient, and self-organizing multi-level systems of neuroscience, and ultimately meet the United Nations Sustainable Development goals for health and resilience of social-ecological systems.\n\nDespite this complexity, transformative management can be informed by planning competing scenarios using science-based predictive models, including simulations and group scenarios with stakeholders. Such scenarios can envision different social, environmental, technological, and economic realities that can be reiteratively tested as we move toward an uncertain future.25 There are, however, many challenges that need to be accounted for in scenario planning and transformation, which may be informed by interdisciplinary research, exemplified by the cross-pollination of economics and physics.26 Relevant factors range from the levels of neurons to societies, resilience by design, intervention in health care logistics, responsible governance, economic and energetic transformation, and media communication.27\n\n\n\nDemonstrating a Multi-Level Neuroscience System of Resilience\n\nThe complexity that crystalizes the resilience of multi-level neuroscience systems initially requires a simplified conceptualization as seen in Figure 2. \n\n\n\nA scaffold for a conceptual model for multi-level neuroscience systems resilience can be built through research that increasingly unravels its inherent complexity, including the connectivity and “information flow” across system levels, through a constant iterative learning process.\n\nOne example would be how genetic susceptibility to mental illness at the brain level can trigger disorders following stressful life events. This transforms a healthy regime with fragile resilience into a potentially dysfunctional, highly resistant regime that may need constant health care management to mitigate symptom expressions.16 The brain-level changes resulting from transformation influence the next system level: the individual. At this scale, symptoms affect psychological, physiological, and behavioral functioning that may need to be managed therapeutically. At the population level, it becomes necessary to implement systems that manage patients and other related brain problems for multiple individuals experiencing the same problem. These treatments have economic repercussions at the societal level through loss of productivity and cost of health care.\n\nThis chain of events demonstrates a clear “bottom-up” component in transmitting information in a multi-level neuroscience system. However, “top-down” events also further influence system processes and feedbacks. For instance, public illiteracy about mental illness and stigma, limited resources for managing mental health, and ineffective policies foster the negative societal repercussions of mental illness as well as reinforce stressful environments for patients. Bottom-up and top-down factors combined form negative feedbacks to maintain this demonstrated neuroscience system in a resilient undesired regime. However, they also identify scales in the system where management can be leveraged to create a more desirable regime through transformation.\n\n\n\nLeveraging System Management for Multi-Level Neuroscience Systems of Resilience\n\nThere is a wide range of system management possibilities that may contribute to creating a resilient, multi-level neuroscience system. Management options may likely encompass a wide spectrum of molecular, clinical, technological, educational, economic, and ecological tools and approaches as outlined in Table 2. \n\n\n\nThese options can be exploited for adaptive and transformative management, but specific approaches may be most suitable for only a few specific hierarchical levels that comprise such a system. For instance, at the brain level, the development of nanotechnology may provide opportunities to create nanoparticle-based drugs that improve psychotherapeutic approaches.28 Similarly, experimental data corroborate that mesenchymal stem cell therapy could be a potential treatment for depression based on anti-inflammatory and neurotrophic properties.29\n\nAn example of a novel therapeutic approach is the addition of cytokine markers to antidepressants that provide a protective effect on executive functioning and treatment response in older adults with depression.30,31 Pharmacogenetic innovations could transform the clinical space and complement or refine current adaptive treatment approaches based on medication adjustment for brain disorders. This allows adaptive and transformative management options to target neurocircuits and developmental processes at the next higher scale: the brain.\n\nThe ability of a few interventions to target more than 1 scale in a multi-level neuroscience system has implications for resilience. Specifically, medications currently used to treat disorders include redundant management options that target neuronal molecular structures and physiology and structures at the brain level. Creating redundant management interventions within scales or across them can foster resilience in multi-level neuroscience systems like those proposed for climate change mitigation.32 Brain-level management options cannot directly be used to manage higher hierarchical scales. For example, at the scale of individuals, management targeting suicide rates may build on current clinical tools such as individually adjusted therapy through adaptation. Novel self-reflexive approaches, such as mental health apps monitoring mood states, could provide improved insight through transformation.27\n\nWe acknowledge that our examples focus broadly on factors that directly affect the multi-level neuroscience systems of resilience like the genetic proclivity of mental illness. However, other issues affecting these systems indirectly, like the mental health impact of sickle cell anemia, need to be accounted for. Success in rewiring the brain toward the best possible health can reduce the burden on mental health care systems and associated economic costs. Meanwhile, creating equal and fair access to health care can cascade down to lower levels and contribute to reinforcing improved brain health.\n\nWithin-scale and cross-scale redundancy of management options at the individual and societal level shows the interconnectedness of hierarchical scales that ultimately influences its resilience through the flow of information from the lowest to the highest hierarchical scale in the system and vice versa. It will also be essential to identify additional levels not noted in the previously outlined model, such as organizational levels in which maintaining values and promoting growth at the individual level will nurture desirable behaviors at the society level. Companies, schools, volunteer agencies, and clubs play an important role in shaping adaptive and maladaptive behavior. A toxic or unethical organizational climate can have ill effects that spread to the wider levels, but a positive one may be transformative for a multi-level system.\n\n\n\nCreating and Managing Resilient Multi-Level Neuroscience Systems\n\nA major goal of management is to create self-organizing systems that need minimal intervention in providing necessary goods and services. These can range from food, clean water, and financial security to brain health, sustainable workload, and access to health care. This complexity leads to a multi-level neuroscience system as pictured in Figure 3A. \n\n\n\nDespite comprising an apparent individual entity, such a system must be understood as an integral part of broader social-ecological systems.27 Therefore, the evolution of multi-level neuroscience systems is likely developed in tandem with the dynamics and change of socio-ecological systems and their underlying economic, social, technological, and ecological drivers.\n\nThe increasing global mental health crisis is projected to incur substantial economic and societal costs. This suggests that creating self-organizing, desirable, and resilient multi-level neuroscience systems will likely be impossible.33 Thus, substantial and incrementally intensifying management will be needed to coerce multi-level neuroscience systems into a regime that artificially maintains the desired functioning. There may be contrasting scenarios in which management will either succeed in emulating multi-level neuroscience systems conditions that approximate those of a resilient desired regime (Figure 3B) or fail to do so (Figure 3C).\n\n\n\nA Way Forward\n\nWe have suggested scenarios comprising opposites between best-case and worst-case outcomes of managing coerced multi-level neuroscience systems of resilience. Although scenario planning is a useful tool to suggest how management may be geared for creating best-possible multi-level neuroscience systems of resilience, benchmarked against the worst-case, scenarios must not be seen as static endpoints. They rather need to be refined and recalibrated iteratively. They also can be informed by machine learning to accommodate the unforeseen change that may result from technological, economic, and societal innovation. At the same time, there is a pervasive inability to abate many of the crises that have challenged sustainable development.25,34 The “unforeseeable” is an essential part of the high uncertainty inherent in the dynamics of complex systems of individuals and nature. This means that in addition to known unknowns, we need to account for unknown unknowns.35 Addressing the unknown unknowns comprises a dilemma because defining social-ecological, including brain health, challenges that we do not know to comprise is an absurd contradiction.36\n\nCompartmentalization across spheres of society is ill-suited to deal with the unknown unknowns. Fundamental changes in academia are needed to move away from models emphasizing isolation and metric fulfillment. More room needs to be created for intuitive thinking and collaborative work that allows for novelty and innovation, which arises at the intersection between, rather than within, distinctly different knowledge domains and life experiences.37 Such collaborations will need to be truly transdisciplinary and include cooperation across all spheres of society. Such partnerships can be inspired by a creative, alternative, provocative, and unorthodox dialog at the intersection of the arts, sciences, philosophy, and spirituality. Such collaborations may ultimately facilitate the planning of scenarios that may provide management targets for creating the best-possible resilient multi-level neuroscience systems desirable for human societies.\n\n\n\nDr Angeler is a transdisciplinary researcher at the Swedish University of Agricultural Sciences, adjunct professor at the University of Nebraska-Lincoln, collaborator at the PRODEO Institute and honorary fellow at the Institute for Mental and Physical Health and Clinical Translation (IMPACT) at Deakin University. Dr Lundin is a psychiatry registrar with Barwon Health, an affiliate lecturer with IMPACT, and a PhD candidate with the University of Auckland. Dr Hunter is assistant professor of psychology in the College of Liberal Arts at The University of Massachusetts at Boston.Ms Smith is an Atlantic Fellow for Equity in Brain Health at the Global Brain Health Institute, a Thiel Fellow at Stanford University, and a Steering Committee member for the OECD Neuroscience-inspired Policy Initiative. Dr Wister is director of the Gerontology Research Centre and a professor in the Department of Gerontology at Simon Fraser University. Dr Hynes is an associate fellow at the Johns Hopkins School of Advanced International Studies. Dr Berk is the director of IMPACT at Deakin University. Dr Lavretsky is a professor in residence in the Department of Psychiatry at UCLA in Los Angeles, California. Her work on geriatric depression and integrative mental health using mind-body interventions has received national attention, and she has won numerous grants supporting that work. She is the president-elect of the American Association for Geriatric Psychiatry, a distinguished fellow of the American Psychiatric Association and of the American Association for Geriatric Psychiatry, and a fellow of the American College of Neuropsychopharmacology. She is also on the board of Psychiatric Times™. Dr Trump is senior research social scientist at U.S. Army Engineer Research and Development Center (ERDC). Dr Linkov is senior scientific and technical manager at the US Army Engineer Research and Development Center, where he manages crisis response and resilience project portfolio. Dr Benight is professor, executive director of the Lyda Hill Institute of Human Resilience, University of Colorado at Colorado Springs. Ms Estafany is an associate with The PRODEO Institute Dr Winter is a physician-scientist, social entrepreneur, and health policy analyst. Besides training in neurology at the Charité University Hospital and Berlin Institute of Health, Germany, he is a postdoctoral researcher at the Massachusetts General Hospital at Harvard Medical School, Boston, USA. Mr Edmonds is research associate professor and Master of Humanities & Master of Social Science Programs at The University of Colorado at Denver. Mr Lister is senior clinical system analyst at Stanford Health Care. Dr Storch is professor, vice chair, and McIngvale Presidential Endowed Chair in the Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine. Dr Matthews is professor of engineering psychology, United States Military Academy (West Point). Dr Eyre is lead of the Brain Capital Alliance, co-lead of the OECD Neuroscience-inspired Policy Initiative, senior fellow for Brain Capital with the Meadows Mental Health Policy Institute and advisor to the Euro-Mediterranean Economists Association.\n\n\n\nDr Lavretsky was supported by an AT009198 NIH grant. No other authors have acknowledgments, and no authors report relevant conflicts of interest.\n\n\n\nReferences\n\n1. Holling CS. Resilience and stability of ecological systems. Annu Rev Ecol Syst. 1973;4(1):1-23.\n\n2. Eyre HA, Berk M, Lavretsky H, Reynolds C, eds. Convergence Mental Health: A Transdisciplinary Approach to Innovation. Oxford University Press; 2021:229-254.\n\n3. Patz JA, Frumkin H, Holloway T, et al. Climate change: challenges and opportunities for global health. JAMA. 2014;312(15):1565-1580.\n\n4. Hayes K, Blashki G, Wiseman J, et al. Climate change and mental health: risks, impacts and priority actions. Int J Ment Health Syst. 2018;12:28.\n\n5. Patel V, Saxena S, Lund C, et al. The Lancet Commission on global mental health and sustainable development [published correction appears in Lancet. 2018 Oct 27;392(10157):1518]. Lancet. 2018;392(10157):1553-1598.\n\n6. Berry HL, Bowen K, Kjellstrom T. Climate change and mental health: a causal pathways framework. Int J Public Health. 2010;55(2):123-132.\n\n7. Eyre HA, Lavretsky H, Forbes M, et al. Convergence science arrives: how does it relate to psychiatry? Acad Psychiatry. 2017;41(1):91-99.\n\n8. Angeler DG, Fried-Petersen H, Allen CR, et al. Adaptive capacity in ecosystems. Adv Ecol Res. 2019;60:1-24.\n\n9. Allen CR, Angeler DG, Chaffin BC, et al. Resilience reconciled. Nat Sustain. 2019;2:898-900.\n\n10. McEwen BS. Stress, adaptation, and disease. allostasis and allostatic load. Ann N Y Acad Sci. 1998;840:33-44.\n\n11. Baho DL, Allen CR, Garmestani AS, et al. A quantitative framework for assessing ecological resilience. Ecol Soc. 2017;22(3):1-17.\n\n12. Fried EI, Papanikolaou F, Epskamp S. Mental health and social contact during the COVID-19 pandemic: an ecological momentary assessment study. Clin Psychol Sci. 2021;10(2):340-354.\n\n13. Rist L, Felton A, Nyström M, et al. Applying resilience thinking to production ecosystems. Ecosphere. 2014;5(6):1-11.\n\n14. Lake J, Turner MS. Urgent need for improved mental health care and a more collaborative model of care. Perm J. 2017;21:17-024.\n\n15. Angeler DG, Chaffin BC, Sundstrom SM, et al. Coerced regimes: management challenges in the Anthropocene. Ecol Soc. 2020;25(1):1-4.\n\n16. Angeler DG, Allen CR, Persson ML. Resilience concepts in psychiatry demonstrated with bipolar disorder. Int J Bipolar Disord. 2018;6(1):2.\n\n17. Gulati RD, Dionisio Pires LM, Van Donk E. Lake restoration studies: failures, bottlenecks and prospects of new ecotechnological measures. Limnologica. 2008;38(3-4):233-247.\n\n18. Wichers M, Groot PC; Psychosystems, ESM Group, EWS Group. Critical slowing down as a personalized early warning signal for depression. Psychother Psychosom. 2016;85(2):114-116.\n\n19. Kramer AA, Sebat F, Lissauer M. A review of early warning systems for prompt detection of patients at risk for clinical decline. J Trauma Acute Care Surg. 2019;87(1S Suppl 1):S67-S73.\n\n20. de Mooij SMM, Blanken TF, Grasman RPPP, et al. Dynamics of sleep: exploring critical transitions and early warning signals. Comput Methods Programs Biomed. 2020;193:105448.\n\n21. Burthe SJ, Henrys PA, Mackay EB, et al. Do early warning indicators consistently predict nonlinear change in long-term ecological data?J Appl Ecol. 2015;53(3):666-656.\n\n22. Teasdale GM. National early warning score (NEWS) is not suitable for all patients. BMJ. 2012;345:e5875.\n\n23. Trefois C, Antony PM, Goncalves J, et al. Critical transitions in chronic disease: transferring concepts from ecology to systems medicine. Curr Opin Biotechnol. 2015;34:48-55.\n\n24. Usher K, Bhullar N, Jackson D. Life in the pandemic: social isolation and mental health. J Clin Nurs. 2020;29(15-16):2756-2757.\n\n25. Herrmann DL, Schwarz K, Allen CR, et al. Iterative scenarios for social-ecological systems. Ecol Soc. 2021;26(4):1-9.\n\n26. Hynes W, Trump BD, Kirman A. Systemic resilience in economics. Nat Phys. 2022;18(4):381-384.\n\n27. Angeler DG, Eyre HA, Berk M, et al. Adaptation, transformation and resilience in healthcare comment on “Government Actions and Their Relation to Resilience in Healthcare During the COVID-19 Pandemic in New South Wales, Australia and Ontario, Canada.\"Int J Health Policy Manag. 2022;11(9):1949-1952.\n\n28. Milanesi E, Maj C, Bocchio-Chiavetto L, Maffioletti E. Nanomedicine in psychiatry: new therapeutic opportunities from research on small RNAs. Drug Dev Res. 2016;77(8):453-457.\n\n29. do Prado-Lima PAS, Costa-Ferro ZSM, Souza BSF, et al. Is there a place for cellular therapy in depression? World J Psychiatry. 2021;11(9):553-567.\n\n30. Van Dyk K, Siddarth P, Rossetti M, et al. Memantine can protect against inflammation-based cognitive decline in geriatric depression. Brain Behav Immun Health. 2020;9:100167.\n\n31. Grzenda A, Siddarth P, Laird KT, et al. Transcriptomic signatures of treatment response to the combination of escitalopram and memantine or placebo in late-life depression. Mol Psychiatry. 2021;26(9):5171-5179.\n\n32. Angeler DG, Allen CR. Scales of coercion: resilience, regimes, panarchy. In: Gunderson L, Allen CR, Garmestani A (Eds). Applied Panarchy: Applications and Diffusions Across Disciplines. Island Press; 2022.\n\n33. The Lancet Global Health. Mental health matters. Lancet Glob Health. 2020;8(11):e1352.\n\n34. Grzenda A, Speier W, Siddarth P, et al. Machine learning prediction of treatment outcome in late-life depression. Front Psychiatry. 2021;12:738494.\n\n35. Angeler DG, Allen CR, Carnaval A. Convergence science in the Anthropocene: navigating the known and unknown. People Nat. 2020;2(1):96-102.\n\n36. Szent-Györgyi A. Dionysians and apollonians. Science. 1972;176(4038):966.\n\n37. Johansson F. The Medici Effect, With a New Preface and Discussion Guide: What Elephants and Epidemics Can Teach Us About Innovation. Harvard Business Review Press; 2017.\n\n","description":"Beyond the COVID-19-driven shock, we must develop a resilient future in an increasingly uncertain world. ","author":[{"@type":"Person","name":"David G. Angeler, PhD"},{"@type":"Person","name":"Robert M. Lundin, BSc, MBBCh"},{"@type":"Person","name":"Richard G. 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Eyre, MD, PhD","_createdAt":"2020-06-11T18:06:00Z","_rev":"izljKHbbBN8wkY5oZSGB8Q","_type":"author","_id":"pst_author_695525"}],"issueSection":null,"filter":null,"published":"2022-10-26T20:00:25.822Z","thumbnail":{"asset":{"_ref":"image-972990255d4a55fab15b6cc6ddc7a18b0fdffa6e-1000x422-jpg","_type":"reference"},"_type":"mainImage","alt":"Beyond the COVID-19-driven shock, we must develop a resilient future in an increasingly uncertain world. ","caption":"kras99_AdobeStock"},"title":"Building Brain Resilience: A Multi-Level Systems Approach","articleType":"News","_id":"9b2d9022-e6ee-41d5-97d5-a9fe982159ae","_updatedAt":"2024-02-20T17:09:08Z","body":[{"_type":"figure","imgcaption":[{"children":[{"_type":"span","marks":[],"text":"kras99_AdobeStock","_key":"cbe0972686740"}],"_type":"block","style":"normal","_key":"49899a9cbb03","markDefs":[]}],"upload_doc":null,"uploadAudio":null,"disableLightBox":true,"disableTextWrap":false,"_key":"bd29502de785","alignment":"center","asset":{"_ref":"image-972990255d4a55fab15b6cc6ddc7a18b0fdffa6e-1000x422-jpg","_type":"reference"},"medias":null,"widthP":80},{"children":[{"_type":"span","marks":[],"text":"Societies need to be better prepared for rapid changes in economics, politics, and climate. This will depend on our ability to cope with complexity. We propose a new framework based on neuroscience for understanding resilience at multiple levels. This framework considers adaptation, transformation, and the hierarchical structure from brain cells and physiological stress systems to organizations, communities, cultures, and countries. We also discuss how resilience can be managed through transdisciplinary and collaborative approaches, creating a resilient neuroscience system to withstand potentially catastrophic changes to social-ecological systems.","_key":"0dfc79b7d658"}],"_type":"block","style":"normal","upload_doc":null,"uploadAudio":null,"medias":null,"_key":"46139c49df23","markDefs":[]},{"medias":null,"markDefs":[],"children":[{"text":"The COVID-19 pandemic has clarified that resilience is a complex and multi-tiered phenomenon. Medical specialties have commonly focused on the individual brain systems for resilience, but attention to subcellular, epigenetic, brain connectivity, and organ system factors has been growing. These are embedded in social, environmental, and developmental contexts that play a determinative role in the ability of humans to navigate major challenges successfully. Our proposed multi-level systems neuroscience of resilience framework is based on an ecological conceptualization of resilience.","_key":"a9aefa90644a0","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"1","_key":"8708ec8d8e79"}],"_type":"block","style":"normal","_key":"44116760a02e","upload_doc":null,"uploadAudio":null},{"children":[{"marks":[],"text":"A collaborative approach using concepts of transdisciplinary (known as convergence) science is needed to prepare individuals and societies for the complex social-ecological challenges that lay ahead.","_key":"33e6376642d10","_type":"span"},{"_type":"span","marks":["superscript"],"text":"2","_key":"a129b71d9143"},{"_type":"span","marks":[],"text":" Increasing evidence shows how perturbations negatively affect mental health and sustainable development.","_key":"dd39cff113e3"},{"text":"3-5","_key":"de8f3795545c","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" However, the potential direct and indirect effects of disturbances on mental health, such as those arising from climate change, likely add more complexity by exacerbating the effects evident in a single shock such as COVID-19.","_key":"3dbab390e94e"},{"_type":"span","marks":["superscript"],"text":"4,6","_key":"fae92c63b2f7"},{"_key":"90747f381150","_type":"span","marks":[],"text":" Siloed approaches studying mental health disorders or resilience across the lifespan are inadequate for assessing this complexity. Although this work is meritorious, it needs to be integrated with a holistic perspective. Thus, our framework emphasizes that cognition cannot be properly understood or supported without attention to multiple factors and levels of influence."},{"text":"7","_key":"4022cd9e21ac","_type":"span","marks":["superscript"]}],"_type":"block","style":"normal","upload_doc":null,"uploadAudio":null,"medias":null,"_key":"b4d659d619ac","markDefs":[]},{"medias":null,"_type":"block","style":"normal","_key":"f586bcb5f0a6","markDefs":[{"nofollow":true,"blank":true,"_type":"link","href":"https://cdn.sanity.io/images/0vv8moc6/psychtimes/9aad5fd33d94ac510373d3ff150afa04df959735-726x1472.png/Eyre%20Table%201.png?w=1500\u0026fit=max\u0026auto=format","_key":"cb449c889c08"}],"children":[{"_type":"span","marks":[],"text":"We envision a multi-level neuroscience system as an ","_key":"a8747b31f6f40"},{"_type":"span","marks":["em"],"text":"emergent property","_key":"a8747b31f6f41"},{"_type":"span","marks":[],"text":" or phenomenon that arises from dynamic, nonstationary, multi-scale, hierarchical interaction (for a definition of terms in italics see ","_key":"a8747b31f6f42"},{"marks":["strong","cb449c889c08"],"text":"Table 1","_key":"a8747b31f6f43","_type":"span"},{"_key":"a8747b31f6f44","_type":"span","marks":["superscript"],"text":"8"},{"_type":"span","marks":[],"text":"). 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Definitions of Selected Resilience Terms","widthP":50,"medias":null,"alignment":"right","disableTextWrap":false,"disableLightBox":true,"_key":"5a8b7874934f","upload_doc":null,"uploadAudio":null,"asset":{"_ref":"image-9aad5fd33d94ac510373d3ff150afa04df959735-726x1472-png","_type":"reference"},"blank":true,"_type":"figure","imgcaption":[{"_key":"09df4578d457","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Table 1.","_key":"85875f93175a"},{"_type":"span","marks":[],"text":" Definitions of Selected Resilience Terms","_key":"e81cf243ad5a"},{"marks":["superscript"],"text":"8","_key":"8dcc98b82206","_type":"span"}],"_type":"block","style":"normal"}]},{"_key":"37a2553deb50","markDefs":[],"children":[{"_type":"span","marks":[],"text":"This covers internal factors such as genetics, stress, neurobiology, plasticity, and external forces such as close and extended social supports, positive and adaptive organization, economics, and individual environments. These are the life history factors and trajectories that influence our reactions and capacity to act (","_key":"628c29fbde18"},{"_type":"span","marks":["em"],"text":"adaptive capacity","_key":"a8747b31f6f45"},{"_type":"span","marks":[],"text":") in the present moment (Table 1","_key":"a8747b31f6f46"},{"marks":["superscript"],"text":"8","_key":"a8747b31f6f48","_type":"span"},{"_type":"span","marks":[],"text":").","_key":"2b9693d16f6c"}],"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"block","style":"normal"},{"_key":"3e27a049601d","upload_doc":null,"uploadAudio":null,"medias":null,"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"746a46a91dc00"}],"_type":"block","style":"normal"},{"medias":null,"children":[{"_key":"17b79844043a0","_type":"span","marks":["strong"],"text":"Complex Adaptive Systems"}],"_type":"block","style":"normal","_key":"3bc831fd35d3","markDefs":[],"upload_doc":null,"uploadAudio":null},{"uploadAudio":null,"medias":null,"markDefs":[],"children":[{"_type":"span","marks":[],"text":"This complexity is accounted for in ","_key":"f654c3b9c8bd0"},{"_type":"span","marks":["em"],"text":"ecological resilience","_key":"f654c3b9c8bd1"},{"_type":"span","marks":[],"text":", which we use as the framework scaffold. Ecological resilience emphasizes the emergent property of all complex adaptive systems (such as ecosystems and the human brain), which extends beyond models used in other domains like ","_key":"f654c3b9c8bd2"},{"_type":"span","marks":["em"],"text":"resilience in health care","_key":"f654c3b9c8bd3"},{"_type":"span","marks":[],"text":" and ","_key":"f654c3b9c8bd4"},{"_type":"span","marks":["em"],"text":"disaster resilience","_key":"f654c3b9c8bd5"},{"text":".","_key":"f654c3b9c8bd6","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"1,9","_key":"d0b361bade83"},{"_type":"span","marks":[],"text":" These disciplines focus on adaptation, ","_key":"46b0d0b5aa65"},{"marks":["em"],"text":"recovery","_key":"f654c3b9c8bd7","_type":"span"},{"_type":"span","marks":[],"text":", and coping with stressful events. As such, features are individual manifestations of patterns and processes integrated and subsumed within adaptive capacity as in the allosteric model","_key":"f654c3b9c8bd8"},{"_type":"span","marks":["em"],"text":".","_key":"f654c3b9c8bd9"},{"_type":"span","marks":["superscript"],"text":"10","_key":"f654c3b9c8bd10"}],"_type":"block","style":"normal","_key":"cdcf37626d4f","upload_doc":null},{"style":"normal","_key":"72cbf38804d8","markDefs":[{"href":"https://cdn.sanity.io/images/0vv8moc6/psychtimes/69ea5b65bc2bc5c61f0b5ee99f837bd2d8f185ad-426x516.png/Figure%201.png?w=1500\u0026fit=max\u0026auto=format","_key":"f2bb009f76bb","nofollow":true,"blank":true,"_type":"link"}],"upload_doc":null,"uploadAudio":null,"medias":null,"children":[{"_type":"span","marks":[],"text":"At an individual level, adaptive capacity is often predicated on prior adaptation and mastery of challenges. However, at a systemic level, the function is to maintain equilibrium and contribute to the stationary dynamics of specific system regimes as outlined in ","_key":"7a601c1358050"},{"_key":"7a601c1358051","_type":"span","marks":["strong","f2bb009f76bb"],"text":"Figure 1"},{"_type":"span","marks":[],"text":".","_key":"7a601c1358052"},{"_type":"span","marks":["superscript"],"text":"8","_key":"9fa273999341"},{"_type":"span","marks":[],"text":" ","_key":"004d62f6494c"}],"_type":"block"},{"imgcaption":[{"markDefs":[],"children":[{"_key":"cd24bd62b89f0","_type":"span","marks":["strong"],"text":"Figure 1. "},{"text":"Ecological Resilience Model Showing the Transformation of Resilience Over Time Following Erosion of Adaptive Capacity Until a Shift to a Novel Regime Can Occur","_key":"71c55c3b474c","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"a82ae7452e22"}],"alignment":"right","blank":true,"upload_doc":null,"uploadAudio":null,"medias":null,"asset":{"_ref":"image-69ea5b65bc2bc5c61f0b5ee99f837bd2d8f185ad-426x516-png","_type":"reference"},"disableLightBox":true,"_key":"b2093d2aac43","_type":"figure","widthP":50,"disableTextWrap":false,"alt":"Figure 1. Ecological Resilience Model Showing the Transformation of Resilience Over Time Following Erosion of Adaptive Capacity Until a Shift to a Novel Regime Can Occur"},{"_key":"1119682cdeeb","markDefs":[],"children":[{"_type":"span","marks":[],"text":"The adaptive capacity, therefore, allows the complex system (individual or ecosystem) to return to the predisturbance conditions after disruptions. In a practical setting, this can be boosted by additional management interventions such as psychotherapy and preventative fitness interventions. Adaptive capacity is thus a system component that is nested in ecological resilience.","_key":"3e098556a02e"},{"marks":["superscript"],"text":"11","_key":"0f55ef35294a","_type":"span"}],"_type":"block","style":"normal","upload_doc":null,"uploadAudio":null,"medias":null},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"An important caveat is that complex adaptive systems cannot infinitely cope with disturbances. They operate within defined bounds of system dynamics that are at least partly learned from prior appropriate adaptations to environmental demands.","_key":"c9a87da1b4b70"},{"text":"12,13","_key":"946a8dc14804","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" Once adaptive capacity is exhausted, a critical disturbance threshold is passed, and the system flips into a novel, ","_key":"8844cbbbf38f"},{"_type":"span","marks":["em"],"text":"alternative regime","_key":"c9a87da1b4b71"},{"text":" with different system dynamics (Figure 1). Such fundamental, often abrupt, nonlinear system change is inherent in ecological resilience. It highlights the ability of complex systems to undergo a ","_key":"c9a87da1b4b72","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"nonstationary","_key":"c9a87da1b4b73"},{"_type":"span","marks":[],"text":" transformation and to exist in regimes with each of their structures, processes, ","_key":"c9a87da1b4b74"},{"_type":"span","marks":["em"],"text":"feedbacks","_key":"c9a87da1b4b75"},{"_type":"span","marks":[],"text":", and adaptive capacity.","_key":"c9a87da1b4b76"}],"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"block","style":"normal","_key":"4cab8bcc195d"},{"uploadAudio":null,"medias":null,"_key":"61acc2519c7a","markDefs":[],"children":[{"text":"Consider a democracy shifting to an authoritarian regime, rainforests turning into deserts and healthy individuals and populations developing chronic diseases. Once complex systems are “degraded,” such as individuals and communities living with persistent health problems, resilience-based management allows for purposefully eroding the adaptive capacity of an impaired, suboptimal regime to make it prone to transformation into a more “desired” regime that would allow fostering of improved health.","_key":"b22808b261060","_type":"span","marks":[]},{"marks":["superscript"],"text":"14","_key":"8e6ad287a294","_type":"span"},{"_type":"span","marks":[],"text":" Alternative regimes may lose critical functions, such as food rationing, energy, and communication, relative to previous social-ecological systems regimes. Degraded regimes often need constant costly management to force desired functions artificially. In such ","_key":"019e8f968ae0"},{"_key":"b22808b261061","_type":"span","marks":["em"],"text":"coerced regimes"},{"_type":"span","marks":[],"text":" functions can no longer be sustained by the system itself.","_key":"b22808b261062"},{"_type":"span","marks":["superscript"],"text":"15","_key":"9a94d954ee20"}],"_type":"block","style":"normal","upload_doc":null},{"medias":null,"children":[{"_type":"span","marks":[],"text":"Management of adaptive capacity does not necessarily achieve recovery to a previous regime or the creation of a novel one, and it is often limited to mitigating the effects of disturbances. This is due to previous coping regimes having become maladaptive or obsolete, leading to deeply entrenched feedbacks that stabilize the novel, alternative, or degraded regime (Figure 1). This can be exemplified in therapeutic interventions that merely mitigate mental illness without recovering patients to a symptomless regime where further therapy or medication is unnecessary.","_key":"97838209a02e0"},{"_type":"span","marks":["superscript"],"text":"16","_key":"b9370dd744f6"},{"_type":"span","marks":[],"text":" Similarly, biological and technological solutions often only mitigate turbid, nutrient-enriched lakes with toxic algal blooms and fail to create a clear-water regime with abundant plants and good water quality.","_key":"7d91062ae854"},{"_type":"span","marks":["superscript"],"text":"17","_key":"f2a0bb4ad805"}],"_type":"block","style":"normal","_key":"1dc5c18d4e85","markDefs":[],"upload_doc":null,"uploadAudio":null},{"_type":"block","style":"normal","upload_doc":null,"uploadAudio":null,"medias":null,"_key":"8f25d00c99f6","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Alternative regimes underscore the importance of accounting for transformation in theory and practice because adaptation and transformation both need to be considered when managing resilient multi-level systems. However, transformative management is plagued by high uncertainty. Despite developing early warning scores for impending system transitions used in psychiatry, these often have limited predictability within ecosystems.","_key":"709ecfac56c40"},{"_type":"span","marks":["superscript"],"text":"18-23","_key":"6373fef2d371"},{"_type":"span","marks":[],"text":" This uncertainty is exemplified by the increased mental health challenges associated with the COVID-19 pandemic, where the future trajectory is impossible to predict.","_key":"b0251d47d156"},{"_type":"span","marks":["superscript"],"text":"24","_key":"905ddb4bbd26"},{"_type":"span","marks":[],"text":" As such, it is currently not possible to ascertain whether the global mental health crisis is a mirror image of social-ecological systems having already flipped into novel regimes, possibly triggered by the pandemic and social media, or whether regime shifts will likely occur in the future.","_key":"a69129168fbc"}]},{"uploadAudio":null,"medias":null,"markDefs":[],"children":[{"text":"Consider the Russian invasion of Ukraine, which has had international ramifications through military rearmament, inflation, mass migration, and supply of resources. All these considerations must be accounted for if the transformation goal is to create desirable, resilient, and ","_key":"cf3dfcaced320","_type":"span","marks":[]},{"marks":["em"],"text":"self-organizing","_key":"cf3dfcaced321","_type":"span"},{"_type":"span","marks":[],"text":" multi-level systems of neuroscience, and ultimately meet the United Nations Sustainable Development goals for health and resilience of social-ecological systems.","_key":"cf3dfcaced322"}],"_type":"block","style":"normal","_key":"41a2c042ce16","upload_doc":null},{"_key":"de251ad99d5b","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Despite this complexity, transformative management can be informed by planning competing scenarios using science-based predictive models, including simulations and group scenarios with stakeholders. Such scenarios can envision different social, environmental, technological, and economic realities that can be reiteratively tested as we move toward an uncertain future.","_key":"fedd67f3ab800"},{"text":"25","_key":"5514968e34f7","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" There are, however, many challenges that need to be accounted for in scenario planning and transformation, which may be informed by interdisciplinary research, exemplified by the cross-pollination of economics and physics.","_key":"dad5c163c7ca"},{"marks":["superscript"],"text":"26","_key":"ac3faa988a90","_type":"span"},{"_type":"span","marks":[],"text":" Relevant factors range from the levels of neurons to societies, resilience by design, intervention in health care logistics, responsible governance, economic and energetic transformation, and media communication.","_key":"bff697cc8ea8"},{"_type":"span","marks":["superscript"],"text":"27","_key":"f891f83546c9"}],"_type":"block","upload_doc":null,"uploadAudio":null,"medias":null,"style":"normal"},{"medias":null,"_type":"block","style":"normal","_key":"c72b94a3f978","markDefs":[],"children":[{"_key":"6bcc12857fee0","_type":"span","marks":[],"text":""}],"upload_doc":null,"uploadAudio":null},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Demonstrating a Multi-Level Neuroscience System of Resilience","_key":"fd657d2147ee0"}],"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"block","style":"normal","_key":"a4a18096444d"},{"_key":"c7583ad3168c","markDefs":[{"href":"https://cdn.sanity.io/images/0vv8moc6/psychtimes/4614fb162293aec2a3dfba113fdd17014bfbbff5-816x348.png/Figure%202.png?w=1500\u0026fit=max\u0026auto=format","_key":"7a34f8acd5a1","nofollow":true,"blank":true,"_type":"link"}],"children":[{"_type":"span","marks":[],"text":"The complexity that crystalizes the resilience of ","_key":"1e15d1478a660"},{"marks":["em"],"text":"multi-level","_key":"1e15d1478a661","_type":"span"},{"_type":"span","marks":[],"text":" neuroscience systems initially requires a simplified conceptualization as seen in ","_key":"1e15d1478a662"},{"_type":"span","marks":["strong","7a34f8acd5a1"],"text":"Figure 2","_key":"1e15d1478a663"},{"_type":"span","marks":[],"text":". ","_key":"1e15d1478a664"}],"_type":"block","style":"normal","upload_doc":null,"uploadAudio":null,"medias":null},{"medias":null,"disableLightBox":true,"alt":"Figure 2. Simplified Conceptualization of the Multi-Level Systems Neuroscience of Resilience","alignment":"right","widthP":50,"blank":true,"upload_doc":null,"_type":"figure","imgcaption":[{"_type":"block","style":"normal","_key":"01dd1a3c0b93","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Figure 2. ","_key":"1a574da1a6440"},{"_type":"span","marks":[],"text":"Simplified Conceptualization of the Multi-Level Systems Neuroscience of Resilience","_key":"8f1629a7f30c"}]}],"asset":{"_ref":"image-4614fb162293aec2a3dfba113fdd17014bfbbff5-816x348-png","_type":"reference"},"disableTextWrap":false,"_key":"4669db5d2e43","uploadAudio":null},{"_key":"23cea924d770","upload_doc":null,"uploadAudio":null,"medias":null,"markDefs":[],"children":[{"marks":[],"text":"A scaffold for a conceptual model for multi-level neuroscience systems resilience can be built through research that increasingly unravels its inherent complexity, including the connectivity and “information flow” across system levels, through a constant iterative learning process.","_key":"4352033dc405","_type":"span"}],"_type":"block","style":"normal"},{"children":[{"text":"One example would be how genetic susceptibility to mental illness at the brain level can trigger disorders following stressful life events. This transforms a healthy regime with fragile resilience into a potentially dysfunctional, highly resistant regime that may need constant health care management to mitigate symptom expressions.","_key":"48e173aa84f20","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"16","_key":"11d68a291214"},{"text":" The brain-level changes resulting from transformation influence the next system level: the individual. At this scale, symptoms affect psychological, physiological, and behavioral functioning that may need to be managed therapeutically. At the population level, it becomes necessary to implement systems that manage patients and other related brain problems for multiple individuals experiencing the same problem. These treatments have economic repercussions at the societal level through loss of productivity and cost of health care.","_key":"0f7b16c49522","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"1e991acf23cc","upload_doc":null,"uploadAudio":null,"medias":null,"markDefs":[]},{"style":"normal","_key":"4b778f94ecc3","markDefs":[],"children":[{"_type":"span","marks":[],"text":"This chain of events demonstrates a clear “bottom-up” component in transmitting information in a multi-level neuroscience system. However, “top-down” events also further influence system processes and feedbacks. For instance, public illiteracy about mental illness and stigma, limited resources for managing mental health, and ineffective policies foster the negative societal repercussions of mental illness as well as reinforce stressful environments for patients. Bottom-up and top-down factors combined form negative feedbacks to maintain this demonstrated neuroscience system in a resilient undesired regime. However, they also identify scales in the system where management can be leveraged to create a more desirable regime through transformation.","_key":"c2caba945f670"}],"_type":"block","upload_doc":null,"uploadAudio":null,"medias":null},{"uploadAudio":null,"medias":null,"_key":"7015840a4794","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"69d44b6558070"}],"_type":"block","style":"normal","upload_doc":null},{"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"block","style":"normal","_key":"51e16d8b3b5b","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Leveraging System Management for Multi-Level Neuroscience Systems of Resilience","_key":"8f5a5994e2e90"}]},{"_type":"block","style":"normal","_key":"4a5d2a014a24","upload_doc":null,"uploadAudio":null,"medias":null,"markDefs":[{"_key":"8bbd09130cf0","nofollow":true,"blank":true,"_type":"link","href":"https://cdn.sanity.io/images/0vv8moc6/psychtimes/9555a92c140c2877467e730f1b1fc874a6023109-928x1002.png/Eyre%20Table%202.png?w=1500\u0026fit=max\u0026auto=format"}],"children":[{"_type":"span","marks":[],"text":"There is a wide range of system management possibilities that may contribute to creating a resilient, multi-level neuroscience system. Management options may likely encompass a wide spectrum of molecular, clinical, technological, educational, economic, and ecological tools and approaches as outlined in ","_key":"dd4b2ee43fce0"},{"_type":"span","marks":["strong","8bbd09130cf0"],"text":"Table 2","_key":"dd4b2ee43fce1"},{"_key":"dd4b2ee43fce2","_type":"span","marks":[],"text":". "}]},{"disableLightBox":true,"disableTextWrap":false,"alt":"Table 2. Examples of Adaptive and Transformative Approaches Across Scales as Crucial Components of Multi-Level Systems Neuroscience of Resilience","widthP":50,"imgcaption":[{"style":"normal","_key":"dc9b791b4aa0","markDefs":[],"children":[{"_key":"cb55eae056e3","_type":"span","marks":["strong"],"text":"Table 2. "},{"_type":"span","marks":[],"text":"Examples of Adaptive and Transformative Approaches Across Scales as Crucial Components of Multi-Level Systems Neuroscience of Resilience","_key":"1f7909761fe3"}],"_type":"block"}],"_type":"figure","asset":{"_ref":"image-9555a92c140c2877467e730f1b1fc874a6023109-928x1002-png","_type":"reference"},"blank":true,"upload_doc":null,"_key":"113ad2a809fa","alignment":"right","uploadAudio":null,"medias":null},{"uploadAudio":null,"medias":null,"markDefs":[],"children":[{"_type":"span","marks":[],"text":"These options can be exploited for adaptive and transformative management, but specific approaches may be most suitable for only a few specific hierarchical levels that comprise such a system. For instance, at the brain level, the development of nanotechnology may provide opportunities to create nanoparticle-based drugs that improve psychotherapeutic approaches.","_key":"bb576200cee7"},{"_type":"span","marks":["superscript"],"text":"28","_key":"52bf5e55228c"},{"_type":"span","marks":[],"text":" Similarly, experimental data corroborate that mesenchymal stem cell therapy could be a potential treatment for depression based on anti-inflammatory and neurotrophic properties.","_key":"6af5d157f8a6"},{"_type":"span","marks":["superscript"],"text":"29","_key":"fd623f9ddfeb"}],"_type":"block","style":"normal","_key":"24c22228ff93","upload_doc":null},{"upload_doc":null,"uploadAudio":null,"medias":null,"markDefs":[],"children":[{"_type":"span","marks":[],"text":"An example of a novel therapeutic approach is the addition of cytokine markers to antidepressants that provide a protective effect on executive functioning and treatment response in older adults with depression.","_key":"e6ecc20dc005"},{"_type":"span","marks":["superscript"],"text":"30,31","_key":"9b08aea4fc6d"},{"_key":"27f2d44601d3","_type":"span","marks":[],"text":" Pharmacogenetic innovations could transform the clinical space and complement or refine current adaptive treatment approaches based on medication adjustment for brain disorders. This allows adaptive and transformative management options to target neurocircuits and developmental processes at the next higher scale: the brain."}],"_type":"block","style":"normal","_key":"463c9ca6ef42"},{"children":[{"text":"The ability of a few interventions to target more than 1 scale in a multi-level neuroscience system has implications for resilience. Specifically, medications currently used to treat disorders include redundant management options that target neuronal molecular structures and physiology and structures at the brain level. Creating redundant management interventions within scales or across them can foster resilience in multi-level neuroscience systems like those proposed for climate change mitigation.","_key":"7ecfa34c49000","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"32","_key":"dc5375e72990"},{"text":" Brain-level management options cannot directly be used to manage higher hierarchical scales. For example, at the scale of individuals, management targeting suicide rates may build on current clinical tools such as individually adjusted therapy through adaptation. Novel self-reflexive approaches, such as mental health apps monitoring mood states, could provide improved insight through transformation.","_key":"743cd77bef02","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"27","_key":"66efbbd05048"}],"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"block","style":"normal","_key":"2c9f97359217","markDefs":[]},{"uploadAudio":null,"medias":null,"_key":"cc7121386a3a","markDefs":[],"children":[{"marks":[],"text":"We acknowledge that our examples focus broadly on factors that directly affect the multi-level neuroscience systems of resilience like the genetic proclivity of mental illness. However, other issues affecting these systems indirectly, like the mental health impact of sickle cell anemia, need to be accounted for. Success in rewiring the brain toward the best possible health can reduce the burden on mental health care systems and associated economic costs. Meanwhile, creating equal and fair access to health care can cascade down to lower levels and contribute to reinforcing improved brain health.","_key":"b3fd155570cb0","_type":"span"}],"_type":"block","style":"normal","upload_doc":null},{"medias":null,"_key":"b830b993a1a2","markDefs":[],"children":[{"text":"Within-scale and cross-scale redundancy of management options at the individual and societal level shows the interconnectedness of hierarchical scales that ultimately influences its resilience through the flow of information from the lowest to the highest hierarchical scale in the system and vice versa. It will also be essential to identify additional levels not noted in the previously outlined model, such as organizational levels in which maintaining values and promoting growth at the individual level will nurture desirable behaviors at the society level. Companies, schools, volunteer agencies, and clubs play an important role in shaping adaptive and maladaptive behavior. A toxic or unethical organizational climate can have ill effects that spread to the wider levels, but a positive one may be transformative for a multi-level system.","_key":"ce38e2962b530","_type":"span","marks":[]}],"_type":"block","style":"normal","upload_doc":null,"uploadAudio":null},{"_type":"block","style":"normal","upload_doc":null,"uploadAudio":null,"medias":null,"_key":"1dca43037868","markDefs":[],"children":[{"marks":[],"text":"","_key":"46e3632197e30","_type":"span"}]},{"_key":"7baeb6985d6c","markDefs":[],"upload_doc":null,"uploadAudio":null,"medias":null,"children":[{"_type":"span","marks":["strong"],"text":"Creating and Managing Resilient Multi-Level Neuroscience Systems","_key":"7ae4863275e70"}],"_type":"block","style":"normal"},{"medias":null,"markDefs":[{"_type":"link","href":"https://cdn.sanity.io/images/0vv8moc6/psychtimes/2376da87c2cd6dda6384f62095ed31be9de3044c-358x604.png/Figure%203.png?w=1500\u0026fit=max\u0026auto=format","_key":"3f9239967d59","nofollow":true,"blank":true}],"children":[{"_type":"span","marks":[],"text":"A major goal of management is to create self-organizing systems that need minimal intervention in providing necessary goods and services. These can range from food, clean water, and financial security to brain health, sustainable workload, and access to health care. This complexity leads to a multi-level neuroscience system as pictured in ","_key":"175eb56019450"},{"marks":["strong","3f9239967d59"],"text":"Figure 3A","_key":"175eb56019451","_type":"span"},{"_type":"span","marks":[],"text":". ","_key":"175eb56019452"}],"_type":"block","style":"normal","_key":"09c13e0a2d18","upload_doc":null,"uploadAudio":null},{"disableLightBox":true,"alt":"Figure 3 A-C. Model Scenarios of Desired and Undesired Social-Ecological Regimes of Multi-Level Neuroscience Systems","blank":true,"widthP":50,"disableTextWrap":false,"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"figure","_key":"a33fddb073e3","asset":{"_ref":"image-2376da87c2cd6dda6384f62095ed31be9de3044c-358x604-png","_type":"reference"},"imgcaption":[{"_key":"f6e2d5cd8822","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Figure 3 A-C. ","_key":"8b9566f2f1b00"},{"_type":"span","marks":[],"text":"Model Scenarios of Desired and Undesired Social-Ecological Regimes of Multi-Level Neuroscience Systems","_key":"3d8410e2345e"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"e9c572f66e8b"}],"_type":"block","style":"normal","_key":"a3e15e34353e"},{"markDefs":[],"children":[{"_type":"span","marks":["em"],"text":"Desired social-ecological regimes of multi-level neuroscience systems are in green, and undesired social-ecological regimes are in red. The ball and blue arrow indicate system trajectories that can lead to (A) self-organizing systems in a desirable regime, (B) coerced regime approximating the desired scenario, or (C) a failure to reach one despite coercion.","_key":"4ff9287d30470"}],"_type":"block","style":"normal","_key":"9bf8fb5602cc"}],"alignment":"right"},{"_key":"cb11548b5daf","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Despite comprising an apparent individual entity, such a system must be understood as an integral part of broader social-ecological systems.","_key":"18dd155819e7"},{"_type":"span","marks":["superscript"],"text":"27","_key":"83f6a46c50d1"},{"marks":[],"text":" Therefore, the evolution of multi-level neuroscience systems is likely developed in tandem with the dynamics and change of socio-ecological systems and their underlying economic, social, technological, and ecological drivers.","_key":"9dbf3f69b007","_type":"span"}],"_type":"block","upload_doc":null,"uploadAudio":null,"medias":null,"style":"normal"},{"medias":null,"_type":"block","style":"normal","_key":"c5c8fcc65485","markDefs":[],"children":[{"_type":"span","marks":[],"text":"The increasing global mental health crisis is projected to incur substantial economic and societal costs. This suggests that creating self-organizing, desirable, and resilient multi-level neuroscience systems will likely be impossible.","_key":"4852da93e9b60"},{"_type":"span","marks":["superscript"],"text":"33","_key":"a048a7d348d0"},{"_type":"span","marks":[],"text":" Thus, substantial and incrementally intensifying management will be needed to coerce multi-level neuroscience systems into a regime that artificially maintains the desired functioning. There may be contrasting scenarios in which management will either succeed in emulating multi-level neuroscience systems conditions that approximate those of a resilient desired regime (","_key":"4a09d7aa97eb"},{"_type":"span","marks":["strong"],"text":"Figure 3B","_key":"4852da93e9b61"},{"text":") or fail to do so (","_key":"4852da93e9b62","_type":"span","marks":[]},{"_type":"span","marks":["strong"],"text":"Figure 3C","_key":"4852da93e9b63"},{"marks":[],"text":").","_key":"4852da93e9b64","_type":"span"}],"upload_doc":null,"uploadAudio":null},{"uploadAudio":null,"medias":null,"style":"normal","_key":"c2dba6ddae76","markDefs":[],"children":[{"text":"","_key":"6f4b75d03aa90","_type":"span","marks":[]}],"_type":"block","upload_doc":null},{"_key":"a5761063e836","upload_doc":null,"uploadAudio":null,"medias":null,"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"A Way Forward","_key":"d98a6e5190d80"}],"_type":"block","style":"normal"},{"upload_doc":null,"uploadAudio":null,"medias":null,"markDefs":[],"children":[{"_key":"499a8c477c7f0","_type":"span","marks":[],"text":"We have suggested scenarios comprising opposites between best-case and worst-case outcomes of managing coerced multi-level neuroscience systems of resilience. Although scenario planning is a useful tool to suggest how management may be geared for creating best-possible multi-level neuroscience systems of resilience, benchmarked against the worst-case, scenarios must not be seen as static endpoints. They rather need to be refined and recalibrated iteratively. They also can be informed by machine learning to accommodate the unforeseen change that may result from technological, economic, and societal innovation. At the same time, there is a pervasive inability to abate many of the crises that have challenged sustainable development."},{"_type":"span","marks":["superscript"],"text":"25,34","_key":"f23dc28e7051"},{"text":" The “unforeseeable” is an essential part of the high uncertainty inherent in the dynamics of complex systems of individuals and nature. This means that in addition to known unknowns, we need to account for unknown unknowns.","_key":"3bab94842c58","_type":"span","marks":[]},{"text":"35","_key":"9e882c7500cb","_type":"span","marks":["superscript"]},{"marks":[],"text":" Addressing the unknown unknowns comprises a dilemma because defining social-ecological, including brain health, challenges that we do not know to comprise is an absurd contradiction.","_key":"3c666698b6e4","_type":"span"},{"_type":"span","marks":["superscript"],"text":"36","_key":"7cbd44cc7076"}],"_type":"block","style":"normal","_key":"0ae29d897ba4"},{"style":"normal","_key":"4ad83e93df35","markDefs":[],"upload_doc":null,"uploadAudio":null,"medias":null,"children":[{"marks":[],"text":"Compartmentalization across spheres of society is ill-suited to deal with the unknown unknowns. Fundamental changes in academia are needed to move away from models emphasizing isolation and metric fulfillment. More room needs to be created for intuitive thinking and collaborative work that allows for novelty and innovation, which arises at the intersection between, rather than within, distinctly different knowledge domains and life experiences.","_key":"185a8cfe76600","_type":"span"},{"text":"37","_key":"83fd8e76dd98","_type":"span","marks":["superscript"]},{"marks":[],"text":" Such collaborations will need to be truly transdisciplinary and include cooperation across all spheres of society. Such partnerships can be inspired by a creative, alternative, provocative, and unorthodox dialog at the intersection of the arts, sciences, philosophy, and spirituality. 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Tampi MD, MS, DFAPA, DFAAGP, Editor","_key":"12ca9eb5e6e9","_type":"span"}]},{"_key":"5b6f70c151c2","markDefs":[],"children":[{"_type":"span","marks":[],"text":"While pharmacological and therapy-based treatments have shown therapeutic efficacy in obsessive-compulsive disorder (OCD), there are many patients who have inadequate responses to these treatment modalities. Repetitive transcranial magnetic stimulation (rTMS) has shown promise for treatment-refractory affective disorders. This meta-analysis included 25 randomized controlled trials (RCTs) with 860 participants. The aim was to assess the therapeutic benefit of rTMS in patients with OCD and explored the moderators of its treatment effect.","_key":"c346786b0d6c"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"78dccbe6cd640"}],"_type":"block","style":"normal","_key":"68f7e9a1c953"},{"style":"normal","_key":"2baa14ba8e48","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"The Study","_key":"7537ff2823690"}],"_type":"block"},{"children":[{"_type":"span","marks":[],"text":"Steuber ER, McGuire JF. ","_key":"5b88e5b38c3b0"},{"text":"A meta-analysis of transcranial magnetic stimulation in obsessive-compulsive disorder.","_key":"5b88e5b38c3b1","_type":"span","marks":["753cd38161b3"]},{"_type":"span","marks":[],"text":" ","_key":"6b5e6ac7c8c1"},{"marks":["em"],"text":"Biol Psychiatry Cogn Neurosci Neuroimaging.","_key":"5b88e5b38c3b2","_type":"span"},{"_type":"span","marks":[],"text":" 2023;8(11):1145-1155.","_key":"5b88e5b38c3b3"}],"_type":"block","style":"normal","_key":"bf2f93fcf4fd","markDefs":[{"_key":"753cd38161b3","blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/37343662/"}]},{"_type":"block","style":"normal","_key":"599b822bb622","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"4109d8010fb60"}]},{"markDefs":[],"children":[{"text":"Study Funding","_key":"8c4dc714c0360","_type":"span","marks":["strong"]}],"_type":"block","style":"normal","_key":"a966d8581890"},{"children":[{"_type":"span","marks":[],"text":"None listed.","_key":"1c42973325cd0"}],"_type":"block","style":"normal","_key":"1a6d36a6cb4e","markDefs":[]},{"children":[{"_type":"span","marks":[],"text":"","_key":"75bac16673840"}],"_type":"block","style":"normal","_key":"473ae48048cd","markDefs":[]},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Study Objectives","_key":"b80c64b098950"}],"_type":"block","style":"normal","_key":"a85c95f3d82d"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"To examine the therapeutic benefit of rTMS in patients with OCD and to explore the moderators of its treatment effect.","_key":"20a59adb68bb0"}],"_type":"block","style":"normal","_key":"edb1e4dee75a"},{"markDefs":[],"children":[{"_key":"723d2e388aa50","_type":"span","marks":[],"text":""}],"_type":"block","style":"normal","_key":"1f8104e21d01"},{"children":[{"_type":"span","marks":["strong"],"text":"Methodology","_key":"9611349f138d0"}],"_type":"block","style":"normal","_key":"31e57b156fb2","markDefs":[]},{"children":[{"_key":"f7ec0b9cc5110","_type":"span","marks":[],"text":"This meta-analysis adhered to PRISMA guidelines and included studies from 1997 to December 31, 2022. Pubmed, SCOPUS, and PsycINFO databases were searched using keywords: “obsessive-compulsive disorder,” “transcranial magnetic stimulation,” and “randomized controlled trial.” Inclusion criteria were that the study had to be an RCT that compares rTMS treatment with sham condition. In addition, the participants had to meet diagnostic criteria for OCD, and there had to be sufficient data to calculate treatment effects using psychometrically supported rating scales. The authors screened a total of 159 records for eligibility. After applying inclusion criteria, 25 studies were included with 3 trials having multiple rTMS conditions. This provided a total of 28 treatment comparisons for inclusion. The Yale-Brown Obsessive-Compulsive Scale (YBOCS) was utilized to extract effect sizes for OCD severity. If multiple depression scales were reported in the RCT, the Montgomery-Asberg Depression Scale (MADRS) was favored over the Hamilton Depression Scale (HDS) and Beck Depression Inventory (BDI). To quantify treatment effects, Hedge’s "},{"marks":["em"],"text":"g ","_key":"f7ec0b9cc5111","_type":"span"},{"_type":"span","marks":[],"text":"was selected. Effective sizes were calculated using change scores. Relative risk ratios were used to calculate the treatment response and effective size.","_key":"f7ec0b9cc5112"}],"_type":"block","style":"normal","_key":"51714d2703a9","markDefs":[]},{"style":"normal","_key":"a54173961ed0","markDefs":[],"children":[{"marks":[],"text":"","_key":"58a4ced104110","_type":"span"}],"_type":"block"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Study Results","_key":"44f414d47f190"}],"_type":"block","style":"normal","_key":"a4ddfb4a2a02"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"The random effects model found that rTMS had a moderate therapeutic effect on OCD severity when compared with sham conditions. (","_key":"46e75fb8096c0"},{"_type":"span","marks":["em"],"text":"g","_key":"46e75fb8096c1"},{"_key":"46e75fb8096c2","_type":"span","marks":[],"text":"=0.65, "},{"text":"P","_key":"46e75fb8096c3","_type":"span","marks":["em"]},{"_type":"span","marks":[],"text":"\u003c0.001). Significant heterogeneity was identified (","_key":"46e75fb8096c4"},{"_type":"span","marks":["em"],"text":"P","_key":"46e75fb8096c5"},{"_type":"span","marks":[],"text":"\u003c0.003) and Egger’s test indicated that publication bias was significant (","_key":"46e75fb8096c6"},{"_type":"span","marks":["em"],"text":"P","_key":"46e75fb8096c7"},{"text":"=0.04). Further testing using the Duval and Tweedie’s trim and fill method indicated that no studies needed to be trimmed and that a moderate therapeutic effect remained (","_key":"46e75fb8096c8","_type":"span","marks":[]},{"text":"g","_key":"46e75fb8096c9","_type":"span","marks":["em"]},{"_type":"span","marks":[],"text":"=0.65).","_key":"46e75fb8096c10"}],"_type":"block","style":"normal","_key":"2d53a2bb77b2"},{"_key":"7b8acc57fb95","markDefs":[],"children":[{"_type":"span","marks":[],"text":"For treatment response, the average rate across trials was 39.5% for rTMS and 8.8% for sham conditions. A large treatment effect of rTMS when compared with sham conditions was found using the random effects model (Relative Risk [RR] =3.15, ","_key":"c3f01fb62ca70"},{"_type":"span","marks":["em"],"text":"P","_key":"c3f01fb62ca71"},{"marks":[],"text":"\u003c0.001). There was little heterogeneity across trials (","_key":"c3f01fb62ca72","_type":"span"},{"_type":"span","marks":["em"],"text":"P","_key":"c3f01fb62ca73"},{"text":"=0.61), but publication bias was present (","_key":"c3f01fb62ca74","_type":"span","marks":[]},{"marks":["em"],"text":"P","_key":"c3f01fb62ca75","_type":"span"},{"marks":[],"text":"=0.03). When Duval and Tweedie’s trim-and-fill method was used, rTMS continued to show a moderate effect (RR=2.67), although 4 studies had to be trimmed. There were no significant differences between trials that used \u003e 25% improvement on the YBOCS scale compared with \u003e30%, \u003e35%, or \u003e40% improvement (","_key":"c3f01fb62ca76","_type":"span"},{"text":"P","_key":"c3f01fb62ca77","_type":"span","marks":["em"]},{"_type":"span","marks":[],"text":"=0.86).","_key":"c3f01fb62ca78"}],"_type":"block","style":"normal"},{"_key":"118e864d818c","markDefs":[],"children":[{"_key":"88b9ac5f555d0","_type":"span","marks":[],"text":"Three treatment moderators were found to be statistically significant when analyzing heterogeneity. First, when patients had a greater improvement in depression severity, this was found to produce a larger treatment effect of rTMS on OCD ("},{"_type":"span","marks":["em"],"text":"P","_key":"88b9ac5f555d1"},{"_type":"span","marks":[],"text":"=0.02). Second, longer TMS sessions were associated with greater improvement in OCD (","_key":"88b9ac5f555d2"},{"_type":"span","marks":["em"],"text":"P","_key":"88b9ac5f555d3"},{"_type":"span","marks":[],"text":"=0.05). And lastly, a lower number of TMS sessions were associated with greater improvement in OCD severity (","_key":"88b9ac5f555d4"},{"marks":["em"],"text":"P","_key":"88b9ac5f555d5","_type":"span"},{"_type":"span","marks":[],"text":"=0.02).","_key":"88b9ac5f555d6"}],"_type":"block","style":"normal"},{"children":[{"_type":"span","marks":[],"text":"It is important to note that patient average age, sex, duration of OCD illness, concurrent use of serotonin reuptake inhibitor pharmacotherapy or antipsychotic pharmacotherapy, baseline OCD symptom severity, and/or use of medication free status were not statistically significant regarding the treatment effect of rTMS on OCD severity. Other intervention characteristics that were not found to be statistically significant included rTMS motor thresholds, rTMS frequencies, coils used for rTMS, total number of pulses used, and the location of rTMS treatment including the dorsolateral prefrontal cortex, orbitofrontal cortex, and supplementary motor area.","_key":"45af34743b360"}],"_type":"block","style":"normal","_key":"629094e89acc","markDefs":[]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"When looking through trial design characteristics as moderators of rTMS treatment effects, sample size, trial attrition, and year of publications were not found to be statistically significant. There was no difference between studies that used full sham conditions vs those that did not (","_key":"3b3148c602600"},{"_type":"span","marks":["em"],"text":"P","_key":"3b3148c602601"},{"text":"=0.75). Finally, there was no statistical significance between trials that used treatment refractory patients, vs nontreatment refractory patients (","_key":"3b3148c602602","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"P","_key":"3b3148c602603"},{"marks":[],"text":"=0.81).","_key":"3b3148c602604","_type":"span"}],"_type":"block","style":"normal","_key":"340d2b25eb91"},{"children":[{"_type":"span","marks":[],"text":"","_key":"eb2d1768b6a90"}],"_type":"block","style":"normal","_key":"cba7ec021871","markDefs":[]},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Study Strengths","_key":"e7b92274f3770"}],"_type":"block","style":"normal","_key":"ee7f97e230ef"},{"_type":"block","style":"normal","_key":"e3989420e3a1","markDefs":[],"children":[{"_type":"span","marks":[],"text":"1. This review included 25 studies and 860 participants.","_key":"41f586fa31b50"}]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"2. Only RCTs were included.","_key":"5d8d43efed160"}],"_type":"block","style":"normal","_key":"7f0626127b21"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"3. Trials included different rTMS coils, frequencies, motor thresholds, and anatomical locations.","_key":"439258ced4970"}],"_type":"block","style":"normal","_key":"18eac58de530"},{"_type":"block","style":"normal","_key":"dbc8a43454d7","markDefs":[],"children":[{"marks":[],"text":"4. There were no conflicts of interest for the authors.","_key":"eb9bd3d137fe0","_type":"span"}]},{"_type":"block","style":"normal","_key":"a9ab2d713138","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"143bc959b9290"}]},{"_key":"bdb9dfe50669","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Study Limitations","_key":"591cc0828a2f0"}],"_type":"block","style":"normal"},{"style":"normal","_key":"a3456ec4324c","markDefs":[],"children":[{"_type":"span","marks":[],"text":"1. The studies included only focused on acute treatment outcomes.","_key":"68cab9fcd22b0"}],"_type":"block"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"2. Statistical analysis did not correct for multiple comparisons.","_key":"a69ecb269a0c0"}],"_type":"block","style":"normal","_key":"5564852255f8"},{"_key":"ca95428eb679","markDefs":[],"children":[{"_type":"span","marks":[],"text":"3. Limited patient characteristics were available for extraction across trials, such as whether exposure and response therapy had been trialed.","_key":"174b455c00800"}],"_type":"block","style":"normal"},{"style":"normal","_key":"aeab51476381","markDefs":[],"children":[{"_key":"d71b26b10e6f0","_type":"span","marks":[],"text":"4. Publication bias was present."}],"_type":"block"},{"_type":"block","style":"normal","_key":"b4436e517e61","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"2de6d4bf21ed0"}]},{"_type":"block","style":"normal","_key":"0bba84d479aa","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Conclusions","_key":"5deba80fdece0"}]},{"children":[{"text":"This meta-analysis found that rTMS had a moderate therapeutic effect for the treatment of OCD. In addition, greater improvement in depression severity, longer TMS sessions, and fewer number of TMS sessions were moderators associated with greater improvement in OCD severity.","_key":"1c6b83747fc30","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"ecf65d121661","markDefs":[]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"80b3132b67790"}],"_type":"block","style":"normal","_key":"657e07e93cda"},{"_type":"block","style":"normal","_key":"4357b9c51e84","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Practical Applications","_key":"89ad068c44b50"}]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"OCD is a heterogenous disorder that can be debilitating for patients. This study shows that rTMS has moderate therapeutic effects on OCD severity.","_key":"04289f1555c50"}],"_type":"block","style":"normal","_key":"7da82891fb7e"},{"_type":"block","style":"normal","_key":"f891977db9a1","markDefs":[],"children":[{"marks":[],"text":"","_key":"a94404cf2fe70","_type":"span"}]},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Bottom Line","_key":"aee38074d46b0"}],"_type":"block","style":"normal","_key":"755657fc7115"},{"children":[{"_type":"span","marks":[],"text":"Clinicians should consider rTMS as an intervention to alleviate OCD symptoms, especially in those who have failed other treatments or those with comorbid depression.","_key":"e51f954da3c20"}],"_type":"block","style":"normal","_key":"bbc8eb2cb3b2","markDefs":[]},{"_type":"block","style":"normal","_key":"110fca7774c2","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"86267235b37a0"}]},{"_type":"block","style":"normal","_key":"0ae7eff1ec6c","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Dr Sung ","_key":"82fc7e49d63c0"},{"_type":"span","marks":["em"],"text":"is a psychiatry second year resident at Creighton University in Omaha, Nebraska.","_key":"82fc7e49d63c1"},{"_type":"span","marks":["strong"],"text":" Dr Eilers ","_key":"82fc7e49d63c2"},{"text":"is a fourth-year psychiatry resident at Creighton University in Omaha, Nebraska.","_key":"82fc7e49d63c3","_type":"span","marks":["em"]},{"marks":[],"text":" ","_key":"82fc7e49d63c4","_type":"span"},{"_key":"82fc7e49d63c5","_type":"span","marks":["strong"],"text":"Dr Schuster"},{"text":" ","_key":"82fc7e49d63c6","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"is a fourth-year psychiatry resident at Creighton University in Omaha, Nebraska.","_key":"82fc7e49d63c7"},{"_key":"82fc7e49d63c8","_type":"span","marks":[],"text":" "},{"text":"Dr Mullen","_key":"82fc7e49d63c9","_type":"span","marks":["strong"]},{"text":" ","_key":"82fc7e49d63c10","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"is an assistant professor of Psychiatry at Saint Louis University School of Medicine.","_key":"82fc7e49d63c11"},{"_type":"span","marks":[],"text":" ","_key":"82fc7e49d63c12"},{"text":"Dr Tampi ","_key":"82fc7e49d63c13","_type":"span","marks":["strong"]},{"text":"is professor and Chairman of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives (CHI) Health Behavioral Health Services. 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Symptoms include urticaria, gastrointestinal distress, and anaphylaxis.\n\n• Diagnosis is challenging due to the lack of standardized testing and the rarity of the condition, often leading to delayed identification.\n\n• AGS impacts mental health, causing dietary restrictions, social isolation, and financial stress, necessitating interdisciplinary care.\n\n• Climate change may increase AGS prevalence by expanding the range of lone star ticks, complicating management and diagnosis.\n\n• Effective management involves allergists, psychiatrists, and pharmacists to address both physical and psychological aspects of AGS.","published":"2024-10-22T16:00:00.000Z","_rev":"yfV8wp4eUDtgm1JJ6avfWu","body":[{"disableTextWrap":false,"alt":"tick","_key":"d4c284b59b6e","asset":{"_type":"reference","_ref":"image-4d334999fcf64afe7e821bce3a9230aae30a5918-5998x3999-jpg"},"disableLightBox":true,"imgcaption":[{"style":"normal","_key":"d790799c6b8b","markDefs":[],"children":[{"_type":"span","marks":[],"text":"ondreicka/AdobeStock","_key":"bf8c44d2eaf30"}],"_type":"block"}],"alignment":"left","_type":"figure","widthP":50},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Alpha-gal syndrome (AGS) arises via delayed allergic (IgE) reaction to galactose-alpha-1,3–galactose (alpha-gal), which is an oligosaccharide molecule found in mammalian products such as meat, milk, and mammalian byproducts, including medications and medical devices.","_key":"e2fc311168c00"},{"_type":"span","marks":["superscript"],"text":"1","_key":"77e8581c52bc"},{"_type":"span","marks":[],"text":" Bites from the lone star tick are the most common cause of AGS, sensitizing individuals to the alpha-gal molecule on subsequent exposure to mammalian products; however, globally there may be other explanatory vectors. Symptoms present hours to days after exposure and include urticaria, gastrointestinal distress, angioedema, and possibly anaphylaxis, with significant variability among individuals. The psychological impacts of AGS are broad, and this vector-borne disease may cause patients to seek or be referred to psychiatric care.","_key":"e53d8b434bb7"}],"_type":"block","style":"normal","_key":"4afef286faa0"},{"style":"normal","_key":"d99a297fa557","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"f9e481c308a60"}],"_type":"block"},{"_type":"block","style":"normal","_key":"5a890d1283b4","markDefs":[],"children":[{"marks":["strong"],"text":"Case Example","_key":"ca1de9a3248c0","_type":"span"}]},{"children":[{"_key":"3c8316ddd4660","_type":"span","marks":[],"text":"“Ben” is an 11-year-old boy referred to the psychiatric clinic by his pediatrician after experiencing years of gastrointestinal symptoms, including nausea, diarrhea, and episodic stomach pains. Workup including upper gastrointestinal endoscopy and colonoscopy was unrevealing and conservative management has failed. He has been missing school due to his symptoms and the school district is concerned about truancy. He lives in rural Missouri with his family who manages a tight budget, saving money by purchasing half of a steer or a whole hog at a time to feed the family. Ben is a picky eater, preferring meat with most meals."}],"_type":"block","style":"normal","_key":"42d89574bc61","markDefs":[]},{"_type":"block","style":"normal","_key":"d3e46cfaea56","markDefs":[],"children":[{"text":"","_key":"a581f0ed38490","_type":"span","marks":[]}]},{"_key":"874a0dcb082d","markDefs":[],"children":[{"_key":"7c557dad5d8d0","_type":"span","marks":["strong"],"text":"Psychiatric Concerns"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"AGS lies at the intersection of physical and mental health. This case emphasizes some of the principal psychiatric concerns originating from AGS. This syndrome, which can arrive unannounced, may be triggered by foods and medications the patient has consumed their entire life. Suddenly, individuals with AGS may be limited in the types of food they eat, which can ostracize them from their family and culture, as well as place undue financial and administrative stressors on the individual and family. Of the top 20 pharmaceutical companies, only 60% were able to accurately provide information on whether there were animal products in their formulation. Of those respondents, many required repeated calls and prompting to coax out this information.","_key":"9551113830620"},{"_type":"span","marks":["superscript"],"text":"2 ","_key":"744a36f9d3bf"},{"_type":"span","marks":[],"text":"Climate change applies additional pressure onto mental health concerns, from increased AGS range to changes in food choice/availability, and even potential disruptions to supply chains for medication.","_key":"842be518b3f7"}],"_type":"block","style":"normal","_key":"8ee4e996549e"},{"style":"normal","_key":"034688161565","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"8639a3e38abb0"}],"_type":"block"},{"markDefs":[],"children":[{"_key":"c0483753cd1b0","_type":"span","marks":[],"text":"The prevalence of AGS is greatest in the United States, where the link between tick bites and AGS was initially identified by an Australian group in 2009. Subsequently, an American group discovered that cetuximab reactions overlapped with Rocky Mountain Spotted fever, a Rickettsial infection transmitted by the lone star tick (Amblyomma americanum)."},{"_type":"span","marks":["superscript"],"text":"1","_key":"33261792e545"},{"_type":"span","marks":[],"text":" Recent data showed 18,885 positive tests in the United States in 2021, rising from 13,371 in 2017 with geographic preference for the Midwest, Southern, and Mid-Atlantic regions, which not so coincidentally mirrors the distribution of the lone star tick.","_key":"e31024bb0d6c"},{"_type":"span","marks":["superscript"],"text":"3","_key":"85bca20fcb02"},{"_type":"span","marks":[],"text":" Without established surveillance for AGS, its exact prevalence is largely unknown. A survey from the same Centers for Disease Control and Prevention (CDC) weekly morbidity and mortality report highlights the lack of provider knowledge on AGS and its underdiagnosis.","_key":"8599def10961"},{"_type":"span","marks":["superscript"],"text":"4","_key":"8211256330fe"}],"_type":"block","style":"normal","_key":"25ab86fab149"},{"markDefs":[],"children":[{"marks":[],"text":"","_key":"52468ef0c6650","_type":"span"}],"_type":"block","style":"normal","_key":"e6e3f871d64f"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Changing climates alter regions suitable for ticks, and the range of AGS will likely follow such migrations.1 The northward expansion of lone star ticks and AGS is amplified by the acceleration of the tick life cycle from climate impacts. One study identified that milder northeastern winters facilitated increased survival of the lone star tick, where patients with AGS may appear in the clinic of unsuspecting clinicians.5","_key":"534a792fb45f0"}],"_type":"block","style":"normal","_key":"db781f6bde69"},{"style":"normal","_key":"2d00dc4ae40b","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"4e67beec185a0"}],"_type":"block"},{"markDefs":[],"children":[{"_key":"6fe0c939ad000","_type":"span","marks":["strong"],"text":"Diagnosis"}],"_type":"block","style":"normal","_key":"5599e8c0e152"},{"children":[{"marks":[],"text":"This condition poses a challenge for many physicians. There is no consensus diagnostic threshold of IgE to alpha-gal molecules, as testing itself is relatively new. Likewise, there are no curative treatments for this condition, which can be life-threatening.","_key":"69786a7dfcc90","_type":"span"},{"_type":"span","marks":["superscript"],"text":"1,4","_key":"17d88e251d9b"},{"_type":"span","marks":[],"text":" A 28-person survey from 2016 found an average time to diagnosis of 7 years, requiring repeat visits, workups, and independent research, with roughly 3 out of 4 patients self-diagnosing their unique presentation of this presently rare condition.","_key":"0a16e27e0c01"},{"_type":"span","marks":["superscript"],"text":"6","_key":"954d0fa84ca6"},{"marks":[],"text":" This increased time to diagnosis for a chronic condition with a risk of repeated symptom flares can have an immense psychological impact. Core aspects of people’s lives now have the potential to induce a reaction, making you think twice about pets, eating out, apparel choices (leather), and personal care products. Unlabeled food and drug products pose a hazard to patients seeking to manage their condition chronically. Products containing alpha-gal moieties are ubiquitous—even when excluding red meat. Currently, the US Food and Drug Administration does not require labeling products this way, which is an added daily stressor for patients, seeding doubt, anxiety, and isolation even after a drawn-out diagnosis. The costs for health care, prescriptions including EpiPens, social impacts, and ambiguity when seeking information about the syndrome compound. The distress felt by patients and families navigating AGS can be immense. Supportive communities and resources with appropriate therapy can help manage this condition.","_key":"b203efbb8dd5","_type":"span"}],"_type":"block","style":"normal","_key":"0a66578f3872","markDefs":[]},{"_key":"f16bc9bd24bd","markDefs":[],"children":[{"_key":"b163c44ff9100","_type":"span","marks":[],"text":""}],"_type":"block","style":"normal"},{"_type":"block","style":"normal","_key":"26ee1d09128c","markDefs":[],"children":[{"_type":"span","marks":[],"text":"For the practicing psychiatrist, there are obstacles to medical management for many psychiatric conditions. Gelatin capsules and animal-derived stabilizers, including lactose and other mammalian products, frequently occupy selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, 1st and 2nd generation antipsychotics, mood stabilizers (lithium, anticonvulsants), and anxiolytic (benzodiazepine and nonbenzodiazepine) medications. These were found just from a cursory glance online, because not even the CDC has a comprehensive list, deferring to the patient’s provider.","_key":"6a2663c2fd720"},{"_key":"7209baa560a0","_type":"span","marks":["superscript"],"text":"7-10"},{"_type":"span","marks":[],"text":" A column from the American Academy of Allergy, Asthma, and Immunology takes a similar stance to the CDC, where a blanket response defers patient risk, treatment consent, and care decisions to the institution, as there is no standardized reporting of product ingredients.","_key":"d4a4ee5a1493"},{"_type":"span","marks":["superscript"],"text":"11","_key":"75e818277f9e"},{"_type":"span","marks":[],"text":" This significantly impinges on the therapeutic latitude available for patients with AGS and psychiatric concerns, with elevated risks in acute management. Pharmacies themselves may only receive information from the manufacturer, who may be rather lax in their reporting. A case report on initiating psychotropic treatment in the setting of AGS emphasized the necessity of interdisciplinary care for initiating appropriate treatment, and that generic manufacturers may use different ingredients, so generalizing alpha-gal content from one formulation to another is not possible.","_key":"007f48955e0a"},{"_key":"7795510a69ce","_type":"span","marks":["superscript"],"text":"7"},{"_type":"span","marks":[],"text":" For some patients, multiple trials of medication may be needed for effective treatment. Chronic illness is related to psychiatric comorbidities such as depression and anxiety.","_key":"182dcc36152f"},{"_type":"span","marks":["superscript"],"text":"12","_key":"c0ebe67ada21"},{"_type":"span","marks":[],"text":" Addressing mental health alongside organic disease should be pursued in patients with AGS if applicable, as this diagnosis can be life-altering.","_key":"e27e31cc1a3d"}]},{"_key":"4ced177c21f4","markDefs":[],"children":[{"_key":"2a0ff53db8eb0","_type":"span","marks":[],"text":""}],"_type":"block","style":"normal"},{"children":[{"_type":"span","marks":[],"text":"Challenges in managing patients with AGS have been documented across many specialties. In the emergency department, AGS should be on the differential for anaphylaxis of unknown origin, as well as an adverse drug reaction in an unknown patient.","_key":"c507bf5a8bcf0"},{"_type":"span","marks":["superscript"],"text":"13","_key":"ecf7dead1967"},{"_type":"span","marks":[],"text":" In the operative setting, porcine valves, certain types of sutures, and common drugs including heparin and oxycodone are off-limits.","_key":"fb9e68fc8dd5"},{"_type":"span","marks":["superscript"],"text":"14","_key":"1b81a57dddaa"},{"_type":"span","marks":[],"text":" Once outpatient, compounding pharmacies with custom medication formulations can provide an answer to the uncertainty of living with AGS, but these are often more expensive than traditional pharmacies. Rural patients may not have access to this, or other options if there are no pharmacies in their area with the available prescriptions to turn to when first-line meds contain the alpha-gal epitope. Prescription medications are something individuals living with AGS become hyperaware of, as common entities can cause flares in symptoms. In a recent survey, half of patients with AGS have had an anaphylactic reaction to a health product.","_key":"f55985f62d27"},{"_type":"span","marks":["superscript"],"text":"8","_key":"90455d642d80"},{"_type":"span","marks":[],"text":" ","_key":"ecdea9ab7859"}],"_type":"block","style":"normal","_key":"2b69ccd692c6","markDefs":[]},{"children":[{"marks":[],"text":"","_key":"a7d632936f750","_type":"span"}],"_type":"block","style":"normal","_key":"a663545e9b82","markDefs":[]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Treatment of AGS involves avoiding allergens and having rescue medications available if a reaction occurs.","_key":"4ce16a225e570"},{"_type":"span","marks":["superscript"],"text":"15","_key":"80728d891b61"},{"_type":"span","marks":[],"text":" On first presentation, if suspicious for AGS physicians should encourage mammalian meat and product avoidance, provide an EpiPen and antihistamine prescription, and refer the patient to an allergist.","_key":"b7c2ce9ed69c"},{"marks":["superscript"],"text":"13","_key":"69f543f4065b","_type":"span"},{"_type":"span","marks":[],"text":" Once diagnosed, significant patient education surrounding lifestyle changes is needed to help avoid reactions, though complete avoidance is next to impossible. After reviewing the broad swath of everyday products where we encounter alpha-gal, education on label reading can help mitigate encountering the antigen. Advocating for more information about medical treatments like vaccines and prescriptions is key to reducing iatrogenic risks, and tick avoidance remains essential in preventing disease onset or worsening. Psychiatrists have an important role in the interdisciplinary treatment of patients with AGS to address psychological sequelae. Collaboration with pharmacists and registered dietitians helps in providing comprehensive care to people with AGS, too.","_key":"e0f5f446d26b"},{"_type":"span","marks":["superscript"],"text":"15","_key":"c3f493b30d0a"},{"_type":"span","marks":[],"text":" As with many of the rarer chronic diseases receiving insufficient attention from research, there seems to be a robust, supportive online community for those living with AGS. With accelerating climate change, the reality of AGS becoming more prevalent and significant for practicing physicians including psychiatrists, provides another incentive to allocate more energy towards the diagnosis and management of AGS. Through gene editing, an alpha-gal free porcine products are on the horizon, but increasing awareness on the part of physicians to identify and adequately treat people with AGS would yield substantial benefit to those unfortunate enough to be sensitized to the oligosaccharide.","_key":"65860d1ace65"}],"_type":"block","style":"normal","_key":"105c6a841ee2"},{"_key":"0d43acdc779f","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"4b6841a22e5a0"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_key":"15986115b0660","_type":"span","marks":["strong"],"text":"Concluding Thoughts"}],"_type":"block","style":"normal","_key":"fa6443acdb2f"},{"_type":"block","style":"normal","_key":"84421899e092","markDefs":[],"children":[{"_key":"5fe5b1a69d430","_type":"span","marks":[],"text":"AGS is a chronic disease affecting an increasing number of Americans and is difficult for physicians to identify. Its physical and psychological impact on patients is significant, and providers should have a plan in place in their practice for addressing the needs of these patients. Mandated reporting of all drug ingredients would go a long way in managing their care and alleviating stress for both patients and their providers. Future efforts to evaluate the burden of this disease, clear guidelines for AGS diagnosis, and improved labeling would have substantial benefits to those learning to live with alpha-gal."}]},{"_key":"6b9904a7c1c9","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"6d2cb61f3f640"}],"_type":"block","style":"normal"},{"children":[{"_key":"4428d062ea5b0","_type":"span","marks":["strong"],"text":"List of Resources for Patients and Providers"}],"_type":"block","style":"normal","_key":"563785eb05e8","markDefs":[]},{"markDefs":[{"_type":"link","href":"https://alphagalinformation.org/","_key":"29424b7fc5c6","blank":true}],"children":[{"_type":"span","marks":["29424b7fc5c6"],"text":"https://alphagalinformation.org/","_key":"b3f1c558d7670"}],"level":1,"_type":"block","style":"normal","_key":"fe058bcf379d","listItem":"bullet"},{"_type":"block","style":"normal","_key":"47aee12221bd","listItem":"bullet","markDefs":[{"nofollow":true,"blank":true,"_type":"link","href":"https://www.aaaai.org/allergist-resources/ask-the-expert/answers/2023/alpha-gal","_key":"c8950079b449"}],"children":[{"text":"https://www.aaaai.org/allergist-resources/ask-the-expert/answers/2023/alpha-gal","_key":"9611b5be5b470","_type":"span","marks":["c8950079b449"]}],"level":1},{"markDefs":[{"nofollow":true,"blank":true,"_type":"link","href":"https://www.twoalphagals.com/blog/psychological-impacts","_key":"c63ffdef68fc"}],"children":[{"text":"https://www.twoalphagals.com/blog/psychological-impacts","_key":"5211e11b9a2d0","_type":"span","marks":["c63ffdef68fc"]}],"level":1,"_type":"block","style":"normal","_key":"9acc93d5bc0f","listItem":"bullet"},{"children":[{"marks":["9fe0589279f1"],"text":"https://tickedoffmastcells.org/?p=181","_key":"adcc8fc5a32a0","_type":"span"}],"level":1,"_type":"block","style":"normal","_key":"5fce3ec7828e","listItem":"bullet","markDefs":[{"blank":true,"_type":"link","href":"https://tickedoffmastcells.org/?p=181","_key":"9fe0589279f1"}]},{"_type":"block","style":"normal","_key":"2df59ce2f29a","markDefs":[],"children":[{"text":"","_key":"6db5fd9260740","_type":"span","marks":[]}]},{"_type":"block","style":"normal","_key":"34afbb545661","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Mr Babineau","_key":"5137e130d91e0"},{"text":" is a medical student at Virginia Commonwealth University School of Medicine.","_key":"5137e130d91e1","_type":"span","marks":["em"]},{"_type":"span","marks":["strong"],"text":" Dr Daily ","_key":"5137e130d91e2"},{"_key":"5137e130d91e3","_type":"span","marks":["em"],"text":"is adjunct faculty at the Oklahoma State University School of Osteopathic Medicine at The Cherokee Nation."}]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"62e571d0e3e40"}],"_type":"block","style":"normal","_key":"03fec2e8aee6"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"References","_key":"3cd8d9a429b30"}],"_type":"block","style":"normal","_key":"698ff2433a57"},{"markDefs":[{"_key":"193b3b722a33","blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/33529984/"}],"children":[{"_type":"span","marks":[],"text":"1. 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","_key":"0280da0b4af13"},{"_type":"span","marks":["em"],"text":"Insects","_key":"0280da0b4af14"},{"_type":"span","marks":[],"text":". 2019;11(1):13.","_key":"0280da0b4af15"}],"_type":"block","style":"normal","_key":"82cfb8255ce2"},{"markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/28447914/","_key":"1a65756f8ac1"}],"children":[{"_type":"span","marks":[],"text":"6. Flaherty MG, Kaplan SJ, Jerath MR. ","_key":"a16f84c912390"},{"_key":"a16f84c912391","_type":"span","marks":["1a65756f8ac1"],"text":"Diagnosis of life-threatening alpha-gal food allergy appears to be patient driven."},{"_type":"span","marks":[],"text":" ","_key":"6292175303ac"},{"marks":["em"],"text":"J Prim Care Community Health","_key":"a16f84c912392","_type":"span"},{"_type":"span","marks":[],"text":". 2017;8(4):345-348.","_key":"a16f84c912393"}],"_type":"block","style":"normal","_key":"e8b49167fa56"},{"style":"normal","_key":"1bd092ced1cf","markDefs":[{"blank":true,"_type":"link","href":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9512307/","_key":"cfb6af3a3f7e"}],"children":[{"_type":"span","marks":[],"text":"7. Narlesky MR, Palting A, Sukpraprut-Braaten S, et al. ","_key":"33550e8344e10"},{"_key":"33550e8344e11","_type":"span","marks":["cfb6af3a3f7e"],"text":"Initiating psychotropic treatment in a patient with alpha-gal syndrome. 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","_key":"93896808993c1"},{"_type":"span","marks":["em"],"text":"Br J Psychiatry","_key":"93896808993c2"},{"text":". 2001;178(2):184-184.","_key":"93896808993c3","_type":"span","marks":[]}],"_type":"block"},{"_type":"block","style":"normal","_key":"d50ac0cde3aa","markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/12091220/","_key":"33377b91a01a"}],"children":[{"_key":"006d29637a350","_type":"span","marks":[],"text":"10. Sauer J, Howard R. "},{"marks":["33377b91a01a"],"text":"The beef with atypical antipsychotics. ","_key":"006d29637a351","_type":"span"},{"_type":"span","marks":["em"],"text":"Am J Psychiatry","_key":"006d29637a352"},{"marks":[],"text":". 2002;159(7):1249.","_key":"006d29637a353","_type":"span"}]},{"_key":"4c0b70a3360d","markDefs":[{"blank":true,"_type":"link","href":"https://www.aaaai.org/allergist-resources/ask-the-expert/answers/2023/alpha-gal","_key":"0301e2c052a3"}],"children":[{"_type":"span","marks":[],"text":"11. Alpha-gal and medications. American Academy of Allergy, Asthma, and Immunology. January 10, 2023. Accessed October 4, 2024. ","_key":"75f4f9a7770d0"},{"_type":"span","marks":["0301e2c052a3"],"text":"https://www.aaaai.org/allergist-resources/ask-the-expert/answers/2023/alpha-gal","_key":"75f4f9a7770d1"}],"_type":"block","style":"normal"},{"markDefs":[{"_key":"21b106f720a4","blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/28628766/"}],"children":[{"marks":[],"text":"12. Read JR, Sharpe L, Modini M, Dear BF. ","_key":"9fec0a80158d0","_type":"span"},{"_type":"span","marks":["21b106f720a4"],"text":"Multimorbidity and depression: a systematic review and meta-analysis. 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","_key":"4108666330b31"},{"_key":"4108666330b32","_type":"span","marks":["em"],"text":"Ann Emerg Med"},{"_type":"span","marks":[],"text":". 2024;83(4):380-384.","_key":"4108666330b33"}],"_type":"block","style":"normal","_key":"413f052db4a4"},{"_type":"block","style":"normal","_key":"17b9a0cef267","markDefs":[{"href":"https://pubmed.ncbi.nlm.nih.gov/29847378/","_key":"c5434eabef0f","blank":true,"_type":"link"}],"children":[{"text":"14. Dunkman WJ, Rycek W, Manning MW. ","_key":"815b583e89880","_type":"span","marks":[]},{"_type":"span","marks":["c5434eabef0f"],"text":"What does a red meat allergy have to do with anesthesia? Perioperative management of alpha-gal syndrome. 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","_key":"70135ab7aefd1"},{"_type":"span","marks":["em"],"text":"Expert Rev Clin Immunol","_key":"70135ab7aefd2"},{"_type":"span","marks":[],"text":". 2020;16(7):667-677.","_key":"70135ab7aefd3"}],"_type":"block","style":"normal","_key":"f5643f78caf6"},{"_type":"block","style":"normal","_key":"2c02fb2f233e","markDefs":[{"blank":true,"_type":"link","href":"https://www.revivicor.com/technologies","_key":"bbd5801a3222"}],"children":[{"_type":"span","marks":[],"text":"16. Technologies. Revivicor. Accessed October 4, 2024. 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Griesbach, PhD","_createdAt":"2024-09-30T13:44:12Z","_rev":"CHUkpLRK3ESqW5j2unhLxY","_type":"author","_id":"d81c7c60-6652-4668-9313-0fc1d283462b","biography":[{"markDefs":[],"children":[{"text":"Dr Griesbach ","_key":"5f9021a02a160","_type":"span","marks":["strong"]},{"_type":"span","marks":["em"],"text":"is the national director of clinical research for the Centre of Neuro Skills. She currently holds an appointment at the Neurosurgery Department, Geffen School of Medicine, UCLA, and is past president and chair for the National Neurotrauma Society.","_key":"5f9021a02a161"}],"_type":"block","style":"normal","_key":"df5c4eefa0b2"}],"_updatedAt":"2024-09-30T13:44:12Z"}],"_type":"article","authors":[{"displayName":"Grace S. Griesbach, PhD","url":"grace-s-griesbach-phd"}],"factCheckAuthorMapping":null,"documentGroup":null,"summary":"A traumatic brain injury sustained earlier in adult life is likely to interact with normal aging processes. Learn more here. ","thumbnail":{"_type":"mainImage","alt":"aging brain","caption":"Ramunas/AdobeStock","asset":{"_type":"reference","_ref":"image-c530ea8991dc158368cf0165173630a0e66cdf08-5376x3584-jpg"}},"published":"2024-10-01T14:00:00.000Z","_id":"abd80119-fed6-4089-bf72-0a1a7be185e1","body":[{"imgcaption":[{"style":"normal","_key":"e03465c8d151","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Ramunas/AdobeStock","_key":"be62b1d476270"}],"_type":"block"}],"_key":"f3b1412f25ec","widthP":50,"alignment":"left","alt":"aging brain","disableLightBox":true,"_type":"figure","asset":{"_ref":"image-c530ea8991dc158368cf0165173630a0e66cdf08-5376x3584-jpg","_type":"reference"},"disableTextWrap":false},{"_type":"block","style":"normal","_key":"2e80073ac3f4","markDefs":[],"children":[{"_type":"span","marks":[],"text":"A significant number of individuals who sustained a traumatic brain injury (TBI) during early and mid-adulthood are living with disabilities within the US. When considering the impact of TBI over the years, it becomes clear that the effects of TBI may become more evident as aging takes place. This is because a TBI sustained earlier in adult life is likely to interact with normal aging processes.","_key":"0fc0b62dbe490"}]},{"_key":"c0941f5acc99","markDefs":[],"children":[{"marks":[],"text":"","_key":"208ea6c9429e0","_type":"span"}],"_type":"block","style":"normal"},{"_type":"block","style":"normal","_key":"39596641a051","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"TBI Can Exacerbate Age Related Changes","_key":"46275b42154b0"}]},{"style":"normal","_key":"c6132477b2d5","markDefs":[],"children":[{"_type":"span","marks":[],"text":"As the brain ages, there is naturally occurring atrophy of cerebral tissue including structures such as the hippocampus, which plays a significant role in memory and cognitive processing. The hippocampus is frequently impacted by TBI, thus increasing the likelihood of developing memory impairments as one ages.","_key":"219b6164bb5a0"},{"_key":"16fa957a1345","_type":"span","marks":["superscript"],"text":"1"},{"_type":"span","marks":[],"text":" Interestingly, a large hippocampal volume appears to offer protection from dementia.","_key":"dbe187f848e0"},{"_type":"span","marks":["superscript"],"text":"2","_key":"9ff1fabf1a98"},{"_type":"span","marks":[],"text":" A decline in white matter volume is also observed during normal aging.","_key":"ef6014575e3e"},{"_type":"span","marks":["superscript"],"text":"3","_key":"5ec622ae380e"},{"_type":"span","marks":[],"text":" White matter is mainly composed of myelinated axons and decreases in myelin density will hinder the capacity to transmit signals across the nervous system. Following TBI, these changes can occur at an accelerated rate compared with normal aging.","_key":"a4a51262d38d"},{"_type":"span","marks":["superscript"],"text":"4","_key":"15aea21bacec"}],"_type":"block"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"899f708c19890"}],"_type":"block","style":"normal","_key":"8bfb59bf72ab"},{"style":"normal","_key":"06958899648b","markDefs":[],"children":[{"_key":"a3885508d4da0","_type":"span","marks":[],"text":"The natural process of remyelination is also altered as the brain ages."},{"_type":"span","marks":["superscript"],"text":"3","_key":"1491cc52497e"},{"text":" Oligodendrocyte loss arising from the original injury may predispose the brain to decreased remyelination capacity.","_key":"657a3512df87","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"5","_key":"8abba1cec22d"},{"_type":"span","marks":[],"text":" Oligodendrocytes are critical in maintaining the myelin sheath. White matter deterioration can manifest as cognitive deficits by affecting the efficiency of connectivity.","_key":"b0e511e2c13a"},{"_type":"span","marks":["superscript"],"text":"6,7","_key":"1393cfbf5891"},{"_type":"span","marks":[],"text":" Studies utilizing functional imaging have shown that there is a change in network connections during normal aging that is exacerbated with brain injury.","_key":"65775570bcee"},{"text":"8","_key":"423e002c187e","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" Primary pathways that were established during development may be affected by injury and replaced with redundant pathways that, while enabling function, are not as effective as the originals and will render the brain more vulnerable to the effects of aging.","_key":"fe0801d97674"},{"_key":"cc554d91844e","_type":"span","marks":["superscript"],"text":"9"},{"marks":[],"text":" Given that even mild TBI can have an impact on connectivity, it is not surprising that the risk of dementia is increased with repeated injury.","_key":"d25c855f9fb8","_type":"span"},{"_type":"span","marks":["superscript"],"text":"10,11","_key":"08377f772894"}],"_type":"block"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"97b5a7e0c4910"}],"_type":"block","style":"normal","_key":"a738f94ae387"},{"_type":"block","style":"normal","_key":"4afced5422b0","markDefs":[],"children":[{"text":"Normal aging also has an impact on neuroendocrine and immunological systems that can contribute to age-related cognitive decline.","_key":"35a42050c2a30","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"12,13","_key":"dce4290814f2"},{"_type":"span","marks":[],"text":" Long lasting hormonal dysregulation is not uncommon in many patients after TBI and may well contribute to neurodegenerative processes across time.","_key":"b584ffd6f37b"},{"_type":"span","marks":["superscript"],"text":"10,11","_key":"d371f203cffc"},{"_type":"span","marks":[],"text":" Particularly noteworthy is the impact that hormones have on emotional health and cognition.","_key":"3a1ddb847c6f"},{"_type":"span","marks":["superscript"],"text":"14","_key":"09fff016ad79"},{"text":" Hormones also are known to have immunomodulatory effects. Microglia, the brain’s primary immune cells, are known to be especially vulnerable to the effects of age.","_key":"8ca2211fb141","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"15","_key":"e164d068f7cc"},{"marks":[],"text":" Age related immune changes are also likely to be exacerbated by a history of TBI. 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Syphilitic infection rates are on the rise in the US, and more cases of antibiotic resistance are reported. Of interest for this series is the reminder that a thorough medical workup is necessary before symptoms are labeled as being of primary psychiatric origin.","_key":"3bb4c039c1ff2","_type":"span"}],"_type":"block","style":"normal","_key":"c898d958d52a","markDefs":[]},{"children":[{"marks":[],"text":"","_key":"c9eafb410e670","_type":"span"}],"_type":"block","style":"normal","_key":"ae94d1566e20","markDefs":[]},{"children":[{"_type":"span","marks":["strong"],"text":"Case Vignette","_key":"7b7fb8a413c00"}],"_type":"block","style":"normal","_key":"81b0499ee173","markDefs":[]},{"style":"normal","_key":"4adae98b6337","markDefs":[],"children":[{"text":"“Ms Kate” is a 45-year-old woman with a history of hypertension, polysubstance use, and no past psychiatric history of psychotic disorder, who was brought to the ED by emergency medical services after exhibiting bizarre behavior at her apartment. She called 911 to report dead bodies in her neighbor's apartment, but when police arrived, they found nothing unusual except Ms Kate, an irascible 911 caller complaining about the tracker in her ear, alleged dead bodies in the building, and that her husband was going to kill her. In the ED, Ms Kate is unable to participate in an interview and demands that you “take the tracker out of my ear and discharge me.” She is cooperative with labs but is displaying agitated behavior while interacting with staff and is observed to verbally respond to internal stimuli when left alone.","_key":"47f7bdb3335d0","_type":"span","marks":[]}],"_type":"block"},{"_type":"block","style":"normal","_key":"3f4d860a413f","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"cd3475adbd5c0"}]},{"children":[{"_key":"c71cbb6bd9120","_type":"span","marks":[],"text":"On physical exam, she has poor dentition, is disheveled, malodorous, and has dilated pupils that are unresponsive to light. Her disorganized and agitated behavior, along with her history, places her at an acutely elevated risk of self-harm. Despite wanting to leave, she is kept for observation and further work-up. Becoming increasingly angry, Ms Kate begins yelling, threatening staff, and throwing things. She is restrained and given 2 mg of lorazepam, 10 mg of haloperidol, and 50 mg of diphenhydramine intramuscularly. Despite this, she continues to be agitated and responds to internal stimuli for 2 hours even after receiving an additional dose of haloperidol. Only a dose of midazolam finally helps her sleep. Lab results show an elevated white count, a urine drug screen positive for amphetamines, and a positive rapid plasma reagin (RPR) test. Chart review reveals a prior positive RPR more than 10 years ago, and it was later confirmed that Ms Kate never got treatment."}],"_type":"block","style":"normal","_key":"88a11178d1c4","markDefs":[]},{"children":[{"_key":"b8c531d5693b0","_type":"span","marks":[],"text":""}],"_type":"block","style":"normal","_key":"e84e40075eae","markDefs":[]},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"What Is Neurosyphilis?","_key":"81c20531f36b0"}],"_type":"block","style":"normal","_key":"448d0c3e6cb5"},{"blank":true,"_type":"figure","_key":"16f3f8ddbcbd","asset":{"_ref":"image-b296abce5e001e45ed6f5859435b37731e80fede-1012x604-png","_type":"reference"},"disableLightBox":true,"alignment":"right","widthP":50,"disableTextWrap":false,"alt":"Table. Stages of Neurosyphilis","imgcaption":[{"children":[{"_type":"span","marks":["strong"],"text":"Table. ","_key":"8f781dcfda4a0"},{"_key":"8f781dcfda4a1","_type":"span","marks":[],"text":"Stages of Neurosyphilis"}],"_type":"block","style":"normal","_key":"ee18ef58dd47","markDefs":[]}]},{"style":"normal","_key":"8af77217d529","markDefs":[{"_key":"fdcb692f1788","nofollow":true,"blank":true,"_type":"link","href":"https://www.psychiatrictimes.com/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F0f5b5111593b42c10d482ca5327184bc2f0b03f9-990x606.png%3Ffit%3Dcrop%26auto%3Dformat\u0026w=2048\u0026q=75"}],"children":[{"marks":[],"text":"Syphilis is a sexually transmitted infection caused by the spirochete bacterium ","_key":"7e1e3d9ae4730","_type":"span"},{"_type":"span","marks":["em"],"text":"Treponema pallidum","_key":"7e1e3d9ae4731"},{"_type":"span","marks":[],"text":". Syphilis has been referred to as “the great imitator,” as it can present many different ways","_key":"7e1e3d9ae4732"},{"_key":"9f38bd748b5c","_type":"span","marks":["superscript"],"text":"1"},{"_key":"faf13b5d6102","_type":"span","marks":[],"text":"; however, there are certain key features that are commonly associated with each stage of infection. Primary infection presents as a chancre, a painless ulcer forming within 3 to 4 weeks of exposure."},{"_key":"613bfbe6ebd0","_type":"span","marks":["superscript"],"text":"2"},{"_key":"b4f89f59b738","_type":"span","marks":[],"text":" If untreated, it progresses to secondary syphilis, characterized by a diffuse, rough, red or brown rash that can spread to the whole body and can include the palms and soles."},{"text":"3","_key":"57dcfad6a5b3","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" Neurosyphilis occurs when the infection invades the blood-brain barrier and colonizes the cerebrospinal fluid (CSF).","_key":"406ae0089269"},{"_type":"span","marks":["superscript"],"text":"4","_key":"8c42de34c1f1"},{"_type":"span","marks":[],"text":" Neurosyphilis may occur during any stage of syphilis (","_key":"1a3f35c5eae2"},{"_type":"span","marks":["strong","fdcb692f1788"],"text":"Table","_key":"7e1e3d9ae4733"},{"text":"). Approximately 25% to 40% of patients experience neuroinvasion during the course of the disease with a majority of patients clearing the infection without developing symptoms of or requiring treatment for neurosyphilis.","_key":"7e1e3d9ae4734","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"1","_key":"2e28cd14b6b2"},{"_type":"span","marks":[],"text":" Late forms of syphilis causing general paresis and tabes dorsalis are considered a tertiary infection.","_key":"ed8e22da5826"},{"marks":["superscript"],"text":"5","_key":"6b39a87a1033","_type":"span"},{"text":" Essentially, the more mature the infection, the more pervasive the symptoms become. Latent syphilis occurs when primary and secondary stages of the disease’s presentation improve despite no treatment and patients become asymptomatic but still positive on serologic studies. Approximately one third of patient without treatment develop tertiary syphilis 20 to 40 years after primary infection, with cardiovascular and/or neurological involvement. Neurosyphilis is considered tertiary only when it develops during the late latent course of the disease, otherwise neurological symptoms may occur during any phase of infection including primary and secondary stages.","_key":"7892e25dfbf3","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"1","_key":"9e2672d029d8"}],"_type":"block"},{"markDefs":[],"children":[{"text":"","_key":"70809b8414b20","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"0425e374cc19"},{"style":"normal","_key":"16e2bf50e7f7","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Syphilis has been prevalent throughout modern society and has a long, complex history across the globe. Some hypotheses suggest that the endemic infection we know today, or something very closely related, first emerged in 7000 BC, and spread to Europe from South-Western Asia in 3000 BC.","_key":"7b0b07f3a31a0"},{"_type":"span","marks":["superscript"],"text":"6","_key":"86f51af48d64"},{"_type":"span","marks":[],"text":" Many argue that syphilis was brought to the Americas from Europe in 1492, but other studies suggest the existence of the organism prior to the arrival of colonialism.","_key":"d8955075a134"},{"_type":"span","marks":["superscript"],"text":"6","_key":"51e0e942aad9"},{"marks":[],"text":" Over the past 600 years or so, ","_key":"7582717be5c7","_type":"span"},{"text":"T. pallidum","_key":"7b0b07f3a31a1","_type":"span","marks":["em"]},{"_type":"span","marks":[],"text":" was not unique to any one group, as it has infected common folk, royalty, artists, philosophers, and more. Even Al Capone allegedly developed neurosyphilis in his later years.","_key":"7b0b07f3a31a2"},{"_type":"span","marks":["superscript"],"text":"6","_key":"005c62374a51"},{"_type":"span","marks":[],"text":" That said, the landscape radically changed with the widespread adoption of penicillin. Before antibiotics, asymptomatic neurosyphilis was developed in 25% to 35% of patients with early syphilis and 13.5% of those with tertiary syphilis.","_key":"cd983033d817"},{"_type":"span","marks":["superscript"],"text":"5","_key":"d0a6c8d4c0b7"},{"_type":"span","marks":[],"text":" Following World War II, and coinciding with the widespread availability of antibiotics, the incidence in the US and other industrial countries decreased from 76 per 100,000 people in 1945 to 4 per 100,000 almost a decade later.","_key":"1755f6763293"},{"_type":"span","marks":["superscript"],"text":"1","_key":"b366966ba0da"},{"_type":"span","marks":[],"text":" Today, it is most frequently diagnosed in those coinfected with HIV.","_key":"aec72231a4c7"},{"_type":"span","marks":["superscript"],"text":"7","_key":"f544f418d87c"}],"_type":"block"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"2fd7a4197d850"}],"_type":"block","style":"normal","_key":"952ec7760deb"},{"_key":"e0440fd1ea2d","markDefs":[],"children":[{"marks":[],"text":"When ","_key":"15c319056d900","_type":"span"},{"_key":"15c319056d901","_type":"span","marks":["em"],"text":"T. pallidum"},{"_type":"span","marks":[],"text":" colonizes the CSF and invades the central nervous system, patients can present with severe neurological complications.","_key":"15c319056d902"},{"_type":"span","marks":["superscript"],"text":"4","_key":"832d5ea02a7d"},{"marks":[],"text":" Symptoms can include headache, neck stiffness, sensory ataxia, bladder dysfunction, severe neuralgia, incontinence, and Argyll Robertson pupils—an appropriate pupillary constriction to accommodation, but not to light.","_key":"f42ca81c7fae","_type":"span"},{"_type":"span","marks":["superscript"],"text":"2","_key":"4711ba4cb68d"},{"_type":"span","marks":[],"text":" Severe neurosyphilis can lead to dementia and other neuropsychiatric symptoms years after the initial infection.","_key":"73d5f5dc6680"},{"_type":"span","marks":["superscript"],"text":"3","_key":"d833f545a4b7"},{"_key":"ba644d6ae2d8","_type":"span","marks":[],"text":" If untreated, neurosyphilis can lead to severe and permanent neurological damage, psychiatric symptoms, and cognitive decline. The prognosis of neurosyphilis largely depends on the stage of diagnosis and treatment."},{"_type":"span","marks":["superscript"],"text":"2,3,5","_key":"412b1b35913d"},{"_type":"span","marks":[],"text":" When treated too late, or not at all, it can have life-long complications.","_key":"ece53fb016de"}],"_type":"block","style":"normal"},{"_key":"f3cbf4cd59b7","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"0fb350442aea0"}],"_type":"block","style":"normal"},{"children":[{"_type":"span","marks":["strong"],"text":"Discussion","_key":"bcaf77ae20100"}],"_type":"block","style":"normal","_key":"654972864a60","markDefs":[]},{"markDefs":[],"children":[{"marks":[],"text":"Severe ","_key":"3899625df1780","_type":"span"},{"_type":"span","marks":["em"],"text":"T. pallidum","_key":"3899625df1781"},{"_type":"span","marks":[],"text":" infection may be asymptomatic for years but can present with a variety of nonspecific psychiatric symptoms.","_key":"3899625df1782"},{"text":"4","_key":"1293c53a2e25","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" Early symptoms may include personality changes and emotional instability, which can be confused with other psychiatric disorders.","_key":"a5f7aa37d95b"},{"text":"2,3","_key":"bde5baac21e3","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" Later symptoms may progress to depression, manic-like behavior, and even psychosis.","_key":"1fb5322988d5"},{"_type":"span","marks":["superscript"],"text":"3","_key":"c5c0d7bad9eb"},{"marks":[],"text":" To complicate matters further, those with histories of homelessness, sex work, or polysubstance abuse are at higher risk of contracting an initial infectionand should be tested for syphilis if presenting with bizarre behavior and psychosis.","_key":"1f5ff024d154","_type":"span"},{"_type":"span","marks":["superscript"],"text":"8","_key":"478e986f5550"}],"_type":"block","style":"normal","_key":"de1ee2d3e150"},{"style":"normal","_key":"47f36196f58c","markDefs":[],"children":[{"marks":[],"text":"","_key":"39f0d690005f0","_type":"span"}],"_type":"block"},{"_type":"block","style":"normal","_key":"e7d0057a3346","markDefs":[],"children":[{"text":"Polysubstance use and syphilis are common comorbidities, and treatment of one often needs to be considered in the context of the other. Substances like methamphetamine and phencyclidine (PCP) can exacerbate symptoms of neurosyphilis specifically, leading to severe neurotoxicity, cognitive decline, paranoia, anxiety, and psychosis.","_key":"9462b134570c0","_type":"span","marks":[]},{"text":"3,5,9,10","_key":"37839d8d1979","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" Drug-induced psychosis, such as that from PCP or methamphetamine, typically responds to antipsychotic medication, which blocks D2 dopamine receptors and reduces symptoms.","_key":"69b879f7dd04"},{"_type":"span","marks":["superscript"],"text":"11","_key":"9401c1aa47da"}]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"0117b00b97670"}],"_type":"block","style":"normal","_key":"89299cb9dd37"},{"_key":"9b7d71c4a5fb","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Psychosis secondary to neurosyphilis, on the other hand, is often caused by structural damage to the brain. Direct infection and subsequent inflammation, immune response, neuronal damage, and general encephalopathy may result in psychotic features that are not directly caused by a neurotransmitter imbalance, and therefore can be refractory to antipsychotic medication.","_key":"a4e6983bdd1f0"},{"_key":"5600ed48f742","_type":"span","marks":["superscript"],"text":"11,12"},{"text":" Overall, chronic infection and inflammation can lead to permanent CNS changes, making the brain less responsive to antipsychotic medications.","_key":"29d2e5ac0984","_type":"span","marks":[]},{"text":"12","_key":"45552d775138","_type":"span","marks":["superscript"]},{"_key":"985e04492df1","_type":"span","marks":[],"text":" These drugs may temporarily mitigate symptoms but will not treat the infection or significantly improve CNS damage."}],"_type":"block","style":"normal"},{"style":"normal","_key":"c89f053fbfbc","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"f5d8963169c50"}],"_type":"block"},{"_type":"block","style":"normal","_key":"30d2c1ab2c68","markDefs":[],"children":[{"text":"A standard psychiatric workup in the ED should include vital signs, a metabolic panel, a complete blood count, a urinalysis with microscopic analysis, a urine drug screen, a TSH with free T4, and a treponemal and/or nontreponemal tests. Serum nontreponemal tests include venereal disease research laboratory (VDRL) or rapid plasma reagin (RPR). The serum treponemal tests include fluorescent treponemal antibody absorption (FTA-ABS), ","_key":"51241040ed3b0","_type":"span","marks":[]},{"text":"T. Pallidum ","_key":"51241040ed3b1","_type":"span","marks":["em"]},{"_type":"span","marks":[],"text":"particle agglutination assay (TPPA), and ","_key":"51241040ed3b2"},{"marks":["em"],"text":"T. Pallidum","_key":"51241040ed3b3","_type":"span"},{"_key":"51241040ed3b4","_type":"span","marks":[],"text":" enzyme immunoassay (TP-EIA). Confirmation of active syphilis infection is very likely when tests from both categories are positive; however, nontreponemal tests may be nonreactive in late neurosyphilis."},{"marks":["superscript"],"text":"13","_key":"90bbd7f90749","_type":"span"},{"_type":"span","marks":[],"text":" For this reason, serum treponemal tests should always be performed as they should remain reactive for life regardless of treatment history. That said, if neurosyphilis is truly suspected, definitive diagnosis is confirmed with a lumbar puncture (LP) and CSF examination.","_key":"33d7dcbea53b"},{"_type":"span","marks":["superscript"],"text":"3,5","_key":"2edd6c498210"}]},{"markDefs":[],"children":[{"marks":[],"text":"","_key":"4dd060a3b1b60","_type":"span"}],"_type":"block","style":"normal","_key":"8b8efc090779"},{"children":[{"_type":"span","marks":[],"text":"Neurosyphilis can occur at any time during a ","_key":"e4f7123bad1c0"},{"_key":"e4f7123bad1c1","_type":"span","marks":["em"],"text":"T. Pallidum"},{"marks":[],"text":" infection, but its management requires significantly more comprehensive treatment than that for primary syphilis. In early syphilis, a since intramuscular dose of 2.4 million units of Penicillin G is sufficient for treatment.","_key":"e4f7123bad1c2","_type":"span"},{"marks":["superscript"],"text":"2,3,5,14","_key":"6ec1a08797c0","_type":"span"},{"marks":[],"text":" To achieve adequate CNS penetration, the treatment of neurosyphilis, on the other hand, consists of aqueous penicillin G 3 to 4 million units IV every four hours for 10 to 14 days.","_key":"cf9abb96bef7","_type":"span"},{"_type":"span","marks":["superscript"],"text":"3,5","_key":"5ec31df3daa0"},{"_type":"span","marks":[],"text":" Early treatment with penicillin can prevent disease spread, but chronic syphilis may be refractory to single doses and persist despite treatment. In some instances of late neurosyphilis, those with severe symptoms, an additional IM dose of 2.4 million units may be recommended after the IV course. Neurological examination and LP should be repeated every 6 months following treatment until the CSF white blood cell count (WBC) is normal and the CSF-VDRL is nonreactive.","_key":"7ac45a94fec8"},{"_type":"span","marks":["superscript"],"text":"3","_key":"5ae5897d924d"},{"_type":"span","marks":[],"text":" Retreatment may be indicated if the follow up CSF WBC is seen to be increased or the CSF-VDRL shows a significant increase in titer.","_key":"9d379bf2055a"},{"_type":"span","marks":["superscript"],"text":"3","_key":"f6a8f5592a12"},{"_key":"eca7e6da0327","_type":"span","marks":[],"text":" The mainstay of treatment is penicillin, and the more pervasive the infection, the more involved the treatment must be to combat it."}],"_type":"block","style":"normal","_key":"89c48f804fd1","markDefs":[]},{"children":[{"text":"","_key":"6be3e4d8126b0","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"1a24df9ceb0b","markDefs":[]},{"_type":"block","style":"normal","_key":"734023dec52d","markDefs":[],"children":[{"_type":"span","marks":[],"text":"The psychiatric management of psychosis secondary to neurosyphilis ultimately involves treating the underlying infection.","_key":"90e577aca3780"},{"_type":"span","marks":["superscript"],"text":"3-5","_key":"4d7b0e1eebb5"},{"_type":"span","marks":[],"text":" Antipsychotics may help manage symptoms, but can be less effective than in psychosis secondary to neurotransmitter imbalance.","_key":"8b65df2fa7f6"},{"_type":"span","marks":["superscript"],"text":"11,12,15","_key":"a2e72babe35a"},{"_type":"span","marks":[],"text":" Patients with concurrent illicit substance abuse pose additional challenges, requiring careful management to ensure adherence to treatment and observation to avoid misuse of vascular access sites. Close monitoring and a comprehensive care plan involving addiction specialists and regular follow-up are recommended.","_key":"0c7714ef0c6e"}]},{"_key":"bdee93f85968","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"f4b49cb712d60"}],"_type":"block","style":"normal"},{"_key":"1274977c5822","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Concluding Thoughts","_key":"d3d844a1641e0"}],"_type":"block","style":"normal"},{"style":"normal","_key":"2d57c3ad5168","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Neurosyphilis, though less common today, remains a critical diagnostic consideration in patients presenting with neuropsychiatric symptoms, particularly those with risk factors such as polysubstance abuse, homelessness, and sex work. Differentiating neurosyphilis from substance-induced psychosis involves a comprehensive workup, including serologic and CSF tests. Early and appropriate treatment with penicillin is crucial to prevent long-term neurological damage. Managing neurosyphilis requires a multidisciplinary approach, addressing both the infection and any concurrent psychiatric and substance use issues, to improve patient outcomes and quality of life.","_key":"9fabec899d4b0"}],"_type":"block"},{"style":"normal","_key":"e29b7a877af0","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"ee3e8fd58dbb0"}],"_type":"block"},{"_type":"block","style":"normal","_key":"a8b00c74cdd2","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Mr Hendricks ","_key":"5643a2fb98d70"},{"_type":"span","marks":["em"],"text":"is a medical student at Texas A\u0026M EnMed and he is interested in emergency medicine.","_key":"5643a2fb98d71"},{"_type":"span","marks":[],"text":" ","_key":"5643a2fb98d72"},{"_type":"span","marks":["strong"],"text":"Dr Safavi ","_key":"5643a2fb98d73"},{"marks":["em"],"text":"is the system director of emergency psychiatry at Houston Methodist, an assistant professor of Psychiatry \u0026 Behavioral Sciences at Baylor College of Medicine, and attending physician at Methodist Hospital, Houston.","_key":"5643a2fb98d74","_type":"span"}]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"701c951c0e860"}],"_type":"block","style":"normal","_key":"86c2dc5f9a59"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"References","_key":"50824388d9090"}],"_type":"block","style":"normal","_key":"0c31c35d939e"},{"_key":"dd9e3e4fcc2a","markDefs":[{"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/29478035/","_key":"2f23f78d1558","blank":true}],"children":[{"_type":"span","marks":[],"text":"1. Hobbs E, Vera JH, Marks M, et al. ","_key":"385c8029a0080"},{"_type":"span","marks":["2f23f78d1558"],"text":"Neurosyphilis in patients with HIV.","_key":"385c8029a0081"},{"_type":"span","marks":[],"text":" ","_key":"e987f1596ab7"},{"_type":"span","marks":["em"],"text":"Pract Neurol","_key":"385c8029a0082"},{"_key":"385c8029a0083","_type":"span","marks":[],"text":". 2018;18(3):211-218."}],"_type":"block","style":"normal"},{"markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/7340118/","_key":"c533fc643108"}],"children":[{"_key":"8163440c4fab0","_type":"span","marks":[],"text":"2. Hotson JR, Jose S. "},{"_key":"8163440c4fab1","_type":"span","marks":["c533fc643108"],"text":"Modern neurosyphilis: a partially treated chronic meningitis."},{"_type":"span","marks":[],"text":" ","_key":"3812fc2c52a2"},{"_type":"span","marks":["em"],"text":"West J Med","_key":"8163440c4fab2"},{"marks":[],"text":". 1981;135(3):191-200.","_key":"8163440c4fab3","_type":"span"}],"_type":"block","style":"normal","_key":"7e7ae2cdc32d"},{"children":[{"text":"3. Tso MK, Koo K, Tso GY. ","_key":"3dfff5d3fa840","_type":"span","marks":[]},{"_type":"span","marks":["c053089c8a76"],"text":"Neurosyphilis in a non-HIV patient: more than a psychiatric concern.","_key":"3dfff5d3fa841"},{"_key":"6adff46ad2d6","_type":"span","marks":[],"text":" "},{"_type":"span","marks":["em"],"text":"McGill J Med","_key":"3dfff5d3fa842"},{"_type":"span","marks":[],"text":". 2008;11(2):160-163.","_key":"3dfff5d3fa843"}],"_type":"block","style":"normal","_key":"f65e91da8877","markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/19148316/","_key":"c053089c8a76"}]},{"markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/31533185/","_key":"ceb9345c0507"}],"children":[{"_type":"span","marks":[],"text":"4. Gonzalez H, Koralnik IJ, Marra CM. ","_key":"57033ee903340"},{"_type":"span","marks":["ceb9345c0507"],"text":"Neurosyphilis.","_key":"57033ee903341"},{"_key":"0633ddf8cac2","_type":"span","marks":[],"text":" "},{"_type":"span","marks":["em"],"text":"Semin Neurol","_key":"57033ee903342"},{"_type":"span","marks":[],"text":". 2019;39(4):448-455.","_key":"57033ee903343"}],"_type":"block","style":"normal","_key":"171ff1d5a6a1"},{"markDefs":[],"children":[{"_key":"feb3878e3e990","_type":"span","marks":[],"text":"5. Ha, T., Tadi, P., Leslie, S. W. \u0026 Dubensky, L. Neurosyphilis. StatPearls (2024)."}],"_type":"block","style":"normal","_key":"93f3596d7056"},{"_key":"9cefd43212db","markDefs":[{"_key":"ab88e21a7e23","blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/24653750/"}],"children":[{"_type":"span","marks":[],"text":"6. Tampa M, Sarbu I, Matei C, et al. ","_key":"c66effd80b5a0"},{"_type":"span","marks":["ab88e21a7e23"],"text":"Brief history of syphilis.","_key":"c66effd80b5a1"},{"_type":"span","marks":[],"text":" ","_key":"74b1227cff0c"},{"_type":"span","marks":["em"],"text":"J Med Life","_key":"c66effd80b5a2"},{"_type":"span","marks":[],"text":". 2014;7(1):4-10.","_key":"c66effd80b5a3"}],"_type":"block","style":"normal"},{"style":"normal","_key":"23dff91862cf","markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/25890619/","_key":"1d98fb22669f"}],"children":[{"_type":"span","marks":[],"text":"7. Ho EL, Spudich SS. ","_key":"b288f2c3fd690"},{"_type":"span","marks":["1d98fb22669f"],"text":"Neurosyphilis and the impact of HIV infection.","_key":"b288f2c3fd691"},{"_type":"span","marks":[],"text":" ","_key":"67889c10024f"},{"_type":"span","marks":["em"],"text":"Sex Health.","_key":"b288f2c3fd692"},{"text":" 2015;12(2):148-154.","_key":"b288f2c3fd693","_type":"span","marks":[]}],"_type":"block"},{"children":[{"_type":"span","marks":[],"text":"8. Jennings JM, Wagner J, Tilchin C, et al. 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