Accelerated repetitive transcranial magnetic stimulation (arTMS; ≥2 sessions/day) delivers high neuromodulatory doses over compressed timelines. It is increasingly used to target circuit-level dysfunction and treat diverse psychiatric conditions. However, its domain-specific efficacy and dose-dependent neuroplastic mechanisms remain incompletely understood.

Hallmark behaviors associated with depression-related disorders include reduction in reward responsivity and increased despair. However, the neurocircuits and mechanisms underlying reward responding and despair-like behavior have remained unclear. Our current studies show that pituitary adenylate cyclase activating polypeptide (PACAP, ADCYAP1) connections from the bed nucleus of the stria terminalis (BNST) to the dorsal medial habenula (dMHb) may contribute to depression-like behaviors.

The visual system, as one of the most well-understood components of the central nervous system, offers a unique framework for understanding mechanistic aspects of psychosis. This review explores the clinical translational potential of visual system alterations in psychosis spectrum disorders, emphasizing their relevance across neurodevelopmental and neurodegenerative processes. The current evidence supporting the clinical significance of visual alterations is reviewed, covering aspects from the retina to low- and mid-level visual regions of the brain, emphasizing the feasibility, accessibility, and cost-effectiveness of vision science tools compared to more invasive, burdensome, and costly neuroimaging biomarkers. Additionally, this review discusses the therapeutic promise of visual system assessments for guiding personalized treatments, monitoring responses to novel pharmacological agents, and advancing approaches such as visual remediation and non-invasive brain stimulation to target vision-related symptoms in psychosis spectrum disorders. By addressing current gaps and proposing a roadmap for integrating these tools into psychiatric research and clinical care, this review underscores the significant potential of leveraging the visual system to enhance diagnostic precision and improve clinical outcomes in psychosis spectrum disorders.

Orexin/hypocretin (Orx) peptides critically contribute to stress and arousal circuits' flexibility and equilibrium. New discoveries highlight plasticity of orexin neurons themselves, as well as plasticity-inducing properties of orexin peptides within projection circuits, as an integral part of this function. Specifically, orexin peptide release in response to stress alters the microcircuitry and gene expression profile of downstream stress regions. Here, we propose that orexin-mediated plasticity within stress circuitry is constructed across a lifetime in response to a myriad of variable challenges, ultimately enhancing neural flexibility and future adaptive behavioral responses. This provides a framework through which exposure to unusually salient stressors, either acutely or over extended periods, can result in altered engagement of stress circuitry and maladaptive affective behavioral outcomes (as in general anxiety disorder, post-traumatic stress disorder). We further posit that the diversity of plastic orexin functions is regulated, at least in part, by unique signaling roles for Orx 1 and 2 receptors in distinct brain regions. By extension, therapeutics with selective actions at these receptors might offer viable treatments designed to override pathological rewiring of stress circuits and restore adaptive stress responsivity.

Chronic stress is a major risk factor for several psychiatric disorders, including major depressive disorder and posttraumatic stress disorder. This review synthesizes rodent-based findings showing that stress modifies immune function in the central nervous system (e.g., microglia), the neurovascular unit, and the peripheral circulation. Stress paradigms such as chronic social defeat stress or chronic variable stress induce morphological and transcriptomic changes in microglia, disrupt blood-brain barrier integrity, and mobilize immune cells (e.g., monocytes, neutrophils). These cells, in turn, secrete pro-inflammatory mediators, including interleukin-6 and matrix metalloproteinase 8, which can penetrate limbic brain regions and contribute to behavioral changes. Integrating next-generation molecular insights with refined behavioral models, particularly those that capture sex-related differences, holds promise for advancing personalized strategies to prevent and treat stress-related disorders.

Depression is a common and debilitating psychiatric disorder that is associated with substantial morbidity and mortality. For nearly 40 years, scientists have attempted to localize depression in the brain with neuroimaging. Despite concerted research, many meta-analyses of neuroimaging research in depression have not identified a single brain region that, when lesioned, causes depression. However, recent work using coordinate and lesion network mapping has identified a distributed network from functional magnetic resonance imaging that is relevant for depression. In this review, we propose that multiple sclerosis (MS) is a powerful model to study the relationship between perturbations to white matter brain networks and depression. We highlight recent successes in using lesion network mapping to find associations between depression and MS lesion location and burden in retrospective samples. Next, we describe why prospective, longitudinal studies that track the onset of white matter lesions in MS with the emergence and resolution of depression may provide a way to understand both the pathophysiology of depression in MS and network mechanisms of depression more broadly.

Synaptic loss and altered network function in fronto-limbic brain regions have been implicated in the neurobiology of bipolar disorder (BD), but in vivo evidence remains limited. Synaptic vesicle glycoprotein 2A (SV2A), a biomarker of synaptic density, can be quantified using [C]UCB-J positron emission tomography (PET).

Dysregulation of the neuroimmune system is increasingly recognized as a key contributor to psychiatric illness, yet its complexity and the limitations of current methodologies have hindered a clear understanding of its role. Advances in positron emission tomography (PET) molecular brain imaging have significantly expanded our ability to study targets expressed on microglia, the brain's resident immune cells, in vivo. While PET imaging of the 18-kDa translocator protein (TSPO) has been widely used to assess microglial levels and activation, its limitations have driven the development of novel radiotracers targeting more specific microglia-related pathways. This review and explores the evolving landscape of PET imaging biomarkers. By advancing our ability to study neuroimmune dynamics, these approaches hold promise for refining diagnostic strategies and identifying novel therapeutic targets for psychiatric disorders.

Ventral Tegmental Area (VTA) dopamine neurons are intermixed with glutamate and GABA neurons, which had been implicated in aversion. While it is unclear the neuronal circuitry involved in regulation of different VTA neurons that mediate aversion, a potential component of this circuitry is the parabrachial nucleus (PBN), which is involved in encoding threats and innervate VTA.

Posttraumatic stress disorder (PTSD) is a heterogeneous condition with diverse symptom presentations and emotional experiences. While fear is traditionally viewed as central, growing evidence highlights the role of non-fear-based emotions - such as sadness, guilt, and shame - collectively termed Emotional Pain. This study aimed to identify Emotional Pain and Fear-based PTSD symptom profiles and their neural correlates across two independent samples.

Since the early 1900s, clinical and epidemiological observations have suggested a link between schizophrenia and the immune system, yet genetic evidence for a pathophysiological connection has remained elusive. Here, we review evidence for immune involvement from a variety of genetic studies to characterize the contribution of genetic variation in immune genes and pathways to schizophrenia risk. Across studies, the strongest and most consistent associations remain in neuronal pathways, but several studies have revealed involvement of peripheral lymphocyte populations, including CD4 T cells, mature B cells, and, to a lesser extent, natural killer cells. Cross-trait genetic analyses are mixed but point to a modest shared genetic architecture between schizophrenia and several immune traits. Collectively, current evidence supports a primarily neuronal genetic architecture for schizophrenia with a modest immunogenetic component. Advancing our understanding of the immune contribution to schizophrenia risk will require integration of genomic, proteomic, and deep immunophenotyping approaches to capture these subtle and dynamic processes. Ultimately, combining genetic, immunologic, and clinical data will be essential for improving diagnostic precision, identifying novel therapeutic targets, and tailoring treatment to individual biological profiles. Main article text.

Immune dysregulation has been implicated in the pathophysiology of psychiatric disorders, with peripheral inflammatory markers correlating with symptom severity, treatment refractoriness, and neural circuit dysfunction. This has led to growing interest in immunomodulatory drugs as potential treatments. Several clinical trials have explored the efficacy of anti-cytokine treatments [monoclonal antibodies (mAbs)], nonsteroidal anti-inflammatory drugs, and minocycline, among other agents. While there have been some promising results, such as improvement in depression with infliximab among subgroups with peripherally elevated inflammation, overall results have been mixed. Several key lessons have emerged from these studies that can guide future research and clinical care. While most immunomodulatory trials were small and did not utilize biomarker-based enrichment, some recent studies of mAbs have started to use inflammatory markers to guide subgroup analyses and/or enrollment. Outcome measures in many trials relied on broad symptom scales that did not focus on neuroimmune-related psychiatric phenotypes, such as anhedonia. While immunomodulatory drugs for most medical conditions are used as chronic treatments, the trials in psychiatric disorders assessed their effects over short durations, limiting insights into their long-term efficacy, safety, and potential for sustained psychiatric benefits. Absence of large, multi-center, well-powered studies limits the generalizability. Translational research on neuroimmune interactions is needed to refine therapeutic targets and optimize study designs. These lessons highlight the potential of immunomodulatory drugs in psychiatric disorders while emphasizing the need for larger, well-powered trials, biomarker-driven treatment selection, and long-term monitoring. With a targeted approach, immunomodulatory drugs represent an important step toward precision medicine in psychiatry.