Regional gray matter volume (GMV) differences between individuals with mental disorders and comparison subjects may be confounded by co-occurring disorders. To disentangle the disorder-specific GMV correlates, we conducted a large-scale multi-disorder meta-analysis using a novel approach that explicitly models co-occurring disorders.

The avoidance of aversive stimuli through negative reinforcement learning is critical for survival in real-world environments, which demand dynamic responding to both positive and negative stimuli that often conflict with each other. Individuals with obsessive-compulsive disorder (OCD) commonly exhibit impaired negative reinforcement and extinction, perhaps involving deficits in amygdala functioning. An amygdala subregion of particular interest is the intercalated nuclei of the amygdala (ITC) which has been linked to negative reinforcement and extinction, with distinct clusters mediating separate aspects of behavior. This study focuses on the dorsal ITC cluster (ITC) and its role in negative reinforcement during a complex behavior that models real-world dynamic decision making.

Childhood trauma experience increases risk for neuropsychiatric and neurodevelopmental disorders, including posttraumatic stress disorder (PTSD), autism spectrum disorders (ASDs), and attention deficit/hyperactivity disorder (ADHD). While the biological mechanisms connecting adverse experiences with later disease presentation are not clear, the concept of Gene x Environment x Development (GxExD) interactions has significant implications for improving our understanding of these diseases. We recently utilized this approach in a study where we found that women exposed to interpersonal violence trauma (the E) uniquely during adolescence (the D), but not childhood or adulthood, had novel protein biomarkers (the G) associated with a sensory cell system in the skin, Merkel cells. Merkel cell mechanosensory signaling is important in gentle and social touch, inflammation-induced pain, and the skin's neuroendocrine stress response. Further, keratinocyte-derived Merkel cell final maturation occurs during the identified vulnerable period of adolescence. Interestingly, many of the genes identified in our study belong to a known 17q21 gene cluster, suggesting an identifiable location in the genome permanently altered by adolescent trauma. These results form a potential functional link between mechanosensory Merkel cells and the pathology and sensory symptomatology in PTSD. Future research directions could identify specific mechanisms involved in tactile alterations following trauma in hopes of revealing additional biomarkers and potentially leading to novel tactile-involved therapies (e.g., massage, electroacupuncture, or focused ultrasound).

Impulsivity is a well-known determinant of maladaptive behaviour in cocaine use disorder, but there are currently no effective strategies for managing excessive impulsivity. Growing evidence from preclinical and clinical studies suggests that atomoxetine, a selective noradrenaline reuptake inhibitor, is effective in improving impulse control in both health and neuropsychiatric conditions.

Sleep and arousal disorders are common, but the underlying physiology of wakefulness is not fully understood. The locus coeruleus promotes arousal via alpha-1 adrenergic receptor (αAR) driven recruitment of wake-promoting dopamine (DA) neurons in the ventral periaqueductal gray (vPAG neurons). αAR expression is enriched on vPAG astrocytes, and chemogenetic activation of astrocytic G signaling promotes wakefulness. Astrocytes can release extracellular "gliotransmitters," such as ATP and adenosine, but the mechanism underlying how vPAG astrocytic αARs influence sleep/wake behavior and vPAG neuron physiology is unknown.

Genome wide studies are yielding a growing catalogue of common and rare variants that confer risk for psychopathology. Yet, despite representing unprecedented progress, emerging data also indicate that the full promise of psychiatric genetics - including understanding pathophysiology and improving personalized care - will not be fully realized by targeting traditional, dichotomous diagnostic categories. The current article provides reflections on themes emerging from a 2021 NIMH sponsored conference convened to address strategies for the evolving field of psychiatric genetics. As anticipated by NIMH's Research Domain Framework, multi-level investigations of dimensional and transdiagnostic phenotypes, particularly when integrated with biobanks and big data, will be critical to advancing knowledge. The path forward will also require more diverse representation in source studies. Additionally, progress will be catalyzed by a range of converging approaches, including capitalizing on computational methods, pursuing biological insights, working within a developmental framework, and engaging healthcare systems and patient communities.

Neuropsychiatric and neurodegenerative disorders involve diverse changes in brain functional connectivity. As an alternative to approaches searching for specific mosaic patterns of affected connections and networks, we used polyconnectomic scoring to quantify disorder-related whole-brain connectivity signatures into interpretable, personalized scores.

Although the precise underlying cause(s) of autism spectrum disorder remain unclear, more than 1000 rare genetic variations are associated with the condition. For a large number of people living with profound autism, this genetic heterogeneity has impeded the identification of common biological targets for therapy development for core and comorbid traits that include significant impairments in social communication, and repetitive and restricted behaviors. A substantial number of genes associated with autism encode proteins involved in signal transduction and synaptic transmission that are critical for brain development and function. CAMK4 is an emerging risk gene for autism spectrum disorder that encodes the Ca-calmodulin-dependent protein kinase-4 (CaMK4) enzyme. CaMK4 is a key component of a Ca-activated signaling pathway that regulates neurodevelopment and synaptic plasticity. In this review, we discuss three genetic variants of CAMK4 found in individuals with hyperkinetic movement disorder and comorbid neurological symptoms including autism spectrum disorder that are likely pathogenic with monogenic effect. We also comment on four other genetic variations in CAMK4 that display associations with autism spectrum disorder, as well as twelve examples of autism-associated variations in other genes that impact CaMK4 signaling pathways. Finally, we highlight three environmental risk factors that impact CaMK4 signaling based on studies in preclinical models of autism and/or clinical cohorts. Overall, we review molecular, genetic, physiological, and environmental evidence that suggest defects in the CaMK4 signaling pathway may play an important role in a common autism pathogenesis network across numerous patient groups, and propose CaMK4 as a potential therapeutic target.

Simultaneous interoceptive, emotional, and social cognition deficits are observed across neurodegenerative diseases. Indirect evidence suggests shared neurobiological bases underlying these impairments, termed the allostatic-interoceptive network (AIN). However, no study has yet explored the convergence of these deficits in neurodegenerative diseases or examined how structural and functional changes contribute to cross-domain impairments.

People exhibit an extraordinary capacity to adjust to stressful situations. Here, we argue that the acute stress response is a major driving force behind this adaptive process. In addition to immediately freeing energy reserves, facilitating a rapid and robust neurocognitive response, and helping to reinstate homeostasis, the stress response also critically regulates neuroplasticity. Understanding the healthy acute stress response is therefore crucial for understanding stress resilience: the maintenance or rapid recovery of mental health during and after times of adversity. Contemporary resilience research distinguishes between resilience factors (RFs) and resilience mechanisms (RMs). RFs refer to a broad array of social, psychological, or biological variables that are stable but potentially malleable and predict resilient outcomes. RMs, by contrast, refer to proximate mechanisms activated during acute stress that enable individuals to effectively navigate immediate challenges. In this paper, we review literature related to how neurotransmitter and hormonal changes during acute stress regulate the activation of RMs. We integrate literature on the timing-dependent and neuromodulator-specific regulation of neurocognition, episodic memory, and behavioral and motivational control, highlighting the distinct and often synergistic roles of catecholamines (dopamine and norepinephrine) and glucocorticoids. We conclude that stress resilience is bolstered by improved future predictions and the success-based reinforcement of effective coping strategies during acute stress. The resulting generalized memories of success, controllability, and safety constitute beneficial plasticity that lastingly improves self-control under stress. Insight into such mechanisms of resilience is critical for the development of novel interventions focused on prevention rather than treatment of stress-related disorders.

Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown.

Stress levels are surging, alongside the incidence of stress-related psychiatric disorders. Perhaps a related phenomenon, especially in urban areas, the human gut contains fewer bacterial species than ever before. Although the functional implications of this absence is unclear, one consequence may be reduced stress resilience. Preclinical and clinical evidence has shown how stress exposure can alter the gut microbiota and their metabolites, affecting host physiology. Also, stress-related shifts in the gut microbiota jeopardize tight junctions of the gut barrier. In this context, bacteria and bacterial products can translocate from the gut to the bloodstream, lymph nodes, and other organs, thereby modifying systemic inflammatory responses. Heightened circulating inflammation can be an etiological factor in stress-related psychiatric disorders, including some cases of depression. In this review, we detail preclinical and clinical evidence that traces these brain-to-gut-to-brain pathways that underlie stress-related psychiatric disorders and potentially affect their responsivity to conventional psychiatric medications. We also review evidence for interventions that modulate the gut microbiota (e.g., antibiotics, probiotics, prebiotics) to reduce stress responses and psychiatric symptoms. Lastly, we discuss challenges to translation and opportunities for innovations that could impact future psychiatric clinical practice.