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.

Ketamine is known for its rapid antidepressant effect, but its impact on affective information processing (including attentional bias, a putative cognitive mechanism of depression), remains largely unexplored. We leveraged a novel measurement of attentional bias and sought to: (1) establish adequate test-retest reliability and validity among depressed participants prior to ketamine treatment; and (2) harness a single dose of ketamine to assess mechanistic shifts in attentional bias and their relation to antidepressant efficacy.

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).

Alzheimer's Disease is a progressive, age-related neurodegenerative disorder to which genetic mutations and risk factors contribute. Evidence is increasing that also environmental and lifestyle-related factors, like exercise, nutrition, education, and also exposure to (early life) stress modify the onset, incidence and progression of Alzheimer's Disease. We here discuss recent preclinical findings on putative substrates that can explain or contribute to effects of stress early in life on the risk to develop Alzheimer's Disease. We focus in particular on stress hormones, neural networks, synapses, mitochondria, nutrient and lipid metabolism, adult neurogenesis, engram cell ensembles and neuroinflammation. We discuss that stress-exposure early in life can alter these processes, either combined or in isolation, thereby reducing the capacity of the brain to resist deleterious consequences of for example β-amyloid accumulation thereby accelerating cognitive decline and progression of Alzheimer-related changes, in model systems of the disease. A better understanding of whether experiences early in human life also modify trajectories of cognitive decline and pathology in Alzheimer's Disease, and how the substrates discussed translate to the human situation may help to develop novel preventive and/or therapeutic strategies to mitigate the consequences of stressors early in life, and increase resilience to develop dementia.

The maternal immune activation hypothesis has gained attention over the past two decades as a potential contributor to the etiology of autism. This hypothesis posits that maternal conditions associated with inflammation during pregnancy may increase the risk of autism in offspring. Autism is highly heritable, and causal environmental contributors to autism largely remain elusive. We review studies on maternal conditions during pregnancy, all associated with some degree of systemic inflammation; namely, maternal infections, autoimmunity, and high BMI. We additionally review studies of inflammatory markers in biological samples collected from the mother during pregnancy or from the neonate and their relationship with autism assessed in children later in life. Recent reports indicate familial clustering of autism, autoimmunity and infections, as well as genetic correlations between autism and aspects of immune function. In light of this literature, there is an apparent risk of confounding of the reported associations between inflammatory exposures and autism by familial genetic factors in both clinical and epidemiological cohort studies. We highlight recent studies that have attempted to address potential confounding to assess evidence of causal effects of inflammation during early life in autism.

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.

Neurobiological understanding of eating disorders (EDs) is limited. This study presents the first comparative multi-modal magnetic resonance imaging (MRI) assessments of anorexia nervosa (AN) and bulimia nervosa (BN), uncovering neurobiological differences associated with these disorders.

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.

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.

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.