Biological Psychiatry最新文献

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).

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

Methods: We systematically reviewed voxel-based morphometry studies indexed in PubMed and Scopus up to January 2023 that compared adults with major mental disorders (anorexia nervosa, schizophrenia spectrum, anxiety, bipolar, major depressive, obsessive-compulsive, and posttraumatic stress disorders plus attention-deficit/hyperactivity, autism spectrum, and borderline personality disorders) with comparison participants. Two authors independently extracted data and assessed quality using the Newcastle-Ottawa Scale. We derived GMV correlates for each disorder using: 1) a multidisorder meta-analysis that accounted for all co-occurring mental disorders simultaneously and 2) separate standard meta-analyses for each disorder in which co-occurring disorders were ignored. We assessed the alterations' extent, intensity (effect size), and specificity (interdisorder correlations and transdiagnostic alterations) for both approaches.

Results: We included 433 studies (499 datasets) involving 19,718 patients and 16,441 comparison participants (51% female, ages 20-67 years). We provide GMV correlate maps for each disorder using both approaches. The novel approach, which accounted for co-occurring disorders, produced GMV correlates that were more focal and disorder specific (less correlated across disorders and fewer transdiagnostic abnormalities).

Conclusions: This work offers the most comprehensive atlas of GMV correlates across major mental disorders. Modeling co-occurring disorders yielded more specific correlates, supporting this approach's validity. The atlas NIfTI maps are available online.

Background: 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_d) and its role in negative reinforcement during a complex behavior that models real-world dynamic decision making.

Methods: We investigated the impact of ITC_d function on negative reinforcement and extinction by applying fiber photometry measurement of GCamp6f signals and optogenetic manipulations during a platform-mediated avoidance task in a mouse model of OCD-like behavior: the Sapap3-null mouse.

Results: We find impaired neural activity in the ITC_d of male and female Sapap3-null mice to the encoding of negative stimuli during platform-mediated avoidance. Sapap3-null mice also exhibit deficits in extinction of avoidant behavior, which is modulated by ITC_d neural activity.

Conclusions: Sapap3-null mice fail to extinguish avoidant behavior in platform-mediated avoidance, due to heightened ITC_d activity. This deficit can be rescued by optogenetically inhibiting ITC_d during extinction. Together, our results provide insight into the neural mechanisms underpinning negative reinforcement deficits in the context of OCD, emphasizing the necessity of ITC_d in responding to negative stimuli in complex environments.

Background: Impulsivity is a well-known determinant of maladaptive behavior in cocaine use disorder (CUD), 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 healthy individuals and individuals with neuropsychiatric conditions.

Methods: We investigated the effects of atomoxetine on decisional impulsivity in patients with CUD. In a randomized, double-blind, placebo-controlled, crossover study, 28 patients diagnosed with moderate-to-severe CUD and 28 matched healthy control participants completed the Cambridge Gambling Task in 2 separate sessions, where they received either placebo or a single dose of 40 mg atomoxetine at each session. Computational modeling was used to break down decision making into 3 separable components: value, probability, and decisional impulsivity.

Results: Our analyses revealed that patients with CUD were impaired in all components of decision making. Atomoxetine selectively reduced decisional impulsivity in patients with CUD by reducing their risk-seeking tendencies while enhancing their ability to tolerate delays. By contrast, atomoxetine did not affect impulsivity in control participants, but increased their sensitivity to prospective losses.

Conclusions: Taken together, our findings support the hypothesis of noradrenergic dysfunction in patients with CUD and provide novel translational evidence for the efficacy of atomoxetine in remediating decisional impulsivity in CUD.