Biological Psychiatry最新文献

Cognitive impairment associated with schizophrenia (CIAS) and related deficits in learning (plasticity) are among the leading causes of disability in schizophrenia. Despite this, there are no Food and Drug Administration-approved treatments for CIAS, and the development of treatments has been limited by numerous phase 2/3 failures of compounds that showed initial promise in small-scale studies. NMDA-type glutamate receptors (NMDARs) have been proposed to play an important role in schizophrenia; moreover, the NMDAR has a well-characterized role in cognition, learning, and neuroplasticity. We review previously published clinical trials in CIAS that focused on NMDAR modulator treatments, focusing on published and recent developments of the use of novel NMDAR-modulating treatments for CIAS both alone and combined with plasticity/learning paradigms to enhance learning. We use this discussion of previous studies to highlight the importance of incorporating pharmacodynamic target engagement biomarkers early in treatment development, which can help predict which compounds will succeed or fail in phase 3. A range of direct and indirect NMDAR modulators are covered, including D-serine, D-cycloserine, memantine, and glycine and first-generation glycine transport inhibitors (e.g., sarcosine and bitopertin), as well as recent positive studies of iclepertin, a novel glycine transport inhibitor, and luvadaxistat, a D-amino acid oxidase inhibitor that increases brain D-serine levels, and indirect noninvasive brain stimulation NMDAR-modulating treatments. Several examples of successful use of pharmacodynamic target engagement biomarkers for dose/drug discovery are emphasized, including the mismatch negativity, auditory steady state, and time-frequency event-related potential approaches.

Background: Fine motor challenges are prevalent in autistic populations. However, little is known about their neurobiological underpinnings or how their related neural mechanisms are influenced by sex. The dorsal striatum, comprised of the caudate nucleus and putamen, is associated with motor learning and control and may hold critical information. We investigated how autism diagnosis and sex assigned at birth influence associations between the dorsal striatum and fine motor development in autistic and non-autistic children.

Methods: We used multimodal assessment of striatal structures (volume and cortico-striatal white matter microstructure) and longitudinal assessment of fine motor skills, first at approximately 3 years of age (Time 1) and again 2-3 years later (Follow-up). Fine motor and magnetic resonance imaging (T1 and diffusion) data were collected at Time 1 from 356 children (234 autistic; 128 female) and at Follow-up from 195 children (113 autistic; 76 female).

Results: At Time 1, associations among fine motor skills, putamen volume, and sensorimotor-striatal fractional anisotropy (sensorimotor-affiliated dorsal striatal structures) were different in autistic boys compared to autistic girls and were not significant for non-autistic children. Further, Time 1 sensorimotor-striatal and prefrontal-striatal microstructure predicted fine motor development for autistic girls but not boys.

Conclusions: Sensorimotor-affiliated dorsal striatum structures may contribute to concurrent motor ability and predict fine motor improvement during critical windows of development in a sex-specific and diagnosis-dependent way. Moreover, the dorsal striatum may play a key role in the distinct neural mechanisms underlying motor challenges in autistic males and females.

Background: Minimally verbal children with autism are understudied and lack effective treatment options. Personalized continuous theta-burst stimulation (cTBS) targeting the amygdala and its circuitry may be a potential therapeutic approach for this population.

Methods: In a double-blind randomized controlled trial, minimally verbal children with autism (ages 2-8 years) received 4 weeks of cTBS. An amygdala-optimized functional connectivity (AOFC) group (N=23) received personalized stimulation targeting a left dorsolateral prefrontal cortex site functionally connected with the amygdala. A non-optimized (NO) control group (N=21) received stimulation at a standard prefrontal site. We assessed changes in Autism Diagnostic Observation Schedule scores, amygdala volume, spontaneous neural activity, and functional connectivity.

Results: Personalized AOFC-guided cTBS improved social and communication skills with an effect size twice that of the NO group (Cohen's d = 0.55 vs. 0.24). The AOFC group showed greater reductions in amygdala volume, spontaneous neural activity, and hyper-connectivity. Network-level amygdala connectivity changes with default mode, frontoparietal, and dorsal attention networks were correlated with clinical improvements. Field mapping analysis revealed that greater electric field overlap between standard and optimized targets predicted better treatment outcomes.

Conclusions: Personalized AOFC-guided cTBS enhanced social skills and communication in minimally verbal children with autism by modulating amygdala structure and connectivity. Changes in amygdala network connectivity predicted clinical improvements, suggesting a mechanistic link between neural circuit plasticity and behavioral outcomes. These findings demonstrate the potential of precision-targeted neuromodulation in addressing a critical gap in autism treatment for this understudied population.

Background: Opioid use disorder remains a critical healthcare challenge as current therapeutic strategies have limitations resulting in high recurrence and deaths. We evaluated safety and feasibility of focused ultrasound (FUS) neuromodulation to reduce substance cravings and use in severe opioid- and co-occurring substance use disorders.

Methods: This prospective, open-label, single-arm study enrolled 8 participants with severe, primary opioid use disorder with co-occurring substance use. Participants received a 20-minute session of low-intensity FUS (220 kHz) neuromodulation targeting the bilateral nucleus accumbens (NAc) with follow-up for 90-days. Outcome measures included safety, tolerability, feasibility, and effects of FUS neuromodulation by assessment of adverse events, substance craving, substance use (self-report, urine toxicology), mood, neurologic examinations, and anatomic and functional MRI, at 1-, 7-, 30-, 60, and 90- day post-FUS.

Results: No serious device-related adverse events or imaging abnormalities were observed. Following FUS, participants demonstrated immediate (p<.002) and sustained (p<.0001; mean 91%) reduction in cue-induced opioid craving with median rating on scale from 0-10: 6.9 (pre-FUS) vs. 0.6 (90-day post-FUS). Craving reductions were similar for other illicit substances (e.g., methamphetamine (p<.002), cocaine (p<.02)). Decreases in opioid and co-occurring substance use were confirmed by urine toxicology. Seven participants remained abstinent at 30-days; 5 remained abstinent throughout 90-days post-FUS. Resting-state functional MRI demonstrated decrease in connectivity from the NAc to reward and cognitive regions post-FUS.

Conclusions: NAc FUS neuromodulation is safe and a potential adjunctive treatment for reducing drug cravings and use in individuals with severe opioid- and co-occurring substance use disorders. Larger, sham-controlled, randomized studies are warranted.

Background: Early in life, behavioral and cognitive traits associated with risk for developing a psychiatric condition are broad and undifferentiated. As children develop, these traits differentiate into characteristic clusters of symptoms and behaviors that ultimately form the basis of diagnostic categories. Understanding this differentiation process - in the context of genetic risk for psychiatric conditions, which is highly generalized - can improve early detection and intervention.

Methods: We modeled the differentiation of behavioral and emotional problems from age 1.5-5 years (behavioral problems - emotional problems = differentiation score) in a pre-registered study of ∼79,000 children from the population-based Norwegian Mother, Father, and Child Cohort Study. We used genomic structural equation modeling to identify genetic signal in differentiation and total problems, investigating their links with 11 psychiatric and neurodevelopmental conditions. We examined associations of polygenic scores (PGS) with both outcomes and assessed the relative contributions of direct and indirect genetic effects in ∼33,000 family trios.

Results: Differentiation was primarily genetically correlated with psychiatric conditions via a "neurodevelopmental" factor. Total problems were primarily associated with the "neurodevelopmental" factor and "p"-factor. PGS analyses revealed an association between liability to ADHD and differentiation (β=0.11 [0.10,0.12]), and a weaker association with total problems (β=0.06 [0.04,0.07]). Trio-PGS analyses showed predominantly direct genetic effects on both outcomes.

Conclusions: We uncovered genomic signal in the differentiation process, mostly related to common variants associated with neurodevelopmental conditions. Investigating the differentiation of early life behavioral and emotional problems may enhance our understanding of the developmental emergence of different psychiatric and neurodevelopmental conditions.

There is an increasing awareness that B-cell lymphoma 2 (Bcl-2)-associated athanogene (BAG) proteins play critical roles in maintaining neural homeostasis, and that their dysregulation contributes to neurological disorders. This protein family of nine members is evolutionarily conserved, with each member having at least one BAG domain that binds to the nucleotide-binding domains of Heat Shock Protein (Hsp) 70 family members. Collectively, these proteins are essential for the proper functioning of the central nervous system (CNS). Although there are numerous studies that focus on a specific BAG protein, an understanding of how BAG family members may act cooperatively to maintain cellular homeostasis is needed. In this review, we give an overview of the BAG domain interactors, Hsp72, Hsp70.2, CHIP and METTL3 which are common to all BAG family members. This is followed by a concise description of each BAG family member, with a focus on its function in the CNS and dysfunction in neurological conditions. Finally, we discuss the intersection of the molecular functions of the different BAG family proteins by delineating differences and similarities, and describing how their functions can be either complementary or competing. The information in this review provides a basic conceptual framework for analyzing the roles of a particular BAG family member in the CNS and neurological conditions. This review also provides a basis for examining how BAG family members can play either redundant or antagonistic roles that may modulate experimental outcomes.

Empathy, typically regarded as a positive attribute, is now being critically evaluated for its potential negative implications on mental health. A growing body of research indicates that excessive empathy, particularly high level of affective empathy, can lead to overwhelming emotional states, increasing susceptibility to psychological distress and psychiatric disorders. This review aims to explore the negative effects of empathy on mental health. We review both human and animal studies concerning the relationship between empathy and psychological disorders, revealing that while empathy enhances social interactions and emotional understanding, it may also heighten empathic distress and potentially contribute to the development of pain, internalizing disorders, depression, anxiety, emotional over-involvement, burnout, vicarious trauma and post-traumatic stress disorder. This review contributes to the broader discourse on empathy by delineating its dual impacts, integrating insights from neurobiology, psychology, and behavioral studies. This review may enhance our understanding of empathy's complex role in mental health, offering a nuanced perspective that acknowledges both its beneficial and detrimental impacts.