Progress in Neuro-Psychopharmacology and Biological Psychiatry

BackgroundSchizophrenia (SCZ) is a severe neurodevelopmental disorder with numerous genetic risk loci. However, little is known about the molecular alterations that occur during brain development in SCZ, particularly regarding the role of microRNA (miRNA) mediated regulatory mechanisms. This gap in knowledge is largely due to the limited availability of developing human brain tissue. Patient-derived brain organoids offer a promising alternative model. Here we use 3D dorsal forebrain organoids (DFOs) to investigate miRNA dysregulation in SCZ. MethodsDFOs were generated from human induced pluripotent stem cells (hiPSCs) derived from six SCZ patients and five matched controls and cultured for 120 days. Multi-omics analyses, immunohistochemistry, and in situ hybridization were employed to characterize molecular and spatial features. ResultsDFOs recapitulated key molecular hallmarks of human cortical development. Nineteen miRNAs were differentially expressed in SCZ: nine associated with neural progenitor proliferation were downregulated and ten linked to neuronal differentiation and synaptic maturation were upregulated, reflecting a compressed developmental timeline. Among 77 dysregulated mRNAs, 55 were predicted miRNA targets. SCZ DFOs exhibited significant upregulation of GABAergic pathway genes accompanied by altered expression of their regulatory miRNAs, indicating premature GABAergic lineage specification. The disrupted miRNA-mRNA network converged on glutamatergic and dopaminergic development, synaptic organization, and extracellular matrix remodeling. ConclusionDysregulated miRNAs in SCZ DFOs disrupt neuronal differentiation, excitatory-inhibitory balance, and early circuit formation, implicating miRNA-mediated post-transcriptional regulation as a key mechanism linking molecular alterations to cellular and network-level deficits in SCZ.

Social behavior is a fundamental phenotype across vertebrates. Zebrafish (Danio rerio) have emerged as a valuable translational model for investigating the neurobiological mechanisms underlying sociability, particularly due to their robust shoaling behavior and experimental tractability. However, the literature presents issues of reproducibility and inconsistent findings regarding the modulation of social preference and shoal cohesion in adult zebrafish. We conducted a systematic review and meta-analysis to synthesize studies evaluating the effects of pharmacological interventions that modulate the central nervous system and stress-related interventions on social behavior in adult zebrafish and, when available, anxiety-like behavior. The literature search was performed in three databases (Embase, PubMed, and Web of Science), followed by a two-step screening process based on inclusion/exclusion criteria. The included studies underwent extraction of qualitative and quantitative data, as well as risk of bias assessment. Interventions from the included studies (n = 108) were categorized according to their nature, mechanism of action, and/or therapeutic purpose, resulting in seven, four, and five meta-analyses for social preference, shoal cohesion, and anxiety-related tests, respectively. Ethanol, NMDA antagonists, pro-dopaminergic agents, and stress-related interventions decreased social preference, while stress-related interventions increased shoal cohesion. The fact that stress produced opposite effects suggests that these paradigms measure distinct sociability constructs, or perhaps are differentially modulated by confounding factors, like anxiety for example. The studies presented high heterogeneity, with prediction intervals compatible with effects in both directions, as well as methodological limitations and deficiencies in data reporting, as evidenced by the risk of bias assessment. These findings emphasize the need for well-designed new studies to validate the findings and expand the evidence on interventions that currently lack sufficient studies for quantitative synthesis.

Background: Obsessive-compulsive disorder (OCD) is characterized by disturbing thoughts (obsessions) that initiate anxiety-reducing thoughts or behaviors (compulsions). For patients with treatment-resistant OCD (tr-OCD), neuromodulation techniques, like capsulotomy (a lesion in the anterior limb of the internal capsule) and deep brain stimulation (DBS), have emerged as interventions that likely regulate connectivity between the prefrontal cortex (PFC) and subcortical targets. Three patients (Cap-DBS1-3) underwent a failed capsulotomy followed by successful DBS. Here, we aimed to understand the brain connections disrupted by failed capsulotomy vs modulated by successful DBS. Methods: We used diffusion-weighted magnetic resonance imaging (dMRI) tractography in a control cohort with tr-OCD (n=12) and in two of the Cap-DBS patients themselves to determine connectivity profiles of the capsulotomy, volume of tissue activated (VTA), and potentially necessary tracts (VTA minus capsulotomy tracts). We used whole-brain, PFC-focused, and subcortically-focused tractography algorithms to fully explore the space of possible connections. Results: Capsulotomy regions-of-interest (ROIs) connected with a variety of PFC and subcortical regions. VTA ROIs and potentially necessary tracts had limited and inconsistent PFC connectivity but substantial subcortical connectivity. While correlated to the average OCD connectome (r = 0.214, 95% CI [0.177, 0.251]; r = 0.756, 95% CI [0.739, 0.772]), the Cap-DBS connectomes had many edges that were stronger (z-score > 3). Conclusions: The connectivity profile of potentially necessary tracts for successful DBS treatment after failed capsulotomy revealed a surprising proportion of subcortical regions and inconsistent PFC involvement, highlighting an often-ignored set of connections that may be critical to effective DBS.

Background and Objectives In ADHD, a heterogeneous neurodevelopmental condition, behavioral and motor manifestations may reflect multiple inefficient or perturbed inhibitory systems. To evaluate Transcranial Magnetic Stimulation (TMS) evoked cortical silent period (CSP) duration, an indicator of GABA(B) receptor-mediated inhibition in motor cortex, as a potential biomarker of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. Method We retrospectively analyzed TMS data, obtained using both round and figure-of-8 coils, from three cross-sectional studies conducted in 8- to 12-year-old children with ADHD (n=79; 10.7 +/- 1.5 years old) and age-and-sex-matched typically developing controls (n=96; 10.5 +/- 1.4 years old). Results Median CSP was 32% shorter in ADHD (p=0.02). Regression analysis demonstrated a relationship between shorter CSP and both lower active motor thresholds (p < 0.0001) and more severe hyperactivity symptom rating (p = 0.026). Test-retest CSP measures in 83 children showed moderate reliability (intraclass correlation 0.77 [ADHD], 0.75 [controls]). Conclusion TMS-evoked CSP may be a useful biomarker in future investigations of ADHD subtypes, domains of impaired function, or treatment outcomes.

Alcohol use disorder (AUD) is a significant public health concern. In Canada, about 18% of individuals aged 15 or older will meet the clinical criteria for AUD at some point in their lives (CAMH, 2023). Treatment options for AUD are limited, and the high relapse rates highlight the urgent need for innovative methods to study and address AUD. Zebrafish (Danio rerio) is an emerging model for exploring the neurobiological impacts of alcohol. Previous studies have demonstrated that zebrafish respond to the rewarding effects of alcohol, but most research methods rely on passive administration, such as immersion, which does not reflect the typical routes of alcohol intake in humans. We previously showed that zebrafish can learn to self-administer drugs of abuse in small groups and conditioned animals are displaying key features of substance abuse disorders. However, group-based conditioning limits our understanding of individual drug preference and intake profile. In this study, we improved upon our previous design by establishing an individual self-administration protocol to measure voluntary alcohol intake and model alcohol use disorder. In this novel assay, individual adult fish learn to discriminate between two zones to self-administer a 5% ethanol solution. Moreover, animals conditioned in this assay can perform progressive ratio and display signs of withdrawal upon cessation of ethanol intake. These results suggest zebrafish can develop ethanol abuse-like behaviour, providing a powerful platform to study genetic predisposition and screen for therapeutic compounds.

Acute COVID-19 outcomes are exacerbated by substance use, however, the impact of substance use on Long-COVID is unknown. Here, we investigated the impact of chronic cocaine administration on spike-induced Long-COVID-like outcomes in the rat. Rats received intermittent chronic cocaine administration and a single intravenous injection of the SARS-CoV-2 spike protein. Two months following spike administration, Long-COVID-like outcomes were assessed. Exposure to spike protein in the presence of cocaine produced a persistent reduction in weight gain as compared with controls or spike protein alone. Further, cocaine-treated rats exposed to spike had lower withdrawal thresholds compared to control animals as well as their own baseline, suggesting increased pain sensitivity. Spike and/or cocaine increased the ratio of interleukin-6 (IL-6) to interleukin-10 (IL-10) levels in the hippocampus, indicating a shift towards a proinflammatory state. Paw withdrawal thresholds were positively correlated with IL-10 levels in the hippocampus and prefrontal cortex. Regarding olfaction, rats exposed to spike spent less time sniffing an odor attractant. Cocaine produced an anxiolytic-like phenotype during the elevated plus maze test. Further analysis of behaviors on the maze revealed that the latency to enter the open arms was shorter in rats exposed to spike or cocaine, suggesting a possible impulsive-like phenotype in these animals. These findings demonstrate the negative impact of cocaine on Long-COVID-like outcomes suggesting a need for increased clinical observations of people with co-occurring Long-COVID and cocaine use disorder. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=59 SRC="FIGDIR/small/729575v1_ufig1.gif" ALT="Figure 1"> View larger version (10K): org.highwire.dtl.DTLVardef@12fdc19org.highwire.dtl.DTLVardef@11b1b0dorg.highwire.dtl.DTLVardef@8d1e21org.highwire.dtl.DTLVardef@b53d20_HPS_FORMAT_FIGEXP M_FIG C_FIG

Relapse-prevention strategies aimed at reducing relapse following abstinence, primarily focus on reducing cravings that lead to drug-seeking triggered by stress, drug-related cues, or re-exposure to the drug. Because addictive drugs form persistent associative contextual memories, we investigated how reactivation of cocaine-related hippocampal memories influences subsequent drug-seeking. Here, we tagged dorsal dentate gyrus (dDG) memory ensembles involved in encoding either a first or fourth cocaine exposure (15mg/kg, i.p) in male and female c57BL/6 mice using a TetTag approach. Mice underwent cocaine conditioned place preference (CPP), extinction, and reinstatement. We assessed whether optical reactivation of tagged cocaine-related ensembles could substitute for a cocaine priming injection to reinstate CPP, whether reactivation altered cocaine-induced reinstatement, and if these effects differed depending on stage of drug exposure. We also compared these effects to reactivation of saline-associated ensembles. Cocaine produced robust locomotor activation during conditioning, and sensitization developed across repeated drug exposures. Reactivation of a cocaine-related engram alone did not reinstate CPP. However, reactivation of the first cocaine exposure engram attenuated cocaine-induced reinstatement. In contrast, reactivation of the fourth exposure engram did not confer this protective effect. Interestingly, reactivation of saline-associated ensembles also reduced cocaine-induced reinstatement specifically in females, suggesting dDG ensemble reactivation may modulate relapse-related behavior through interference or neuromodulatory disruption of cocaine-associated representations, consistent with our prior work. These findings raise the possibility that early contextual experiences form competing or destabilizing representations that interfere with later cocaine-seeking when reactivated. Females also displayed greater sensitivity to locomotor-inducing effects of cocaine memory reactivation, although this was dissociated from CPP. Together, these findings show that cocaine memories are distinct across drug experience and selective reactivation of dDG engrams can differentially influence drug-seeking.

IntroductionThe anterior limb of the internal capsule (ALIC) is a major white matter highway connecting prefrontal cortical (PFC) regions to the thalamus, brainstem, and subthalamic nucleus. Structural and functional abnormalities within the ALIC circuit have been associated with many neuropsychiatric disorders, including obsessive-compulsive disorder (OCD) and depression, and deep brain stimulation (DBS) may provide effective treatment to some of these patients. However, it remains unclear whether the well-characterized topographic organization of the ALIC observed in healthy individuals and preclinical models is preserved in treatment-resistant psychiatric populations. MethodsWe first used diffusion tractography to evaluate the topography of PFC and subcortical fibers through the ALIC in patients with treatment-resistant OCD (n=18) and depression (n=5). In depression patients, we also evaluated ALIC topography using cerebro-cerebral evoked potentials (CCEPs) elicited by single-pulse electrical stimulation (SPES) of DBS leads in the ALIC and recordings in the ventral PFC (vPFC). ResultsThe topographic organization of PFC and subcortical projections is preserved in the ALIC among treatment-resistant psychiatric patients, consistent with patterns observed in healthy individuals and preclinical models. CCEP recordings in the ventral PFC showed a ventral ALIC to medial vPFC/dorsal ALIC to lateral vPFC response pattern in the left hemisphere, but not in the right. ConclusionOur findings confirm that topographic patterns within the ALIC previously identified using preclinical models and healthy controls are preserved in treatment-resistant psychiatric patients. Furthermore, by linking white matter topography to stimulation effects, this work supports more precise and individualized neuromodulatory strategies for neuropsychiatric disorders.

Tourette syndrome (TS) is a neurodevelopmental disorder of childhood onset characterised by vocal and motor tics and is associated with cortical-striatal-thalamic-cortical circuit [CSTC] dysfunction. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence. However, many individuals continue to have debilitating tics into adulthood. This indicates that there may be important differences between adults with TS for whom the clinical phenotype is more stable, and children and adolescents with the disorder who may be undergoing developmental neuroplastic changes linked to the reduction of their tics. Previous studies have used transcranial magnetic stimulation (TMS) to investigate changes in cortical motor excitability in individuals with TS, including measurement of resting motor threshold (RMT). However, the findings from these studies have been mixed, have varied between adult and child samples, and have often been based on small sample sizes. Here we report a multi-centre, mega-analytic, study in which RMT data collected from children and adults with TS at multiple research centres was pooled for analysis. Results confirmed that mean RMT was significantly increased in individuals with TS compared to neurotypical controls. However, this result can be explained by the more important findings that: (a) RMT for adults with TS did not differ from that of neurotypical adults; and (b) the rate that RMT decreases with age during childhood and adolescence is reduced in individuals with TS compared to controls. Thus, while neurotypical individuals reach an adult RMT level by ~12-13 years of age, individuals with TS are substantially delayed in doing so, and do not reach an adult RMT level until much later, at ~24 years of age. We conclude therefore that differences in measures of cortical excitability between children and adolescents with TS and chronologically age-matched neurotypical controls may likely reflect a developmental delay in the maturation of functional brain networks in individuals with TS, which may normalise with age.

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising treatment across addictive disorders including Cannabis Use Disorder (CUD). Targeting incentive-salience circuitry via the ventromedial prefrontal cortex (vmPFC) and central-executive circuitry via the left dorsolateral prefrontal cortex (LDLPFC) are both promising treatment approaches; however, to date structural targets have predominated whereas functional targeting may allow for more precision. In this pilot trial we adapted a functional Magnetic Resonance Imaging (fMRI) Regulation of Craving (ROC) task to generate fMRI-based rTMS targets in the vmPFC and LDLPFC. Methods: We recruited treatment-seeking participants with moderate or severe CUD as a part of an open-label trial and administered an adapted ROC-task during fMRI following 24-hours of cannabis abstinence. We identified sub-portions of maximal activation of the LDLPFC when participants thought of long-term consequences of cannabis use (Later) and of the vmPFC when participants thought of short-term positive aspects of cannabis use (Now). We hypothesized that our task would generate acceptable rTMS targets in >66% of baseline fMRI scans. Results: A total of 20-participants enrolled in the trial (50%F, age=33.3+9.8) and completed the baseline fMRI. The adapted ROC-task elicited group level activation in the LDLPFC and precuneus in the Later>Now and in the bilateral vmPFC, ACC, and striatum in the Now>Later contrast. Acceptable functional targets resolved in both the vmPFC and LDLPFC in 19 of 20 participants (one participant did not tolerate MRI). Conclusions: The adapted ROC-task elicits activation in incentive salience and central executive circuitry and can feasibly generate rTMS targets when using a cluster selection algorithm.

The platform-mediated active avoidance (PMA) task has been used as a rodent model of decision-based active avoidance in which rat learn to avoid a tone-signaled shock. Prior studies utilizing the PMA task have primarily investigated avoidance, freezing, and food-seeking behaviors, but few studies have thoroughly assessed darting behavior, a more recently identified measure of fear that has been largely explored in conditional fear paradigms. Here, we investigated the properties of darting that occur during the PMA task, in which rats either acquired the PMA task alone or with a social partner. We found that rats undergoing solitary PMA produced significantly more darting bouts, whereas rats undergoing social partner PMA produced darts that were faster and shorter in duration. We also found that darting in solitary PMA was predominantly concentrated at the platform, whereas darting in social partner PMA occurred more often outside of the platform and lever zones. Analysis of darting trajectories, which included movements surrounding each darting bout, revealed that darting was embedded in a broader movement strategy between the platform and lever zones, especially during solitary PMA, and this pattern increased across training days. These findings suggest that darting during the PMA task serves as a learned strategy to navigate between reward and safety and is modulated by social context, which is distinct from escape-like darting observed in auditory fear conditioning.

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising treatment across addictive disorders including Cannabis Use Disorder (CUD). Stimulation of two rTMS-targets, the ventromedial prefrontal cortex (vmPFC) and the left dorsolateral prefrontal cortex (LDLPFC), limbic and executive control network hubs respectively, may yield differential effects. In this pilot trial, we explored the differential effects of 36-sessions of rTMS applied to either the vmPFC or LDLPFC. Methods: Treatment-seeking participants with moderate or severe CUD (n=20, 10F, age=33.3+9.8SD) were randomized to 36-sessions of open-label rTMS (two sessions-per-visit, two or three visits-per-week) to either the LDLPFC (3000-pulses; 10Hz) or vmPFC (900-pulses; 1Hz) using personalized functional Magnetic Resonance Imaging (fMRI) targets along with three-sessions of Motivational Enhancement Therapy. At baseline and following rTMS, the Time-Line Follow-Back was used to measure Days-per-week of cannabis use and the fMRI Regulation of Craving (ROC) task was used to measure network activation to cues associated with long-term negative ('Later') and short-term positive ('Now') consequences of cannabis use. Results: Eighty percent of participants completed study-rTMS. There was a significant decrease in days-per-week of cannabis use in both groups (vmPFC: d=7.9; DLPFC, d=3.1) between the four-weeks of baseline and seven-weeks of follow-up. LDPFC-rTMS reduced fMRI BOLD signal magnitude and increased LDLPFC functional connectivity in response to cues, while vmPFC-TMS reduced functional connectivity. Conclusions: Treatment-seeking participants with CUD reduced the number of days-per-week they used cannabis when receiving rTMS applied to either the LDPFC or vmPFC, while fMRI effects differed by treatment target. Future larger sham-controlled trials are needed for efficacy and biomarker determination.

Weak inhibition of mitochondrial complex I (mtCI) has been shown to have neuroprotective effects in cellular and animal models of Alzheimers and Huntingtons diseases, at least in part by enhancing mitochondrial biogenesis and function. Mitochondrial dysfunction has also been demonstrated in schizophrenia patients and mouse models of schizophrenia. We tested whether weak inhibition of mtCI would ameliorate mitochondrial and behavioral phenotypes in a mouse model of schizophrenia. In mice with four copies of the Gldc gene, 8 weeks of treatment with the weak mtCI inhibitor, the small-molecule tricyclic pyrone compound CP2, reversed spontaneous alternation deficits in the Y maze, startle habituation deficits, and social novelty deficits in the three-chamber social interaction test. Consistent with the mechanism of action, Western blots revealed that CP2 reverses the reduced expression of PGC-1, a master regulator of mitochondrial biogenesis, and of the VDAC1, a primary gatekeeper for the exchange of metabolites, ions, and ATP between mitochondria and the cytosol. These findings suggest that the improvement of mitochondrial function may represent a novel strategy to reverse pathophysiological and behavioral deficits in schizophrenia.

Background/ObjectivesPersistent cognitive impairments are prevalent in methamphetamine (meth) use disorder and contribute to maladaptive decision-making and increased relapse vulnerability. There are currently no effective treatments for meth-associative cognitive deficits, and their neurobiological underpinnings remain incompletely understood. This study investigated the effects of chronic meth self-administration on episodic-like recognition memory and evaluated whether pharmacological potentiation of metabotropic glutamate receptor subtype 2 (mGlu2) could rescue these deficits. MethodsAdult male Sprague-Dawley rats underwent 7 days of limited- (1h/day) followed by 14 days of extended-access (6h/day) meth self-administration, followed by 30 days of abstinence. Recognition memory was assessed using the object-in-place (OIP) task. A positive allosteric modulator of mGlu2 receptors, LY-487379 (25 mg/kg, s.c.), was administered prior to the memory test. In parallel, changes in total and surface mGlu2/3 protein levels in the prelimbic and perirhinal cortices were evaluated. ResultsRats with extended access to meth self-administration exhibited escalated drug intake and persistent deficits in OIP memory. Administration of LY-487379 reversed this deficit. Total mGlu2/3 protein levels were unaltered; however, meth exposure was associated with a significant increase in surface mGlu2/3 receptor expression in both cortical regions examined. ConclusionsThese results demonstrate that chronic meth produces persistent cognitive dysfunction that can be rescued by mGlu2 receptor potentiation. The observed increase in surface mGlu2/3 expression may represent a compensatory response to chronic glutamatergic dysregulation, but it appears to be insufficient to restore cognitive function alone, without pharmacological enhancement. The current data encourage further exploration of mGlu2 role in stimulant-associated cognitive dysfunction. HighlightsChronic methamphetamine self-administration produced persistent deficits in episodic-like recognition memory in male rats and dysregulation of mGlu2/3 receptors in the prelimbic and perirhinal cortices. Systemic pharmacological potentiation of mGlu2 receptors rescued meth-associated memory deficits. mGlu2 receptor potentiation may represent a promising therapeutic strategy for treating stimulant-associated cognitive dysfunction. Increased surface mGlu2/3 expression may represent a compensatory adaptation to post-methamphetamine glutamatergic dysfunction, but it is not sufficient to restore cognition alone, without pharmacological enhancement.

Abstract Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable psychiatric disorders with complex polygenic architectures. Genome-wide association studies (GWASs) have identified numerous common variant associations, but rarer variants detectable through whole-genome sequencing (WGS) remain underexplored. We conducted rare variant association analysis using WGS data from the Portuguese Island Collection (PIC), including 28 families with SCZ (n = 53) and 41 families with BPD (n = 83) cases, and population controls (n = 62). Following ANNOVAR and CADD annotation, burden analysis of deleterious variants showed that both affected and unaffected family members from SCZ and BPD pedigrees had significantly higher burdens of rare deleterious variants compared to controls (p < 0.0001), with no significant differences observed between affected and unaffected relatives, consistent with shared familial genetic liability. Polygenic Risk Score (PRS) analysis confirmed significant genetic contributions to both disorders within PIC. Association analyses were subsequently performed using SAIGE-GENE+ identifying 483 and 583 nominally significant (suggestive associations) gene sets (p-value [&le;] 0.05; FDR > 0.05) for SCZ and BPD, respectively, including gene sets related to neurotransmission, synaptic function and structure, neurodevelopment, and neuroinflammation as well as major signaling pathways. Cross disorder overlaps also identified shared suggestive enrichment of GABA and glutamate signaling, synaptic signaling, and Wnt signaling gene sets in both SCZ and BPD. These findings support shared rare variant burden within multiplex psychiatric families and highlight the role of gene-set based rare variant analysis in identifying neurobiological pathways relevant to SCZ and BPD. Keywords: WGS, Rare Variants, Schizophrenia, Bipolar Disorder

BackgroundWhile resting-state fMRI demonstrated that brain networks are spatially dynamic (expanding, shrinking, and changing complexity over time), understanding the transient spatial network interactions that remain poorly characterized is critical for revealing the mechanisms underlying brain disorders. MethodsWe introduce DESINE (Dynamic Estimation of Spatially Interactive Networks), a novel framework using joint density distributions (2D histograms) of voxel-wise activity to quantify 4D spatial network interactions across sliding windows. We analysed transient deviations from the average functional state using root-mean-square error (RMSE) and mean absolute deviation (MAD), and characterized recurring interaction patterns using k-means clustering. We applied DESINE to 91 network pairs (14 networks) in a cohort of 508 subjects (315 healthy controls; 193 patients with schizophrenia, SZ). ResultsSZ is characterized by a significantly "constrained dynamic repertoire" of network interactions. SZ patients showed markedly lower means and standard deviations for both RMSE and MAD metrics across network pairs, particularly in regions of high activity, indicating systematic rigidity. Cluster analysis revealed significant alterations in state affinity metrics, suggesting a global breakdown in the brains capacity to preserve diverse, high-fidelity spatial configurations. Critically, these interaction metrics were associated with cognitive performance, symptom scores on the positive and negative syndrome scale, and chlorpromazine equivalent drug scores. ConclusionsThis work introduces DESINE as a global, voxel-agnostic framework for characterizing time-varying spatial interactions. Our findings highlight spatial rigidity as a fundamental feature of psychopathology, suggesting that the inability to express a diverse range of spatial interactions is a factor underlying cognitive deficits in schizophrenia.

Background: Wide-spread mast cell (MC)-associated symptoms and MC activation syndrome (MCAS) are often reported in patients with hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). The goal of this study was to develop a novel MC score based on 11 self-reported MC-related conditions with clinical and research utility to better understand MC symptoms in hEDS and HSD patients. Methods: From November 1, 2019, to June 13, 2025, patients (n=2,141) filled out an Intake Questionnaire at the Mayo Clinic Florida EDS Clinic that included 11 self-reported questions related to categories of MC-related conditions for a MC score ranging from 0/11 to 11/11. Based on the MC score distribution in hEDS and HSD patients, a MC score of 0-1 was considered a low MC score and [&ge;]5 was considered a high MC score. Symptoms/comorbidities were compared between patients with high vs. low MC scores. Results: From the 2,141 hEDS/HSD patients, 535 (25.0%) had a MC score [&ge;]5 (Hi MC). MCAS-specific symptoms such as nausea and vomiting were reported more often in hEDS/HSD patients with a high vs. low MC score (p<0.0001). Random clinical blood tryptase and urinary MC markers were not elevated in patients with high MC scores (n=50/group), although high MC scores were found to significantly reduce urinary creatinine levels indicating that the protein used to normalize data was affected by MC activity. In contrast, random blood IgE, tryptase and major basic protein (MBP) by ELISA were increased in patients with high MC scores (e.g., IgE hEDS p=0.0004, HSD p=0.003). Of note, the percentage of patients reporting abuse or post-traumatic stress disorder was nearly doubled in patients with high vs. low MC scores (Abuse and PTSD: hEDS p < 0.0001; HSD p < 0.0001). Overall, 109/135 (80.7%) in hEDS and 129/135 (95.6%) in HSD reported more symptoms/comorbidities if they had a high MC score. Conclusions: We found that hEDS/HSD patients with high MC scores self-reported more widespread symptoms/comorbidities and higher MC-related blood markers than patients with low MC scores indicating the utility of this tool to evaluate the level of widespread MC activity in hEDS, HSD and other patients.

BackgroundAutism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) share substantial clinical and physiological overlap. While naturalistic and sensory-driven paradigms increasingly capture evoked neurophysiological responses, the intrinsic baseline physiology of these conditions remains poorly defined. We aimed to characterize resting-state autonomic arousal and oculomotor stability across the ASD-ADHD spectrum using both continuous (RDoC) and categorical (DSM-5) analytical frameworks. MethodsWe analyzed resting-state eye-tracking data from a large pediatric cohort (N = 2,640) from the Healthy Brain Network. During an unconstrained baseline, we extracted Pupil Relative Volatility (Coefficient of Variation [CV]) to index intrinsic autonomic arousal, and the Bivariate Contour Ellipse Area (BCEA) to index spatial gaze instability. Data were evaluated using continuous dimensional regressions against the Social Responsiveness Scale (SRS) and SWAN inventories, followed by 2x2 factorial ANCOVAs based on clinical diagnoses. Sensitivity analyses accounted for clinical collinearity, spatial outliers, and psychostimulant medication. ResultsDimensional models revealed that Pupil CV was significantly and uniquely associated with continuous autistic traits (q = 0.0043, joint model), exhibiting a strong statistical suppression effect when controlling for ADHD trait covariance. However, this pupillary biomarker lost significance in binary categorical models. Conversely, spatial gaze instability (BCEA) demonstrated robust categorical threshold effects; isolated ASD and ADHD diagnoses significantly impaired baseline gaze stability. Furthermore, comorbid ASD+ADHD produced a distinct, sub-additive interaction for BCEA (q = 0.005) that remained robust to extreme spatial outliers. Both physiological phenotypes were independent of active psychostimulant use. LimitationsWhile this study included a large and diverse group of children, the eye-tracking data were collected during a brief resting period -- watching a simple cross on a screen -- which may not capture how children behave in everyday, real-world situations. Because holding still for eye-tracking can be difficult, particularly for children with more severe symptoms, some data were lost; however, we statistically accounted for how much data each child contributed. Finally, while we confirmed that ADHD medication taken on the day of testing did not explain our findings, complete medication records were not available for every participant in this large observational study. ConclusionsPupillary dynamics and oculomotor stability associate with the ASD-ADHD spectrum through differing analytical patterns during resting states. Baseline autonomic volatility is more strongly captured by dimensional models of autistic trait severity, whereas baseline gaze instability is more clearly differentiated across categorical diagnostic groups, exhibiting a sub-additive interaction in comorbidity. Integrating both dimensional and categorical frameworks provides a more comprehensive understanding of these physiological variations, establishing a necessary foundation for future naturalistic and sensory-evoked research.

Schizophrenia is a severe psychiatric disorder associated with altered dopaminergic signaling and hippocampal circuit dysfunction. Although antipsychotic medications remain the standard treatment, many are limited by incomplete efficacy and adverse effects. Cariprazine, a dopamine D2/D3 receptor partial agonist, has a favorable clinical profile, but its effects on neuronal excitability and network activity remain incompletely understood. Here, we integrated nationwide real-world clinical data with in vitro electrophysiology, computational modeling, and molecular analyses to define the neuronal actions of cariprazine. Among Hungarian patients diagnosed with schizophrenia and receiving index-drug monotherapy with one of the three prespecified D2/D3 targeting antipsychotics, haloperidol was associated with worse survival and a higher cumulative incidence of first registered suicide attempt than cariprazine or aripiprazole in matched observational cohorts. In primary mouse hippocampal cultures, multielectrode array recordings showed that acute cariprazine treatment moderately reduced spontaneous firing in a dose-dependent manner and prolonged burst intervals while largely preserving network synchronization. These effects were milder than those of haloperidol and aripiprazole. Whole-cell patch-clamp recordings revealed cell-type-dependent effects, with reduced intrinsic excitability and increased firing irregularity mainly in regular- and stuttering-type neurons. Conductance-based modeling identified enhanced Kv1-mediated D-type potassium currents as sufficient to reproduce these effects. Consistent with this mechanism, chronic cariprazine treatment altered Kv1.2 protein distribution without changing Kcna2/Kcna3 or Drd1/Drd2/Drd3 transcript expression. These findings identify modulation of intrinsic excitability via Kv1/D-type potassium currents as a candidate cellular mechanism of cariprazine and provide a translational link between real-world evidence and circuit-level drug effects.

Excessive screen use is associated with childhood behavioral problems, but whether associations differ between typically developing (TD) children and those with autism spectrum disorder (ASD) is unclear. Our cross-sectional study included 108 children aged 5-9 years (61 TD, 47 ASD). ASD was diagnosed using standardized clinical instruments. Measures included parent-reported screen time (excluding TV/DVD), cognitive ability (K-ABC), and behavioral problems (Vineland-II). Screen time and externalizing problems were associated in the TD group (Spearmans {rho} = 0.361, p < 0.01), but not in the ASD group. In the regression model, screen time ({beta} = 0.40, t = 2.60, p < 0.05), ASD status ({beta} = 0.70, t = 8.30, p < 0.001), and their interaction ({beta} = -0.34, t = -2.06, p < 0.05) significantly predicted externalizing problems. Considering the diversity within the autism spectrum, future studies with larger sample sizes should consider individual heterogeneity when examining the association between behavioral outcomes and screen time.