Reliable biomarkers that capture central nervous system (CNS) processes during the earliest stages of psychosis are critically needed to improve early treatment and response monitoring. Brain-derived extracellular vesicles (BDEVs) that traverse the blood-brain barrier (BBB) can be isolated from peripheral blood, thereby offering a novel and minimally invasive approach to quantify CNS molecular biomarkers. We hypothesized that BDEV abundance and BDEV neuroinflammatory and neurotrophic protein cargo would differ between individuals with first-episode psychosis (FEP) and healthy controls (HCs), reflecting altered neuroinflammatory signalling and extracellular biology associated with psychosis and clinical outcomes. In a cohort of untreated individuals with FEP (n = 57) and HCs (n = 28), BDEVs were isolated from serum. Luminex assays quantified concentrations of brain-derived neurotrophic factor (BDNF), S100 calcium-binding protein B (S100B), and C-reactive protein (CRP) in BDEVs and serum. A subset of FEP participants (n = 34) subsequently completed four weeks of antipsychotic treatment. Group differences in BDEV characteristics and protein measures, as well as their associations with case-control status, baseline symptom severtity, and four-week symptom change, were examined. FEP participants showed a trend toward higher BDEV concentration than HCs (median 14.0 × 108 versus 10.2 × 108 particles/mL, p = 0.052), and higher baseline BDEV concentrations were significantly associated with more severe pretreatment symptoms (β = 4.09 × 10-10, p = 0.003) and greater symptom improvement after four-week antipsychotic treatment (β = 3.29 × 10-10, p = 0.029). Within BDEVs, BDNF (β = -1.05; p = 0.0018) and CRP (β = -0.84; p = 0.002) were significantly reduced in FEP vs HC, with a trend toward lower S100B level (β = -0.57; p = 0.061). In contrast, serum protein levels showed no case-control differences and did not correlate with corresponding BDEV protein levels. Lower baseline BDEV BDNF, S100B, and CRP were associated with greater therapeutic response among males. BDEVs offer a minimally invasive window into CNS-enriched biology in early psychosis. BDEV abundance and neuroinflammatory and neurotrophic cargo concentrations show associations with illness severity and sex-specific treatment response not detectable in serum, supporting their potential as biomarkers for early pathophysiology and treatment response in FEP.

Although youth with attention-deficit/hyperactivity disorder (ADHD) and a family history of bipolar I disorder (BD) are at increased risk for developing BD, the underlying neurobiological mechanisms remain poorly understood. Aberrant ventrolateral prefrontal cortex (VLPFC) and amygdala (AMY) functional connectivity (FC) have been implicated in the pathophysiology of BD. This study compared VLPFC-AMY FC in psychostimulant-free ADHD youth with (high-risk, HR) and without (low-risk, LR) a BD family history, and healthy controls (HCs). Subjects received a magnetic resonance scan while performing a continuous performance task with emotional and neutral distractors. Generalized psychophysiological interaction analysis was used to assess VLPFC-AMY FC in response to unpleasant emotional stimuli and attentional targets. A total of 144 adolescents (46 HC, 50 LR, and 48 HR) were included. In response to unpleasant emotional stimuli, FC between right VLPFC and left AMY differed among groups. HR youth exhibited lower right VLPFC-left AMY FC compared with both LR and HC, and LR youth exhibited lower right VLPFC-left AMY FC compared with HC. There were no group differences in right VLPFC-left AMY FC in response to attentional distractors. ADHD in conjunction with BD family history is associated with blunted emotion-generated right VLPFC-left AMY FC compared with ADHD youth without a BD family history and healthy youth, and may represent a neurobiological feature associated with genetic vulnerability to BD.

OBJECTIVE:Although psychostimulants are the first-line treatment for attention-deficit/hyperactivity disorder (ADHD) and can normalize associated brain network abnormalities, their neural effects in ADHD youth with a family history of bipolar I disorder (BD) have not yet been systematically investigated. METHOD:This study investigated the effects of 12-week mixed amphetamine salts-extended release (MAS-XR) treatment on brain functional networks and symptom changes in ADHD youth with ("high-risk" [HR]) and without ("low-risk" [LR]) a first-degree relative with BD. LR received 12-week open-label MAS-XR and HR were randomized to MAS-XR or placebo (PLA). Healthy controls (HC) were included for comparative purposes. Resting-state functional magnetic resonance imaging scans were acquired at baseline and week 12. Global and nodal network topological metrics were evaluated based on functional connectivity matrices using graph theoretical analysis. RESULTS:A total of 135 youth were included (HC, n = 45; LR-MAS, n = 46; HR-MAS, n = 28; HR-PLA, n = 16). For comparisons between HR-MAS and LR-MAS groups, significant group-by-time interactions were identified in global efficiency, characteristic path length, left superior parietal gyrus degree, and right amygdala efficiency. Relative to the HC group, all baseline abnormalities were normalized at week-12 in the LR-MAS group, whereas a decrease in right amygdala efficiency uniquely emerged in the HR-MAS group. Significant correlations were identified between changes in network topology and ADHD symptoms. Connectome-based predictive modeling analysis revealed that baseline network dysconnectivity predicted ADHD treatment outcomes in the HR-MAS group only. CONCLUSION:These findings provide novel evidence that ADHD youth with and without BD familial risk exhibit different changes in brain network topology and associated symptoms following 12 weeks of psychostimulant treatment. PLAIN LANGUAGE SUMMARY:Although psychostimulants can alter brain network connectivity in youth with attention-deficit/hyperactivity disorder (ADHD), their effects in ADHD youth with a family history of bipolar disorder (BD) have not been investigated. This double-blind randomized controlled study compared the effects of psychostimulants on brain networks in a total of 135 youth. Results indicate that ADHD youth with and without BD family history exhibit different brain network changes. These findings suggest that ADHD in conjunction with BD family history may have a neurobiological profile that is distinct from ADHD alone without such a family history. CLINICAL TRIAL REGISTRATION INFORMATION:Neuroimaging Study of Risk Factors for Adolescent Bipolar Disorder (NERF); https://clinicaltrials.gov/study/NCT02478788.

Sensorimotor impairments are common in autism spectrum disorder (ASD) and evident in unaffected first-degree relatives, suggesting that they may serve as endophenotypes associated with inherited autism likelihood. We tested the familiality of sensorimotor impairments in autism across multiple motor behaviors and effector systems and in relation to parental broader autism phenotypic (BAP) characteristics. Fifty-seven autistic individuals (probands), 109 parents, and 89 neurotypical control participants completed tests of manual motor and oculomotor control. Sensorimotor tests varied in their involvement of rapid, feedforward control and sustained, sensory feedback control processes. Subgroup analyses compared families with at least one parent showing BAP traits (BAP+) and those in which neither parent showed BAP traits (BAP-). Results show that probands with BAP- parents (BAP- probands) showed atypical control of rapid oculomotor behaviors, while BAP+ probands showed impairments of sustained manual motor and oculomotor behaviors compared to controls. BAP- parents showed impaired rapid oculomotor and sustained manual motor abilities relative to BAP+ parents and controls. Rapid oculomotor behaviors were highly intercorrelated among probands and their biological parents. These findings indicate that rapid oculomotor behaviors are selectively impacted in BAP- probands and their parents and may reflect a familial likelihood for autism independent of parental autistic traits. In contrast, sustained sensorimotor behaviors were affected in BAP+ probands and BAP- parents, suggesting separate familial pathways associated with autism. Finally, atypical saccade dynamics may serve as strong endophenotypes for autism. These findings provide new evidence that rapid and sustained sensorimotor alterations represent strong but separate familial pathways of inherited likelihood for autism.

Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity (hyperacusis) is a distressing symptom in FXS, its neural basis is not well understood. It is postulated that hyperacusis may stem from temporal lobe hyperexcitability or dysregulation in top-down modulation. Studying the neural mechanisms underlying sound sensitivity in FXS using scalp electroencephalography (EEG) is challenging because the temporal and frontal regions have overlapping neural projections that are difficult to differentiate. To overcome this challenge, we conducted EEG source analysis on a group of 36 individuals with FXS and 39 matched healthy controls. Our goal was to characterize the spatial and temporal properties of the response to an auditory chirp stimulus. Our results showed that males with FXS exhibit excessive activation in the frontal cortex in response to the stimulus onset, which may reflect changes in top-down modulation of auditory processing. Additionally, during the chirp stimulus, individuals with FXS demonstrated a reduction in typical gamma phase synchrony, along with an increase in asynchronous gamma power, across multiple regions, most strongly in the temporal cortex. Consistent with these findings, we observed a decrease in the signal-to-noise ratio, estimated by the ratio of synchronous to asynchronous gamma activity, in individuals with FXS. Furthermore, this ratio was highly correlated with performance in an auditory attention task. Compared to controls, males with FXS demonstrated elevated bidirectional frontotemporal information flow at chirp onset. The evidence indicates that both temporal lobe hyperexcitability and disruptions in top-down regulation play a role in auditory sensitivity disturbances in FXS. These findings have the potential to guide the development of therapeutic targets and back-translation strategies.

Background:Fragile X Syndrome (FXS) is a rare, neurodevelopmental disorder caused by a mutation to the Fragile X messenger ribonucleoprotein 1 (Fmr1) gene and characterized by sensory processing abnormalities and sensitivities, including neural auditory oscillatory disruptions and reduced neural entrainment to chirp stimuli. The present study aims to evaluate the 40 Hz auditory steady state response (ASSR) in FXS to evaluate stimulus representation maintenance in FXS. Methods:Adolescents and adults (N = 67; 34 FXS and 33 age, sex-matched typically developed controls (TDC)) completed a 40 Hz auditory steady state task during electroencephalography (EEG). Time-frequency analyses using Morlet wavelets were completed to evaluate intertrial phase coherence (ITC) and event-related spectral perturbation (ERSP), including characterization of the transient and sustained components of the 40 Hz ASSR. Results:Both ITC (p = .003) and ERSP (p = .004) at 40 Hz were reduced for FXS compared to TDC. Interestingly, TDC exhibited a significantly elevated early, transient component (100 - 400 ms) which reduced in both ITC and ERSP during transition to the sustained component (650 - 3000 ms) whereas FXS were consistently reduced across the ASSR suggesting a reduced ability for FXS to mount a transient response. Conclusions:Individuals with FXS exhibit robust reductions in magnitude and temporal precision of neural entrainment to the steady state stimulus. The reduced ability to mount a transient response may represent reduced GABAergic modulation where the overall reduction in ITC and ERSP may reflect reduced excitatory/inhibitory balance between NMDA and GABAergic input.

Idiopathic psychosis shows considerable biological heterogeneity across cases. B-SNIP used psychosis-relevant biomarkers to identity psychosis Biotypes, which will aid etiological and targeted treatment investigations. Psychosis probands from the B-SNIP consortium (n = 1907), their first-degree biological relatives (n = 705), and healthy participants (n = 895) completed a biomarker battery composed of cognition, saccades, and auditory EEG measurements. ERP quantifications were substantially modified from previous iterations of this approach. Multivariate integration reduced multiple biomarker outcomes to 11 "bio-factors". Twenty-four different approaches indicated bio-factor data among probands were best distributed as three subgroups. Numerical taxonomy with k-means constructed psychosis Biotypes, and rand indices evaluated consistency of Biotype assignments. Psychosis subgroups, their non-psychotic first-degree relatives, and healthy individuals were compared across bio-factors. The three psychosis Biotypes differed significantly on all 11 bio-factors, especially prominent for general cognition, antisaccades, ERP magnitude, and intrinsic neural activity. Rand indices showed excellent consistency of clustering membership when samples included at least 1100 subjects. Canonical discriminant analysis described composite bio-factors that simplified group comparisons and captured neural dysregulation, neural vigor, and stimulus salience variates. Neural dysregulation captured Biotype-2, low neural vigor captured Biotype-1, and deviations of stimulus salience captured Biotype-3. First-degree relatives showed similar patterns as their Biotyped proband relatives on general cognition, antisaccades, ERP magnitudes, and intrinsic brain activity. Results extend previous efforts by the B-SNIP consortium to characterize biologically distinct psychosis Biotypes. They also show that at least 1100 observations are necessary to achieve consistent outcomes. First-degree relative data implicate specific bio-factor deviations to the subtype of their proband and may inform studies of genetic risk.

OBJECTIVE:The authors sought to determine whether genetic predispositions to cognitive ability or psychiatric conditions interact with anticholinergic burden (AChB) to impact cognition and brain structure in individuals with psychotic disorders. METHODS:Participants with psychosis spectrum disorders (N=1,704) from the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium, 18-65 years of age and representing diverse ancestries, underwent cognitive assessments, structural neuroimaging, genotyping, and a comprehensive medication review. The primary cognitive outcome was the Brief Assessment of Cognition in Schizophrenia (BACS) composite score, and the primary brain structural phenotype was total gray matter volume. AChB scores for scheduled medications were quantified using the CRIDECO Anticholinergic Load Scale. Polygenic scores (PGSs) for cognition, schizophrenia, bipolar disorder, and depression were constructed, and a composite psychiatric PGS was subsequently generated. Linear regression models were used to examine AChB-PGS interactions and their associations with cognitive and brain structure outcomes, adjusting for clinical covariates and multiple testing with false discovery rate. Hypothesis-driven moderated mediation models were used to explore potential association pathways. RESULTS:Higher AChB was significantly associated with lower BACS performance and reduced gray matter volume. Individuals with higher cognitive PGS values exhibited greater adverse effects of AChB on BACS, while those with lower composite psychiatric PGS values showed more pronounced gray matter volume reductions from AChB. AChB associations with cognitive impairment were partially mediated by reduced gray matter volume and were moderated by composite psychiatric PGS. CONCLUSIONS:Anticholinergic-polygenic interactions significantly impact cognition and brain structure in individuals with psychotic disorders, highlighting a novel gene-by-environment interaction that advances our mechanistic understanding of cognitive impairments in this population.

BACKGROUND:Bipolar I disorder (BD) is associated with reduced white matter microstructural integrity in the uncinate fasciculus (UF), a primary fiber tract connecting frontolimbic systems. Although familial history for BD, attention-deficit/hyperactivity disorder (ADHD), and psychostimulants are important risk factors implicated in BD pathoetiology, their impact on UF microstructure remains poorly understood. METHODS:This diffusion tensor imaging study investigated UF microstructural integrity prior to and following 12 weeks of psychostimulant treatment in ADHD youth with ('high-risk', HR) and without ('low-risk', LR) a first-degree relative with BD. Healthy controls were included for comparative purposes. LR youth received 12-week open-label mixed amphetamine salts-extended release (MAS-XR), and HR youth were randomized to either MAS-XR or placebo (PLA). Bilateral UF fractional anisotropy (FA) and axial diffusivity (AD) were assessed using automated fiber quantification. RESULTS:A total of 137 participants were included in the analyses. At baseline, there were no significant group differences in bilateral UF microstructural metrics. Following 12-week MAS-XR treatment, significant group-by-time interactions were found for left UF FA and AD between HR-MAS and LR-MAS, as well as for left UF FA between HR-MAS and HR-PLA. Specifically, left UF FA and UF AD decreased significantly in HR-MAS but remained unchanged in LR-MAS and HR-PLA groups. At week 12, left UF FA was lower in HR-MAS relative to HC but not in LR-MAS or HR-PLA. Segment-wise analyses further revealed that UF microstructural changes in the HR-MAS group were localized to the anterior segments. CONCLUSIONS:These results suggest that HR-ADHD youth are uniquely vulnerable to reductions in left UF microstructural integrity following psychostimulant treatment, suggesting potential relevance to BD pathoprogression.

Background: Response to pharmacotherapy varies considerably among youths with bipolar disorder (BD) and is poorly predicted by clinical or demographic features. It can take several weeks to determine whether medication for BD is clinically effective. Although neuroimaging biomarkers are promising predictors, few studies examined the predictive value of the brain connectomic topology. Methods: BD-I youth (N = 121) with no prior psychopharmacotherapy were randomized to 6-weeks of doubleblind quetiapine or lithium. Structural magnetic resonance imaging (MRI) was performed before medication and at one week after medication initiation. Brain structural connectome was established from the MRI scans, and topological metrics were calculated for each patient. Deep learning-based prediction model was built using baseline and one-week connectome topology to predict medication response at week 6. Results: Both baseline topological metrics and one-week topological changes could predict treatment response with significant accuracy (73.8 %- 86.8 %). A longitudinally joint model combining baseline and one-week topology provided the highest accuracy (91.3 %). The transferability between models for quetiapine and lithium was relatively poor. In addition, predictions for the two drugs were driven by similar baseline but distinct one-week salient topological patterns. Limitations: Independent replication is needed to validate our preliminary findings. Conclusion: Brain structural connectomic topology at baseline and its acute changes within the first week enable accurate BD medication response prediction. The most contributive brain regions differed between prediction models for quetiapine and lithium after one week. These findings provide preliminary evidence for the development of neuroimaging-based biomarkers for guiding therapeutic interventions in youth with BD.

AIM:This study aimed to evaluate associations in bipolar disorder (BD) across multimodal measures of white matter microstructure (using diffusion tensor imaging; DTI), cognitive, behavioral, and brain electrophysiological measures (using electroencephalography; EEG). METHODS:Subjects were recruited through the Psychosis and Affective Research Domains and Intermediate Phenotypes Consortium (n = 45 bipolar with psychosis, n = 40 bipolar without psychosis, n = 66 healthy subjects). DTI data were used to quantify the white matter variables, fractional anisotropy (FA) and radial diffusivity (RD). The Brief Assessment of Cognition in Schizophrenia (BACS), Stop Signal Task (SST), pro- and anti-saccades, auditory event-related potentials (ERPs), and intrinsic brain activity were used as estimates of brain function. RESULTS:The combined BD group differed from healthy controls, but no differences between BD with and without psychosis were observed. BD-related white matter abnormalities were seen across multiple tracts: right cingulum-cingulate gyrus, bilateral anterior thalamic radiation, bilateral superior longitudinal fasciculus, right inferior longitudinal fasciculus, and forceps major. Results also showed modestly compromised cognitive performance and elevated intrinsic EEG activity associated with BD. CONCLUSIONS:Further analysis indicated worse white matter integrity related to higher intrinsic EEG and modestly higher ERPs. These multimodal analyses are likely to aid in creating future informative diagnostic, etiological, and treatment targets for BD.

BACKGROUND:Sensory prediction allows the brain to anticipate and parse incoming self-generated sensory information from externally generated signals. Sensory prediction breakdowns may contribute to perceptual and agency abnormalities in psychosis (hallucinations, delusions). The pons, a central node in a cortico-ponto-cerebellar-thalamo-cortical circuit, is thought to support sensory prediction. Examination of pons connectivity in schizophrenia and its role in sensory prediction abnormalities is lacking. METHODS:We examined these relationships using resting-state functional magnetic resonance imaging and the electroencephalography-based auditory N1 event-related potential in 143 participants with psychotic spectrum disorders (PSPs) (with schizophrenia, schizoaffective disorder, or bipolar disorder); 63 first-degree relatives of individuals with psychosis; 45 people at clinical high risk for psychosis; and 124 unaffected comparison participants. This unique sample allowed examination across the psychosis spectrum and illness trajectory. Seeding from the pons, we extracted average connectivity values from thalamic and cerebellar clusters showing differences between PSPs and unaffected comparison participants. We predicted N1 amplitude attenuation during a vocalization task from pons connectivity and group membership. We correlated participant-level connectivity in PSPs and people at clinical high risk for psychosis with hallucination and delusion severity. RESULTS:Compared to unaffected comparison participants, PSPs showed pons hypoconnectivity to 2 cerebellar clusters, and first-degree relatives of individuals with psychosis showed hypoconnectivity to 1 of these clusters. Pons-to-cerebellum connectivity was positively correlated with N1 attenuation; only PSPs with heightened pons-to-postcentral gyrus connectivity showed this pattern, suggesting a possible compensatory mechanism. Pons-to-cerebellum hypoconnectivity was correlated with greater hallucination severity specifically among PSPs with schizophrenia. CONCLUSIONS:Deficient pons-to-cerebellum connectivity linked sensory prediction network breakdowns with perceptual abnormalities in schizophrenia. Findings highlight shared features and clinical heterogeneity across the psychosis spectrum.

Background: The hippocampus is a crucial brain structure in etiological models of major depressive disorder (MDD). It remains unclear whether sex differences in the incidence and symptoms of MDD are related to differential illness-associated brain alterations, including alterations in the hippocampus. This study investigated divergent the effects of sex on hippocampal subfield alterations in drug-naive patients with MDD. Methods: High-resolution structural MR images were obtained from 144 drug-naive individuals with MDD early in their illness course and 135 age- and sex-matched healthy controls (HCs). Hippocampal subfields were segmented using FreeSurfer software and analyzed in terms of both histological subfields (CA1-4, dentate gyrus, etc.) and more integrative larger functional subregions (head, body and tail). Results: We observed a significant overall reduction in hippocampal volume in MDD patients, with deficits more prominent deficits in the posterior hippocampus. Differences in anatomic alterations between male and female patients were observed in the CA1-head, presubiculum-body and fimbria in the left hemisphere. Exploratory analyses revealed different patterns of clinical and memory function correlations with histological subfields and functional subregions between male and female patients primarily in the hippocampal head and body. Limitations: This cross-sectional study cannot clarify the causality of hippocampal alterations or their association with illness risk or onset. Conclusions: These findings represent the first reported sex-specific alterations in hippocampal histological subfields in patients with MDD early in the illness course prior to treatment. Sex-specific hippocampal alterations may contribute to diverse sex differences in the clinical presentation of MDD.

Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

Categorical diagnosis, a pillar of the medical model, has not worked well in psychiatry where most diagnoses are still exclusively symptom based. Uncertainty continues about whether categories or dimensions work better for the assessment and treatment of idiopathic psychoses. The Bipolar Schizophrenia Network for Intermediate Phenotypes (B-SNIP) examined multiple cognitive and electrophysiological biomarkers across a large transdiagnostic psychosis data set. None of the variables supported neurobiological distinctiveness for conventional clinical psychosis diagnoses but showed a continuum of severity. Using numerical taxonomy of these data, B-SNIP identified three biological subtypes (Biotypes) agnostic to DSM diagnoses. Biotype-1 is characterized by reduced physiological response to salient stimuli, while Biotype-2 showed accentuated intrinsic (background or ongoing) neural activity and the worst inhibition. Biotype-3 cases are like healthy persons on many laboratory measures. These Biotypes differed in imaging and other electrophysiological measures not included in subgroup creation, illustrating external validation. The Biotypes solution also replicated in an independent sample of psychosis cases. Biotypes are differentiable by clinical characteristics, leading to a feasible algorithm for Biotype estimates. Identifying Biotypes may aid treatment selection and outcome prediction. As an example, preliminary cross-sectional B-SNIP data suggest that Biotype-1 cases may have physiological features that predict a more favorable response to clozapine. While psychosis Biotypes reveal physiological heterogeneity across cases with similar clinical characteristics, data also suggest a dimensional vulnerability for serious psychopathology that cuts across diagnostic boundaries. Both categorical and dimensional diagnostic approaches should be considered within idiopathic psychosis for optimum diagnosis, care, and research.

OBJECTIVE:Pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur and share dysfunctions in affective and cognitive domains. As the neural substrates underlying their overlapping and dissociable symptomatology have not been well delineated, a meta-analysis of whole-brain voxel-based morphometry studies in PBD and ADHD was conducted.METHOD:A systematic literature search was performed in PubMed, Web of Science, and Embase. The seed-based d mapping toolbox was used to identify altered clusters of PBD or ADHD and obtain their conjunctive and comparative abnormalities. Suprathreshold patterns were subjected to large-scale network analysis to identify affected brain networks.RESULTS:The search revealed 10 PBD studies (268 patients) and 32 ADHD studies (1,333 patients). Decreased gray matter volumes in the right insula and anterior cingulate cortex relative to typically developing individuals were conjunctive in PBD and ADHD. Reduced volumes in the right inferior frontal gyrus, left orbitofrontal cortex, and hippocampus were more substantial in PBD, while decreased volumes in the left precentral gyrus, left inferior frontal gyrus, and right superior frontal gyrus were more pronounced in ADHD. Neurodevelopmental effects modulated patterns of the left hippocampus in PBD and those of the left inferior frontal gyrus in ADHD.CONCLUSION:These findings suggest that PBD and ADHD are characterized by both common and distinct patterns of gray matter volume alterations. Their overlapping abnormalities may represent a transdiagnostic problem of attention and emotion regulation shared by PBD and ADHD, whereas the disorder-differentiating substrates may contribute to the relative differences in cognitive and affective features that define the 2 disorders.PLAIN LANGUAGE SUMMARY:Pediatric bipolar disorder (BD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur, with overlapping changes in emotional and cognitive functioning. This meta-analysis summarizes findings from 10 articles on BD and 32 articles on ADHD to identify similarities and differences in brain structure between youth with BD and youth with ADHD. The authors found that both disorders share decreased gray matter volumes in the right insula and anterior cingulate cortex, which play important roles in emotion processing and attention, respectively. Youth with BD had decreased gray matter volume in the right inferior frontal gyrus, left orbitofrontal gyrus, and left hippocampus, while youth with ADHD had decreased volumes in the left precentral gyrus, left inferior frontal gyrus, and right superior frontal gyrus.STUDY PREREGISTRATION INFORMATION:Structural Brain Abnormalities of Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder in Children/Adolescents: An Overlapping Meta-analysis; https://osf.io; trg4m.

Recent failures translating preclinical behavioral treatment effects to positive clinical trial results in humans with Fragile X Syndrome (FXS) support refocusing attention on biological pathways and associated measures, such as electroencephalography (EEG), with strong translational potential and small molecule target engagement. This study utilized guided machine learning to test promising translational EEG measures (resting power and auditory chirp oscillatory variables) in a large heterogeneous sample of individuals with FXS to identify best performing EEG variables for reliably separating individuals with FXS, and genetically-mediated subgroups within FXS, from typically developing controls. Best performing variables included resting relative frontal theta power, all combined posterior-head resting power bands, posterior peak alpha frequency (PAF), combined PAF across all measured regions, combined theta, alpha, and gamma power during the chirp, and all combined chirp oscillatory variables. Sub-group analyses for resting EEG best discriminated non-mosaic FXS males via frontal theta resting relative power (AUC = 0.8759), even with data reduced to a 20-channel clinical montage (AUC = 0.9062). In the chirp task, FXS females and non-mosaic males were nearly perfectly discriminated by combined theta, alpha, and gamma power (AUC = 0.9444) and a combination of all variables (AUC = 0.9610), respectively. Results support use of resting and auditory oscillatory tasks to reliably identify neural deficit in FXS, and to identify specific translational targets for genetically-mediated sub-groups, supporting potential points for stratification.

BACKGROUND: Although brain structural covariance network (SCN) abnormalities have been associated with suicidal thoughts and behaviors (STBs) in individuals with major depressive disorder (MDD), previous studies have reported inconsistent findings based on small sample sizes, and underlying transcriptional patterns remain poorly understood. METHODS: Using a multicenter magnetic resonance imaging dataset including 218 MDD patients with STBs, 230 MDD patients without STBs, and 263 healthy control participants, we established individualized SCNs based on regional morphometric measures and assessed network topological metrics using graph theoretical analysis. Machine learning methods were applied to explore and compare the diagnostic value of morphometric and topological features in identifying MDD and STBs at the individual level. Brainwide relationships between STBs-related connectomic alterations and gene expression were examined using partial least squares regression. RESULTS: Group comparisons revealed that SCN topological deficits associated with STBs were identified in the prefrontal, anterior cingulate, and lateral temporal cortices. Combining morphometric and topological features allowed for individual-level characterization of MDD and STBs. Topological features made a greater contribution to distinguishing between patients with and without STBs. STBs-related connectomic alterations were spatially correlated with the expression of genes enriched for cellular metabolism and synaptic signaling. CONCLUSIONS: These findings revealed robust brain structural deficits at the network level, highlighting the importance of SCN topological measures in characterizing individual suicidality and demonstrating its linkage to molecular function and cell types, providing novel insights into the neurobiological underpinnings and potential markers for prediction and prevention of suicide.

Background Enlarged pituitary gland volume could be a marker of psychotic disorders. However, previous studies report conflicting results. To better understand the role of the pituitary gland in psychosis, we examined a large transdiagnostic sample of individuals with psychotic disorders.Methods The study included 751 participants (174 with schizophrenia, 114 with schizoaffective disorder, 167 with psychotic bipolar disorder, and 296 healthy controls) across six sites in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. Structural magnetic resonance images were obtained, and pituitary gland volumes were measured using the MAGeT brain algorithm. Linear mixed models examined between-group differences with controls and among patient subgroups based on diagnosis, as well as how pituitary volumes were associated with symptom severity, cognitive function, antipsychotic dose, and illness duration.Results Mean pituitary gland volume did not significantly differ between patients and controls. No significant effect of diagnosis was observed. Larger pituitary gland volume was associated with greater symptom severity (F = 13.61, p = 0.0002), lower cognitive function (F = 4.76, p = 0.03), and higher antipsychotic dose (F = 5.20, p = 0.02). Illness duration was not significantly associated with pituitary gland volume. When all variables were considered, only symptom severity significantly predicted pituitary gland volume (F = 7.54, p = 0.006).Conclusions Although pituitary volumes were not increased in psychotic disorders, larger size may be a marker associated with more severe symptoms in the progression of psychosis. This finding helps clarify previous inconsistent reports and highlights the need for further research into pituitary gland-related factors in individuals with psychosis.

Introduction: Treatment studies in FMR1 knockout rodent models have found that minocycline and lovastatin each improve synaptic, neurological, and behavioral functioning, and open-label chronic dosing studies in human patients with fragile X syndrome (FXS) have demonstrated modest clinical improvements. Findings from blinded studies are mixed, and there is a limited understanding of electrophysiological target engagement that would facilitate cross-species translational studies. Smaller-scale, acute (e.g., single-dose) drug studies may speed treatment identification by detecting subtle electrophysiological and behavioral changes.Materials and Methods: Twenty-nine participants with FXS (31% female) ages 15-45 years completed a randomized, double-blind, crossover study in which they received a single oral dose of 40 mg of lovastatin, 270 mg of minocycline, or placebo, with a 2-week washout period between dosing visits. Participants completed a comprehensive neuropsychological battery and three EEG paradigms (resting state; auditory chirp; auditory habituation) before and 4 hours after dosing.Results: No serious adverse events were reported, and both drugs were well-tolerated. Compared with placebo, there were no overall treatment effects for any outcomes, including EEG, but several modest drug responses varied as a function of sex and age. Lovastatin treatment was associated with improved spatial awareness in older participants and females compared with minocycline and placebo.Discussion: We show that single-dose drug studies are highly feasible in FXS and that patients with FXS can complete a range of EEG and behavioral tasks, many of which have been shown to be reliable and may therefore be sensitive to subtle drug target engagement.Conclusions: Acute single doses of lovastatin or minocycline did not lead to changes in electrophysiological or performance-based measures. This may be due to the limited effects of these drugs in human patients or limited acute effects relative to chronic dosing. However, the study design was further validated for use in neurodevelopmental populations.