Psychiatry and Clinical Neurosciences

AimsDue to the multifaceted nature of "impulsivity", its measurement remains fragmented. Here, we developed the Risky Social Choices task to provide evidence for its validity and reliability, while testing the hypothesis that impaired access to implicit knowledge of negative long-term consequences is of distinct importance for "impulsive" decision-making in a general population sample. MethodsForty participants chose whether to engage in risk-taking behaviors, which combined web-based AI-generated videos with narrated hypothetical scenarios and measured worries related to negative long-term consequences, approach-related motivation for short-term rewards, response time to and accuracy of recognizing degraded auditory prime words denoting negative long-term consequences. ResultsA pre-registered multi-step regression model was constructed with worry, motivation, response time and accuracy as predictors and percentage of risky choices as the outcome. Among all predictors, only prime word recognition accuracy was significantly negatively associated with risky choices, confirming our hypothesis of the role of reduced implicit access to negative long-term consequences in risk-taking decisions. In contrast, approach-related motivation for rewards was the only predictor significantly positively related to percentage of risky choices. DiscussionAs predicted, the negative association between risky choices and implicit access to negative long-term consequences supports its role as a distinct aspect of "impulsivity". The novel task successfully captured this aspect, paving the way for a more precise neurocognitive characterization of clinical conditions where "impulsivity" plays a key role. The findings unveil the importance of implicit social sequential knowledge for impulsivity in neurotypical populations, so far only investigated in patients with brain lesions.

ObjectivesAlarm fatigue is a patient safety concern in ICUs, yet no validated instrument exists to assess alarm fatigue among healthcare professionals in non-Western settings. This study aimed to cross-culturally adapt the Charite Alarm Fatigue Questionnaire (CAFQa) into Japanese and evaluate its reliability and validity among ICU nurses and physicians. MethodsThe Japanese CAFQa was cross-culturally adapted following the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines, including forward translation, back-translation, expert panel review, and cognitive interviews. A multicenter cross-sectional validation study was performed across eight ICUs at five hospitals in Japan. A total of 129 participants (103 nurses and 26 physicians) completed the Japanese CAFQa, the NIOSH Brief Job Stress Questionnaire, and the Insomnia Severity Index (ISI). Structural validity, internal consistency, test-retest reliability (n = 102), convergent validity, and known-groups validity were assessed. ResultsCFA confirmed the two-factor structure with acceptable fit (CFI = 0.922, RMSEA = 0.041, SRMR = 0.076), with standardized factor loadings ranging from 0.33 to 0.82. The two factors were not correlated (r = 0.05). Cronbachs alpha was 0.688 for the overall scale, 0.805 for Alarm Stress, and 0.649 for Alarm Coping. Test-retest ICCs ranged from 0.616 to 0.753. The CAFQa total score correlated with the NIOSH total (r = 0.261) and the ISI total (r = 0.338). Healthcare professionals with [≥]4 years of ICU experience had higher Alarm Coping scores than those with 1-3 years (median 7.0 vs 6.5), and physicians scored higher on Alarm Coping than nurses (median 8.0 vs 7.0). ConclusionsThe Japanese CAFQa demonstrated acceptable structural validity, reliability, and convergent and known-groups validity, providing the first validated tool for quantitatively measuring alarm fatigue in Japan. Implications for Clinical PracticeThe Japanese CAFQa enables ICU managers to quantify alarm fatigue at individual and unit levels, identify high-risk staff, and evaluate the effectiveness of alarm management interventions.

BackgroundAnorexia nervosa (AN) is a severe psychiatric disorder associated with profound malnutrition, multisystem medical complications, and one of the highest mortality rates among mental illnesses. Despite decades of research into its biological and neurocognitive mechanisms, effective pharmacological treatments remain limited. While systematic reviews synthesize results from published studies, clinical trial registries offer a complementary perspective by capturing ongoing research efforts, discontinued studies, and emerging therapeutic strategies that may not yet be reflected in the published literature. ObjectiveThis study aimed to characterize the landscape of clinical research in AN by systematically analyzing studies registered on ClinicalTrials.gov. MethodsWe conducted a structured analysis of studies registered on ClinicalTrials.gov related to AN. Trial characteristics, including study design, intervention type, phase classification, geographic distribution, and recruitment status, were extracted and analyzed using an automated text-based classification pipeline. ResultsNearly 400 studies investigating AN were identified over the past 25 years. Approximately 71% were classified as interventional studies; however, a large proportion were not associated with conventional clinical trial phases, suggesting that many registered trials correspond to mechanistic or exploratory investigations rather than therapeutic development programs. The geographic distribution of studies revealed a strong predominance of North America and Western Europe. A substantial proportion of trials were terminated or discontinued, highlighting the significant challenges associated with conducting interventional studies in this population. Observational studies generally included larger sample sizes than interventional trials. ConclusionsRegistry-based analyses provide valuable insights into the evolving landscape of clinical research in AN. Despite considerable scientific activity, important gaps remain between mechanistic knowledge and the development of therapeutic interventions. Understanding these gaps may help inform future translational research strategies aimed at improving treatment options for this severe disorder.

Objective: Neuropsychiatric presentations are common across neurological and mental health services but they are often inadequately covered by core clinical psychology and clinical neuropsychology training. Consequently, we aimed to identify components for a neuropsychiatry curriculum for clinical psychologists using a Delphi process. Method: We completed a three-round e-Delphi study with 19 experts (clinical psychologists, neuropsychologists, psychiatrists, neurologists, individuals with lived experience of neuropsychiatric disorders). Round 1 collected ratings on 80 syllabus items derived from textbook reviews, conference topics, and a scoping review of neuropsychiatry syllabuses. Items failing to reach consensus were refined, and new topics added via free-text suggestions. Rounds 2 and 3 repeated rating and thematic analysis, culminating in a consensus meeting where items were classified as core or supplementary. Consensus thresholds were set at mean>=2.0, mean distance from the mean<=0.2, and => 75% agreement for final decisions. Results: The process yielded 40 core and 38 supplementary syllabus items. Core topics include autoimmune and neuroinflammatory disorders, delirium, functional neurological disorders, neuropsychiatric sequelae of epilepsy, stroke, traumatic brain injury, dementia, and multidisciplinary working, among others. Supplementary items covered background knowledge of less frequent but still prevalent disorders as well as competencies in interpreting clinical data alongside conceptual and historical issues. The final component list reflects both clinical competencies and emerging areas of practice, emphasising assessment, formulation, psychological interventions, cultural considerations, and medicolegal aspects. Conclusions: The e-Delphi derived curriculum provides a framework for neuropsychiatric competencies for postgraduate psychology training with modification needed for application in diverse healthcare settings.

ObjectiveCognitive behavioral therapy (CBT) is an effective first-line treatment for obsessive-compulsive disorder (OCD), yet it remains difficult to predict who will respond to this intervention. This study investigates associations between neural activity during inhibitory control tasks and CBT outcomes, and whether task-based fMRI data could serve as a predictive marker of individual CBT response. MethodsUsing fMRI data from individuals performing an inhibitory control task across five samples (n=130, age range=8-57, 54% female) of the ENIGMA-OCD consortium, univariate associations were analyzed between activity during response inhibition and error processing and three CBT outcomes: response, remission, and pre-post treatment change in symptom severity. Random forest and support vector machine models using leave-one-sample-out cross-validation were used for prediction of CBT response and remission from fMRI activity and clinical data. ResultsRemission after CBT was associated with weaker activity in default mode regions during response inhibition and in the right supramarginal gyrus during error processing. Greater symptom reduction was linked to weaker pre-treatment activity across frontoparietal, dorsal attention, visual, and subcortical regions during response inhibition, but to stronger default mode activity during error processing. Despite these robust group-level effects, machine learning models failed to predict individual outcomes above chance level with either neuroimaging or clinical data. ConclusionWeaker activity during response inhibition in a widespread network, as well as stronger activity in default mode regions during error processing before treatment, appear beneficial to CBT response. However, these findings cannot yet be translated into individually predictive markers of CBT outcome.

BackgroundNon-invasive gamma entrainment using sensory stimulation (GENUS) is being investigated as a therapy for Alzheimer disease (AD), but the clinical course of participants who fail to show gamma center frequency plasticity remains unclear. We therefore examined whether cognitive decline observed during personalized GENUS was attenuated after cessation in participants stratified post hoc by CF change. MethodsThis case series was derived from an open-label proof-of-concept trial with extended follow-up (mean 26.3 months). Sixteen participants with amyloid-positive early AD completed 12 weeks of home-based daily flickering light stimulation (1 hour/day) at individualized gamma frequency, and 12 completed long-term follow-up. Participants were classified post hoc as ICF+ (CF increase [&ge;]2 Hz; n=5) or ICF- (no CF increase; n=7). MMSE trajectories from baseline to week 12 and from week 12 to final follow-up were analyzed using piecewise linear mixed-effects models. ResultsBaseline characteristics, including MMSE, did not differ significantly between groups. During intervention, MMSE was stable in ICF+ (+0.27 points/month; 95% CI, -0.20 to 0.73) but declined in ICF- (-0.69 points/month; 95% CI, -1.07 to -0.30; between-group p=0.011). After cessation, estimated slopes were similar in ICF+ and ICF- (-0.16 vs -0.17 points/month; p=0.968), and the phasexgroup interaction was significant (p=0.006). Medication intensification during follow-up was more common in ICF-, including antipsychotic initiation in 4 of 7 participants. ConclusionsIn this exploratory post hoc analysis, lack of CF plasticity was associated with accelerated cognitive decline during the intervention phase but not during follow-up. This temporal pattern is consistent with, but does not establish, a dechallenge-like safety signal. Given the small sample, post hoc stratification, and differential medication changes, these findings should be considered hypothesis-generating and require prospective validation with pre-defined electrophysiologic stratification. Trial registrationClinical Research Information Service (CRIS), Republic of Korea (KCT0010618); submitted 6 October 2022; first patient enrolled 2 February 2023. https://cris.nih.go.kr/cris/search/detailSearch.do?seq=31321.

BackgroundThe severity of positive psychotic symptoms largely defines emerging psychosis syndromes. However, depressive and negative symptoms are strongly psychologically and biologically interlinked. A transdiagnostic exploration of symptom severity across early illness syndromes could enhance the understanding of shared common factors and future trajectories of mental illness. We aimed to identify subgroups based on the severity of positive, negative, and depressive symptoms and assess relationships with: 1) premorbid functioning, 2) longitudinal illness course, 3) genetic risk, and 4) brain volume differences. MethodsWe analysed 749 participants from a multisite, naturalistic, longitudinal (18 months) cohort study of: clinical high risk for psychosis (n=147), recent onset psychosis (n=161), and healthy controls (n=286), and recent onset depression (n=155). Participants were stratified into subgroups based on severity of baseline positive, negative, and depression symptoms. Baseline and longitudinal differences between groups for clinical, functioning, and polygenic risk scores (schizophrenia, depression, cross-disorder) were assessed with ANOVAs and linear mixed models. Voxel-based morphometry was used to examine whole-brain grey matter volume differences. Discovery findings were replicated in a held-out sample (n=610). ResultsParticipants were stratified into no (n=241), mild (n=50), moderate (n=182), and severe symptom (n=254) subgroups. The mean (SD) age was 25.3 (6.0) and 344 (47.3%) were male. Symptom severity was associated with poorer premorbid functioning and illness trajectory, greater genetic risk, and lower brain volume. Findings were not confounded by the original study groups or symptoms and were largely replicated. Conclusions and relevanceTransdiagnostic symptom severity is linked to shared aetiologies, prognoses, and biological markers across diagnoses and illness stages. Such commonalities could guide therapeutic selection and future research aiming to detect unique contributions to specific psychopathologies.

Catatonia is a severe psychomotor syndrome that occurs across psychiatric diagnoses and is increasingly conceptualized as reflecting neurodevelopmental vulnerability. The anterior cingulate cortex (ACC) plays a central role in motor initiation and cognitive-affective integration and displays substantial interindividual variability in its sulcal morphology, which is established prenatally and remains stable across life. In this MRI study, we examined whether ACC sulcal patterns represent a structural trait marker of catatonia. We analyzed high-resolution T1-weighted images from a hospital-based cohort comprising patients with catatonia (N = 109), psychiatric patients without catatonia (N = 323), and healthy controls (N = 91). The presence of the paracingulate sulcus (PCS) in each hemisphere was determined through blinded visual inspection, and regression analyses tested associations with diagnostic group, adjusting for age, sex, scanner type, intracranial volume, and benzodiazepine and antipsychotic exposure. Patients with catatonia exhibited a significantly reduced prevalence of the left PCS and diminished hemispheric asymmetry compared with both non-catatonic patients and healthy controls. These effects were independent of whether catatonia occurred within psychotic or mood disorders. PCS size did not differ across groups, and sulcal pattern did not correlate with catatonia severity among affected individuals. The findings demonstrate that ACC sulcal deviations are specifically associated with catatonia across diagnostic categories, supporting a neurodevelopmental etiology and reinforcing ACC involvement in its pathophysiology. Early-determined sulcal morphology may represent a trait-level marker contributing to vulnerability for catatonia, with implications for early identification, risk stratification, and targeted intervention strategies.

Deficits in inhibitory control are common across a wide range of psychiatric disorders and are closely linked to symptom severity, including emotional dysregulation, anxiety, substance misuse, and self-harm, making them an appealing target for intervention. Cognitive training offers a low-cost, scalable, and non-invasive strategy to strengthen inhibitory control; however, most existing paradigms target only a single facet of inhibition and rarely account for environmental influences, such as affective context. To address these gaps, we developed a computerized inhibitory control training paradigm to simultaneously engage three components of inhibition: preemptive, proactive, and reactive, while embedding trials within positive and negative affective contexts to assess the impact of emotional stimuli. Across two online experiments, participants completed the GAMBIT task in one session (Experiment 1, N = 300) or repeated over three sessions (Experiment 2, N = 65). The task included No-Go trials to train preemptive inhibition, stop-signal trials for reactive inhibition, and stop-signal anticipation trials to train proactive inhibition. Affective images of differing valence were presented as background stimuli to evaluate their impact on inhibitory performance. In Experiment 1, participants showed higher accuracy on No-Go versus reference Go trials ({beta}=1.45, SE=0.09, p<.001), confirming successful manipulation of preemptive inhibition. Reaction times were slower during anticipation trials across two different conditions ({beta}=0.16, SE=0.04, p<.001; {beta} = 0.07, SE = 0.04, p = 0.047), consistent with proactive slowing when anticipating a potential stop signal. Additionally, positive affective images ({beta} = 0.10, SE= 0.009, p < 0.001) further slowed RTs, indicating emotional interference with proactive control. In Experiment 2, the pattern of higher No-Go accuracy was replicated ({beta} = 0.91, SE = 0.11, p < .001) and accuracy generally improved over sessions ({beta} = 0.38, SE = 0.06, p < .001). In anticipation trials, RTs become shorter across sessions (session 2: {beta} = -0.25, SE = 0.06, p < .001; session 3: {beta} = -0.45, SE = 0.06, p < .001), reflecting practice-related gains, and SSRTs decreased over time (F(2,56) = 6.26, p = .004), consistent with enhanced reactive inhibition. Proactive inhibition was modulated by affective images, with both negative ({beta} = 0.04, SE = 0.02, p = .039) and positive ({beta} = 0.16, SE = 0.02, p < .001) affective images associated with slower RTs. Participants also reported reductions in self-assessed temper control by the last session (W = 25.5, p = .007, q = .037, d = -0.51) and usability ratings were high (all means [&ge;] 3.87/5). Together, these findings show that this paradigm recruits multiple forms of inhibitory control and yields training-related improvements in both performance and affective outcomes. This provides preliminary validation of a scalable, fully online inhibitory control training tool targeting multiple dissociable inhibitory processes within affective contexts. The approach holds promise as an accessible transdiagnostic intervention to support symptom improvement across psychiatric disorders, with future work needed to evaluate clinical efficacy in patient populations.

ObjectiveLate adolescence is a critical developmental period that typically precedes psychosis onset, yet the neural correlates of subclinical hallucinatory experiences that may impact psychosis risk are poorly understood. Given evidence from adult psychosis models implicating abnormal "triple network" connectivity among the frontoparietal (FPN), default mode (DMN) and salience/cingulo-opercular (CON) networks, as well as dopaminergic abnormalities, we examined whether hallucinatory experiences in adolescents are associated with altered triple network organization and dopamine-related measures in the midbrain. MethodsWe performed a cross-sectional analysis of 171 community adolescents aged 14-17 who underwent resting-state functional magnetic resonance imaging and neuromelanin-sensitive MRI. Hallucinatory experience severity was measured using the Specific Psychotic Experiences Questionnaire. Resting-state functional connectivity was calculated among a priori DMN, FPN, and CON cortical regions; we examined associations between connectivity, hallucinatory experience severity, within-network connectivity, system segregation, and neuromelanin signal in the ventral tegmental area (VTA). ResultsGreater hallucinatory experience severity was associated with stronger connectivity in a subnetwork composed of CON-DMN and CON-FPN edges. Greater hallucinatory experience severity was also associated with lower global network segregation. VTA neuromelanin signal was not directly associated with hallucinatory experience severity, but greater VTA signal predicted lower connectivity in the hallucination-related subnetwork. Greater VTA neuromelanin signal was also associated with a distinct pattern of stronger connectivity within DMN midline regions. ConclusionsThese findings implicate altered triple network organization in hallucinatory experiences during late adolescence and suggest that dopamine-related midbrain signal may reflect broader developmental variation in cortical network organization rather than symptom severity directly. Plain Language SummaryHallucinatory experiences during adolescence may signal increased risk for later psychotic disorders, but their brain basis is unclear. We studied 171 adolescents aged 14-17 using resting-state fMRI to measure brain network activity and neuromelanin-sensitive MRI to estimate dopamine-related midbrain signal. More severe hallucinatory experiences were linked to abnormal communication among three brain networks often implicated in psychosis. Dopamine-related signal was not directly related to hallucination severity but was associated with developmentally relevant network organization. Overall, this work serves to improve our understanding of the risk factors that may contribute to psychosis conversion in adulthood.

Individuals at clinical high risk for psychosis (CHR) are cognitively and neurobiologically heterogeneous, which encourages the use of a clustering approach to parse this heterogeneity. Multimodal approaches are assumed to be superior to unimodal approaches in identifying subgroups. With the success of the use of cognition and electrophysiological measures collectively in established psychotic disorders, and the lack of such an approach in CHR, we were motivated to address this gap. Using the North American Psychosis-Risk Longitudinal Study (NAPLS) 2 consortia (CHR (N=764)), we applied unsupervised cluster analysis on the combined cognitive and electrophysiology measures to identify CHR subgroups and assess their relationship with clinical and functional outcomes. A two-cluster solution with modest separability was found, which prompted the use of an alternative probabilistic, rather than discrete, clustering approach. Individuals who were more likely to be in Cluster 1 exhibited poorer cognitive performance, larger N100, mismatch negativity, and P300 amplitudes, and worse functioning, as well as a younger age of onset. These findings were largely replicated in NAPLS 3 (CHR (N=628)). Taken together, the results of our previous study of cognition-only clustering and the current study of combining cognition and electrophysiology indicate that multimodal clustering, if not developmentally informed, may obscure meaningful subtyping.

Background: The highly influential predictive processing theory of psychosis posits that symptoms arise from imbalances in the weighting of predictions (priors) and sensory evidence. Despite this theory's increasing prominence, studies often present conflicting results. This is particularly problematic as findings from single tasks with modest sample sizes are frequently used to advance a theory for a generalised altered reliance on priors in psychosis. Methods: This study presents a random-effects, multi-level meta-analysis (PROSPERO CRD42024574379) evaluating evidence for aberrant reliance on priors in psychosis across perceptual tasks. The search identified articles in Embase, MEDLINE, APA PsycINFO, and APA PsycArticles published between 1st January 2005 and 31st October 2024, with risk of bias assessed using the Newcastle-Ottawa Scale. Included articles (34 results from 27 studies) compared adults with schizophrenia-spectrum psychosis (SZ; n = 904) to healthy controls (n = 1,039) on behavioural measures representing reliance on priors. Results: Results provided no evidence for atypical reliance on priors in psychosis (g = .03, 95% CI [-0.27, 0.34]; p = .818) or associations with delusions (6 results; SZ = 183; r = -.16, 95% CI [-0.51, 0.19]; p = .293) or hallucinations (10 results; SZ = 370; r = .04, 95% CI [-0.28, 0.36]; p = .780). In contrast with the theory that psychosis may differentially affect priors at different levels of the cognitive hierarchy, a sub-group analysis indicated that a two-level hierarchical model of priors did not account for conflicting results (F(1,32) = 0.1, p = .758). Conclusion: These findings do not suggest that psychosis is associated with a generalised predictive processing deficit spanning multiple aspects of perception. Key words: psychosis, schizophrenia, predictive processing, prior expectations, perception

Background: Attention Deficit Hyperactivity Disorder (ADHD) is characterized by persistent inattention, hyperactivity, and impulsivity. While documented in children, research on its persistence into young adulthood in Jordan remains scarce. This gap is critical given the cognitive demands of higher education. This study estimated attention deficit hyperactivity disorder (ADHD) symptom prevalence among Jordanian university students, examined associations with gender and academic performance, and identified barriers to mental health service accessibility. Methods: A descriptive cross-sectional study using web-based sampling recruited 389 university students (aged [&ge;] 18 years) from various Jordanian universities. Participants completed an online survey, incorporating the validated English and Arabic versions of the Adult ADHD Self-Report Scale (ASRS-v1.1) to assess symptom prevalence, alongside inquiries regarding demographics, academic history, and barriers to care. Results: The prevalence of probable ADHD was 37.5% (n=146). Males constituted a significantly higher proportion of positive cases (69.9%) compared to females (30.1%). A strong statistical association was found between positive ADHD screening and negative academic impact (p<0.001), as well as negative effects on emotional well-being (p<0.001). Comorbidities including anxiety disorders and emotional abuse were significantly linked to probable ADHD (p=0.019). Notably, positive-screened participants were significantly more likely to cite social stigma as a primary barrier to seeking professional help (p=0.024). Conclusion: Self-reported ADHD symptoms are highly prevalent among Jordanian university students, correlating with substantial academic underachievement and emotional dysfunction. These findings highlight an urgent need for targeted university-based screening programs, academic accommodations, and de-stigmatization campaigns to facilitate early intervention and improve educational outcomes in this population.

Adult ADHD is increasingly recognized across the lifespan, yet the psychometric equivalence of the Adult ADHD Self-Report Scale (ASRS) remains unverified for older populations. This study examined age-related Differential Item Functioning (DIF) in 600 adults (n = 100 per decade, ages 20-80) who completed the 18-item ASRS. Using a bi-factor Graded Response Model, we extracted latent ADHD trait scores ({omega}H = .895) and assessed DIF via ordinal logistic regression with adaptive age modeling. Five of 18 items exhibited significant uniform DIF. At equivalent latent severity, older adults were less likely to endorse hyperactivity symptoms in Part A (fidgeting, feeling "driven by a motor") but more likely to endorse specific symptoms in Part B (careless mistakes, misplacing items, interrupting). From ages 20 to 80, expected Part A scores decreased by 1.36 points (~0.27 per decade), while Part B scores increased by 1.15 points (~0.23 per decade). These findings indicate a phenotypic redistribution of ADHD symptoms as individuals age. Because the 6-item Part A screener serves as the primary clinical gatekeeper, its concentration of negative DIF suggests standard screening practice may systematically underestimate ADHD severity in older adults. We recommend using the full 18-item ASRS when screening older populations and suggest that developing age-adjusted norms would improve diagnostic accuracy.

BackgroundSchizophrenia is associated with widespread cognitive impairments. Several early risk factors for schizophrenia have been identified, and some studies suggest associations between these early risk factors and cognition, yet the literature is sparse in psychosis. MethodsClinical cohorts of child/adolescent and adult patients with first-episode psychosis (FEP) and healthy controls (HC) were linked with register-based information (N=276). Gestational age, Apgar scores, birth weight and length, parental age, and season of birth were extracted from the Danish medical birth registry. Cognition was assessed at time of diagnosis using BACS, CANTAB, and WAIS-III/WISC-IV. Missing data was imputed using MICE. Canonical correlation analysis (CCA) was used to examine patterns of associations. Post hoc analyses explored group differences according to diagnosis, age, and sex. ResultsCCA resulted in two significant patterns of associations. CCA1 was stable across imputations (r=0.44, p=.036, pmin= .017, pmax= .055), and constituted by a risk profile of lower maternal age, lower birth length, being small for gestational age, and lower birth weight and a cognitive profile of lower estimated IQ and poorer working memory, mental flexibility, processing speed, verbal fluency, and motor latency. The pattern was more expressed in FEP compared to HC and in adults compared to children. CCA2 was more unstable across imputations (r=0.38, p=.033, pmin=.003, pmax=.168) and constituted by a broad pattern of minor loadings. ConclusionCognitive functioning later in life is associated with multiple early risk factors, underscoring the complexity of developmental processes and the importance of the early developmental context in shaping cognitive trajectories.

In a single-blind randomized controlled trial, we investigated the effectiveness of real-time fMRI neurofeedback delivered in 7 runs over three sessions across two weeks in N = 65 patients with alcohol use disorder. The intervention targeted modulation of ventral striatal cue reactivity to alcohol-related cues as well as enhancement of prefrontal control mechanisms in the right inferior frontal gyrus. The study design incorporate three experimental groups that either were instructed to downregulate a ventral striatum signal, upregulate the right inferior frontal gyrus, or upregulate negative functional connectivity between these two structures. In two active control groups participants were instructed to either up- or downregulate the primary auditory cortex. We did not find an effect of ventral striatal downregulation or negative connectivity feedback, and a reduced striatal activation in the right inferior frontal gyrus upregulation group was accompanied by concurrent lower activation in the target structure, suggesting that our intended modulation approaches were not effective. Identified problems that might have contributed to this unexpected outcome might have been the use of continuous feedback presentation that potentially confuses regulation target and reward processing in the ventral striatum, counterintuitive regulation directions, a lack of explicit strategy guidance and transparency about the targeted process, and generally the difficulty to recruit a sufficient number of eligible voluntary participants for a well-powered study with a complex design. These insights emphasize the complex challenges of real-time fMRI neurofeedback interventions for the treatment of substance use disorders and could provide guidance for the development of more effective future approaches.

Background: Tobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship. Methods: We used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use. Results: Brainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR. Conclusions: More frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.

In-scanner head motion is a recognized source of bias in structural magnetic resonance imaging (sMRI), yet it remains under-addressed in psychiatric neuroimaging where structural difference in patient populations are considered foundational. We examined motion-related bias in grey matter volume estimates across eight independent cohorts comprising 9,664 individuals, including 8,979 neurotypical controls (NC), 497 patients with schizophrenia (SCZ), and 188 patients with bipolar disorder (BD). Motion estimates were derived from multiple fMRI scans acquired within the same scanning session and summarized using principal component analysis. In NC, motion accounted for 1-6% of regional grey matter variance, a magnitude comparable to reported psychiatric case-control effect sizes. Adjusting for motion attenuated SCZ-NC group differences, reducing effect sizes in 85% of brain regions and yielding 5% fewer significant ROIs (pFDR<0.05). In BD, motion correction reduced effect sizes in 97% of regions, with a 24% reduction in significant ROIs. Cross-diagnostic spatial patterns were significantly correlated (r=0.63, p=3x10-{superscript 1}3), explaining a sizable portion of SCZ-BD commonalities. Critically, a falsification analysis in UK Biobank (N=5,123) showed that stratifying NC by motion alone produced grey matter differences accounting for 45-62% of SCZ case-control effect magnitude, underscoring how difficult it is to interpret SCZ-like morphometric differences as tissue properties rather than as motion-driven patterns. These findings urge caution in interpretations of sMRIdifferences in patient-control comparisons and use of systematic fMRI based motion control as standard practice in sMRI analyses.

Background: Prior neuroimaging suggests brain differences between children with attention deficit hyperactivity disorder due to prenatal alcohol exposure (ADHD+PAE) and non-exposed children with ADHD due to other, e.g., familial, causes (ADHD-PAE). There has been interest in regional brain levels of ;gamma-aminobutyric acid (GABA) and glutamate (Glu) measured in vivo with magnetic resonance spectroscopy (MRS) as possible indicators of local inhibitory, respectively, excitatory activity in ADHD. For the first time, we report here a comparison of GABA and Glu in ADHD+PAE vs. ADHD-PAE. Methods: At 3 T, we used J-difference-edited single-voxel MRS to assay GABA and Glu in 28 children with ADHD+PAE, 20 with ADHD-PAE, and 28 typically developing (TD) controls, all aged 8-14 years. MRS was sampled from midline anterior middle cingulate cortex (aMCC), the cognitive cingulate considered functionally relevant to ADHD. Spectra were fit with custom software, including a unique technique for isolating the GABA signal from the confounding macromolecular baseline (MMBL). Results: aMCC GABA was higher in ADHD+PAE and ADHD-PAE than in TD. GABA increased with age in TD, but not in ADHD+PAE or ADHD-PAE. Similar effects were observed for the ratios GABA/Glu and GABA/Glx. For GABA+MMBL (GABA+) these effects were not seen, rather GABA+ and MMBL increased with age for the ADHD+PAE group only. No significant effects were found for Glu or Glx. Conclusions: GABA in the aMCC does not distinguish the two etiologies of ADHD, rather elevated GABA that follows an abnormal developmental appears to be common to both. High GABA may reflect increased inhibition of the aMCC impairing its cognitive functions. GABA+ results in ADHD may not tract reliably with underlying GABA values. Negative results for Glu and Glx should be reexamined at shorter echo-times.

BackgroundDeep brain stimulation (DBS) is effective for approximately two-thirds of patients with treatment-resistant obsessive-compulsive disorder (OCD). While prior work has emphasized the engagement of specific white matter tracts in mediating outcomes, the contribution of region-specific white matter integrity to clinical response remains unclear. MethodsTwelve patients with treatment-resistant OCD underwent preoperative neuroimaging and DBS at our center. We assessed OCD severity preoperatively and at [~]18 months postoperatively. We extracted mean fractional anisotropy (FA) for the anterior limb of the internal capsule (ALIC) and a control tract and used Spearmans rank correlations to evaluate associations between FA and symptom improvement. We additionally evaluated this relationship for 49 white matter bundles. Finally, we used diffusion tractography to determine endpoints connected with ALIC voxels most predictive of symptom improvement. ResultsHigher preoperative ALIC FA was associated with greater clinical improvement following DBS (p=0.002). This effect was specific to the ALIC and not the control tract. Hemispheric asymmetry (right>left) in ALIC FA was moderately correlated with clinical improvement. Among all 49 bundles, the right ALIC demonstrated the strongest association with clinical improvement. Streamlines passing through the ALIC voxels that most strongly correlated with outcome ended in the diencephalon and superior frontal cortex. ConclusionsBaseline structural integrity of the ALIC was associated with the magnitude of clinical improvement following DBS for OCD. These findings suggest that regional variation in white matter integrity may reflect an underlying circuit disruption amenable to DBS, supporting the use of neuroimaging-based metrics as potential biomarkers in DBS treatment.