Progress in Neuro-Psychopharmacology and Biological Psychiatry

BackgroundFunctional neurological disorder (FND) is associated with alterations in functional brain networks, yet relationships between peripheral autonomic physiology and brain architecture remain poorly characterized. This pilot study examined associations between cardiac autonomic metrics and resting-state functional connectivity (rsFC) in FND. MethodsTwenty females with FND and 23 age-matched female psychiatric controls (PCs) completed questionnaires, 10-min resting photoplethysmography recordings, and same-day resting-state fMRI. Interbeat interval (IBI) and heart rate variability (HRV) metrics were extracted. Whole-brain rsFC was quantified using weighted-degree [centrality]. Within-group analyses tested associations between cardiac autonomic metrics and weighted-degree rsFC separately in FND and PC cohorts, adjusting for age, head motion, and antidepressant/{beta}-blocker use - while applying a cluster-wise correction. ResultsCardiac (IBI and HRV) metrics did not differ between FND and PC cohorts, and these metrics did not correlate with FND symptom severity, somatic symptom burden, affective symptoms, or childhood trauma. In FND, shorter IBI (i.e., faster resting heart rate) correlated with increased weighted-degree rsFC in bilateral supplementary motor area (SMA) and right precentral/superior frontal regions, whereas higher HRV primarily correlated with decreased weighted-degree rsFC in the bilateral SMA, mid-cingulate cortex, and right amygdala, anterior insula, and lateral orbitofrontal cortex. In PCs, autonomic-rsFC associations were more spatially restricted to the anterior/mid-cingulate and SMA. ConclusionIn FND, individual differences in resting autonomic physiology related to the centrality of brain areas that are part of the central autonomic, salience, and allostatic-interoceptive networks. These findings suggest that the relationship between autonomic physiology and network architecture may be important in FND.

BackgroundTheta-band oscillation is integral to fronto-parietal connectivity in the executive control network and its top-down regulation on subcortical areas. External frontoparietal synchronization using theta-frequency transcranial alternating current (tACS) is a technology to potentially engage this network. In this pre-registered, triple-blind, sham-controlled trial (NCT03907644), we tested this intervention targeting the right frontoparietal network in people with opioid use disorder (OUD) to measure network engagement and behavioral outcomes. MethodSixty male participants with OUD were randomized to receive 20 minutes of active or sham 6 Hz tACS (HD electrodes over F4 and P4). Structural, resting-state, task-based fMRI drug cue reactivity, and repeated cue-induced craving assessments were collected immediately before and after stimulation. Pre-registered outcome measures were analyzed using timexgroup interaction models to examine (1) modulation of drug cue-related brain activity, (2) changes in craving, (3) alterations in functional connectivity, and (4) relationship between electric field, neural responses, and craving behavior. Results(1) A significant Time x Group interaction revealed decreased post-stimulation opioid cue-related activity in the active group relative to sham, involving key nodes in reward processing (ventral striatum, amygdala and ventral tegmental area) (FWE corrected =0.05) (2) subjective craving did not differ significantly between groups (3) Group by time generalized psychophysiological interaction analyses showed increased right frontoparietal network engagement ({beta}=2.63, p=0.0308) following stimulation, and increased top-down inhibitory regulation of frontoparietal network on right ventral striatum ({beta}=1.99, p=0.037) and left medial amygdala ({beta}=1.97, p=0.039) (4) Electric field strength in the right frontal/parietal node predicted frontoparietal network engagement in the active group (r=0.43, p=0.02). ConclusionTogether, these findings demonstrate that theta-band frontoparietal tACS can modulate activity and task-dependent coupling within cortical-subcortical circuits in OUD, supporting network-targeted neuromodulation as a potential intervention for addiction. Significance StatementAddiction is linked to imbalances in cortico-subcortical brain circuits that control reward processing and craving. This study tested whether a non-invasive brain stimulation method-- theta-band transcranial alternating current stimulation (tACS)--can rebalance these circuits in people with opioid use disorder. Using advanced brain imaging, we found that tACS strengthened communication within frontoparietal brain regions involved in self-control while reducing their connections with reward and emotion centers. These brain changes were linked to reduced craving responses to drug cues. Our results demonstrate that dual-site, network-targeted tACS modulates neural activity and task-dependent engagement of brain circuits during drug cue reactivity in addiction, supporting its potential as a novel therapeutic approach.

Task-based functional magnetic resonance imaging (fMRI) examines how the brain dynamically responds to cognitive and perceptual demands, offering complementary insight beyond traditional activation-based analyses in schizophrenia. Prior task-based fMRI studies have identified reduced functional connectivity within auditory and associated cortical areas. In this study, we investigated task-evoked functional connectivity and brain state dynamics in 25 healthy controls, 23 patients with schizophrenia experiencing auditory verbal hallucinations (AVH+), and 23 patients without hallucinations (AVH-). Participants completed multiple auditory paradigms, including word lists, sentence lists, and reverse speech. The most robust connectivity differences emerged during the word list task, where cluster-level analyses revealed distinct network interaction patterns differentiating controls, AVH+, and AVH-patients. Energy landscape modeling further demonstrated altered stability and organization of brain states in both patient groups, with the largest deviations observed in AVH+ individuals. These alterations point to dysregulated neural dynamics linked to hallucination vulnerability. Overall, the results show that task-based fMRI sensitively captures disruptions in functional connectivity and brain state stability relevant to auditory hallucinations, underscoring its value for characterizing network-level mechanisms underlying perceptual disturbances in schizophrenia.

Despite decades of clinical implementation of medications for opioid use disorder (OUD), overdose mortality rates remain high, underscoring a critical gap in treatments that target brain mechanisms driving addiction. Mindfulness-Oriented Recovery Enhancement (MORE) has demonstrated efficacy in reducing opioid use and craving, hypothetically by restructuring the salience of drug and natural rewards. Yet, to date, MOREs neurobiological mechanisms remain unclear. In this first functional magnetic resonance imaging (fMRI) randomized controlled trial (RCT) of MORE for OUD (NCT04112186), we tested whether compared with an active psychoeducational supportive therapy (PST) control group, MORE rebalanced neural responses to drug and natural reward cues in inpatients with OUD receiving standard of care including medications. Compared with PST, eight weeks of MORE significantly reduced drug-biased activity in the dorsolateral prefrontal cortex (dlPFC) and posterior regions of the default mode network including the precuneus during downregulation of responses to drug cues relative to upregulation of responses to natural reward cues (even when controlling for passive cue viewing). The shift from drug to natural reward responses in the lateral and ventromedial PFC was associated with lower cue-induced craving exclusively in the MORE group. MORE also reduced medial PFC synchronization to naturalistic drug-related movie scenes and significantly extended abstinence duration at follow-up ([~]4 months post-treatment) relative to PST. Together, this neuroimaging RCT demonstrates that MORE normalizes function in PFC nodes of the reward, salience, and control systems, positioning MORE as a biologically-grounded adjunct to pharmacotherapy for OUD.

Substance use disorder (SUD) recovery typically requires transformative change and prioritizing long-term healthy goals. Unfortunately, successful recovery is threatened by relapse rates that often exceed 50% in the first year. We previously reported on an experiential virtual reality (VR) SUD recovery intervention using personalized future self-avatars that produced emotional engagement and positive behavioral change, ie, stronger connection with the future self and future rewards and reduced craving. Here, we used fMRI to identify brain engagement to a future self experience with divergent futures. Twenty adults (14 male, 33 years old) in early SUD recovery (<1 year) interacted with age-progressed versions of themselves in two different VR future realities: an SUD Future Self and a Recovery Future Self. Vivid lifelike visual and audio animation was augmented with a personalized narrative concerning future drug use and recovery. MRI immediately followed. Participants viewed videos of their future selves in the virtual environment and were directed to contemplate what they were seeing. Viewing and contemplating the future selves elicited activation in midline default mode regions (posterior cingulate and ventromedial prefrontal cortices), visual regions including the occipital and fusiform face areas, and left middle frontal gyrus. The Recovery Future Self produced significant left occipital face area activation compared with the SUD Future Self. Midline default mode activation correlated with VR-induced increases in delayed reward preference, and also with greater trait perseverance. Using digital selves as therapeutic agents reveals an entirely novel set of possible interventions and opens exciting new frontiers in behavior change methodology. Future studies targeting decision-making and future behavior could be informed by evaluating increased midline default mode engagement, with uniquely self-focused mechanisms signaled by executive network and face area coactivation. New hope for treatment-resistant mental health conditions is offered by the nearly limitless range of therapeutic experiences enabled by immersive digital therapeutics. Plain Language SummaryHigh relapse rates in early recovery remains a serious challenge. To promote better outcomes, our team recently developed a virtual reality experience where people interacted with future versions of themselves. We used magnetic resonance imaging (MRI) to understand how the brain activated to this experience, and what brain responses were linked to positive outcomes. We worked with 20 adults in early recovery. Each person used virtual reality to interact with two different future selves: one who had returned to substance use, and one who had stayed in recovery. These digital future selves looked and sounded like the participants and were paired with a personalized story about future drug use and recovery. Right after the virtual reality session, participants brains were scanned while they watched videos of these future selves and were asked to think about what they were seeing. When people viewed and reflected on their future selves, brain areas involved in self-reflection and imagining the future became more active, along with regions that process faces. The future selves triggered brain activation in "self-focused" brain networks and in face-processing regions. Activity in key "self-focused" brain regions was linked to choosing larger, delayed rewards over smaller, immediate ones, and to lower impulsivity. These findings suggest that lifelike digital versions of peoples future selves engage brain systems that support thinking ahead, persistence, and valuing long-term outcomes. This creates a promising new avenue for immersive digital therapeutic experiences to encourage lasting behavior change in early recovery from substance use disorder.

As the global burden of addiction intensifies, the neurobiological commonalities and distinctions between substance use disorders (SUDs) and behavioral addictions (BAs) remain poorly characterized. This coordinate-based meta-analysis of 59 fMRI articles (n = 2,951) mapped the neural signatures of visual cue-reactivity across the addictive disorders. Our results revealed a universal core network shared by SUDs and BAs centered in the bilateral opercular inferior frontal gyrus, suggesting a shared disruption in inhibitory control. Distinctively, SUDs exhibited a stronger recruitment of a subcortical salience pathway, with greater involvement of the left thalamus ventral anterior nucleus than BAs, potentially reflecting pharmacologically amplified bottom-up salience attribution. Notably, recovery-related patterns diverged in the left medial superior frontal gyrus. Alcohol use disorder was associated with neural restoration, whereas heroin use disorder showed neural decompensation. These neural signatures establish a rigorous neurobiological basis for differentiating substance and behavioral phenotypes, supporting tailored circuit-based precision treatments.

BackgroundPrediction of response to antipsychotic medications remains elusive, and a biomarker assisting in treatment selection would drastically improve prognosis. The 40 Hz auditory steady state response (ASSR) is an EEG biomarker, mirroring the GABA-glutamate signaling and the excitation/inhibition balance, consistently been reported to be impaired in schizophrenia, on, with inconsistent evidence of an association with specific symptoms. MethodsN=69 schizophrenia inpatients with an acute psychotic episode underwent an EEG recording to assess event related spectral perturbation (ERSP), intertrial phase coherence (ITC) and phase amplitude coupling (PAC) during the ASSR task, aimed to assess their relationship with response to antipsychotics and with positive, negative, disorganized, excited and depressive symptoms. Moreover, patients were compared with controls (N=36), to delineate schizophrenia acute phase ASSR dynamics. ResultsResponders to treatment showed a decreased 40 Hz ERSP in both the early (0-0.2s post-stimulus; P=0.0013; d=-0.936) and late (0-2-1.2s post-stimulus; P=0.0022; d=-0.932) time windows compared to non-responders. Using logistic regression and bootstrap optimism correction, ERSP classified the two groups with 70% accuracy. Responders but not non-responders showed a reduced ERSP compared to controls (P=0.0211; d=-0.558). Patients had reduced early ITPC (P=0.0001; d=-1.015) vs controls. responders compared to non-responders had increased PAC in the early (P=0.0215; d00.65) and in patients vs controls, in both the early (P=0.0002; d=0.57) and the late (P=0.0006; d=0.74) windows. No association emerged between ASSR metrics and symptoms severity. ConclusionsASSR is a candidate biomarker for antipsychotic treatment personalization. Only responders to treatment presented a significant gamma-band impairment, in line with previous literature on stabilized outpatients, but not non-responders, indicating that a distinct neurobiology could exist.

Schizophrenia is a severe neuropsychiatric disorder characterized by positive and negative symptoms and cognitive impairments. The present study aimed to investigate the potential interference of ambient noise on the performance of executive function (EF) tasks in individuals with schizophrenia. The sample consisted of 40 participants, divided equally into two groups: a group of individuals with schizophrenia (SchG) and a healthy control group without neuropsychiatric disorders (HC). All participants did three EF assessment instruments: Trail Making Test, Corsi Block Test, and Maze Test. The experimental design included a test-retest procedure with order counterbalancing: half of the sample began the assessment in the noise condition and the other half in the no-noise condition, to control for order and learning effects. The results indicate that ambient noise has a negative impact on the cognitive performance of individuals with schizophrenia. Specifically, the SchG group performed significantly worse on the Maze Test in the noise condition compared to the no-noise condition. These findings contribute to the understanding of the interactions between sensory and cognitive processes underlying the symptoms of schizophrenia. In addition to their theoretical potential, the results have practical implications, as they support the development of intervention strategies and ambiental adaptations that can improve the functionality and quality of life of people with the disorder.

IntroductionMechanism-of-action studies on Eye Movement Desensitization and Reprocessing have so far focused mainly on the presumed active component of bilateral stimulation (BLS). In this pilot study, a further potential working mechanism was examined for the first time, involving stimulation-induced changes in emotional valence. MethodsTwenty-five patients with posttraumatic stress disorder and 25 healthy controls between 19 and 64 years of age underwent a simulated intervention based on components of Eye Movement Desensitization and Reprocessing (EMDR). Each participant was presented with 18 individual script pairs, simulating different valence shifts (valence switch into neutral, valence switch into positive, no valence shift), whereas BLS vs. no BLS were applied. During the intervention, subjective and physiological emotional responses were measured. ResultsWhen valence shifted to positive or neutral, a significant change in treatment-relevant subjective and physiological effect measures was found compared to scripts without a valence shift. For stimulation type, no subjective, but significant physiological effects were observed: The controls showed a physiological de-arousal under BLS, indicated by a decreased skin conductance level, and the patients showed an accelerated heart rate and an increased M. zygomaticus activity. Significant interaction effects were observed: Under BLS, the arousal-reducing and valence-changing effects of negative to neutral switches increased. Interestingly, these BLS effects became conscious to the participants only when valence switches were applied. DiscussionThe findings provide new insights into the potential emotion-modulating physiological effects of BLS and its interplay with changes in emotional valence.

Schizophrenia is a serious mental disorder characterized by enhanced sensory-perceptual alterations. We investigated face identity recognition in people with schizophrenia with the Facial Identity Recognition Structured Task (FIRST) develop at our laboratory. This was created with natural interference features (beard, makeup and mask). This task consists in six block-trails of six images for identity recognition. Forty three adult volunteers divided into two groups: a Health Control (HC) and a group of hospitalized patients with Schizophrenia (SchG) participated in the study. We measured the total number of correct answers as well as the average reaction time for each block. We observed significant losses in recognition of identity faces with interferences such as make up, beard and facial-mask.

Youth alcohol use is a significant global health concern. Despite the widespread nature of alcohol use-related problems, the longitudinal effects of alcohol on brain structure in youth remain unclear. This review aimed to systematically synthesise the findings from the longitudinal structural magnetic resonance imaging (sMRI) literature on how alcohol use is associated with changes in brain structure in youth. Following PRISMA guidelines, five databases were searched, and studies of youth alcohol use that measured brain structure using sMRI at more than one time-point were included. A label-based meta-analysis (i.e., ratio of number of significant effects for a specific brain region to total number of analyses for that brain region) approach was employed to synthesise the findings. Sixteen studies were included. There was preliminary evidence that youth alcohol use is associated with reduced cortical volume (particularly in temporal regions) and attenuated increases in white matter volume over time. The role of pre-existing structural differences, and other moderating factors remains unclear due to limited research. Future longitudinal studies are needed to clarify the clinical significance of neurodevelopmental changes associated with youth alcohol use. Significance statementThis systematic review synthesises evidence from 16 longitudinal neuroimaging studies on youth alcohol use and brain structure. Preliminary findings suggest adolescent drinking may be associated with reduced grey and white matter volume over time, with heavier consumption amplifying these effects. While methodological limitations prevent definitive conclusions, these potential neurodevelopmental disruptions during a critical brain maturation window could influence cognitive and behavioural outcomes. The review highlights the need for rigorous future research to further clarify the impact of alcohol on developmental brain trajectories, which could support targeted prevention approaches for adolescent brain health.

Background and PurposeThe magnetic resonance imaging (MRI) access for patients with active and passive implants is limited by radiofrequency (RF) safety. The time-averaged root-mean-square RF field (B1+rms) and specific absorption rate (SAR) are being evaluated to monitor and control RF-induced heating near conductive metallic implants, such as deep brain stimulation (DBS) leads, during MRI. However, experimental methods to assess the relationship between RF power, B1+rms, and SAR are lacking for RF coils, metallic implants, and ionic solutions. Materials and MethodsA method is developed to evaluate the variation of RF power, B1+rms, and SAR with RF coils, metallic implants, and ionic solutions using phantoms consisting of water (H2O) and sodium chloride (NaCl) with four ionic concentrations (0, 1, 2, 3 %), four metallic wavelengths (0,{lambda} /2,{lambda} , 2{lambda}), two RF coils (body, head) transmit/receive (Tx/Rx) combinations, and five RF pulse flip angles (30{degrees}, 45{degrees}, 60{degrees}, 75{degrees}, 90{degrees}) in two B0 fields (1.5T and 3T). ResultsThe scanner-reported RF power and SAR varied with RF pulse sequences, RF coils, Tx/Rx, metallic implants, and ionic solutions, whereas B1+rms varied only with RF pulse sequences. The RF power, B1+rms, and SAR relationship depends on RF pulse sequences, RF coils, Tx/Rx, implant wavelengths, and ionic concentrations. SAR (whole-body, head) scaled with RF power by absorption ratios () variable with experimental conditions. ConclusionsB1+rms is insensitive to the presence and absence of conductive metallic implants and ionic solutions, implant wavelengths, ionic concentrations, RF coils, and Tx/Rx combinations. RF power must be monitored because scanner-reported SAR may vary unpredictably with experiments.

Neurological health score (NHS), indicating the health of brain and nervous system, helps in identifying high risk individuals, and in recommending lifestyle modifications. In the present study, we developed NHS based on genetic, lifestyle and biochemical variables associated with eight neurological disorders - dementia, stroke, Parkinsons disease, amyotrophic lateral sclerosis, schizophrenia, bipolar disorder, multiple sclerosis and migraine. UK Biobank data from Caucasian individuals was used to develop the model, and the data from individuals of Indian ethnicity was used to validate the model. Logistic regression and XGBoost algorithms were used in selecting the significant variables for the disorders. NHS developed from the selected variables was found to be very significant after adjusting for age and sex (AUC:0.6, OR: 0.95). Higher NHS was associated with a lower risk of neurological disorders and better social well-being. Highest NHS group (top 25%) showed 1.3 times lower risk compared to the rest of the individuals. Results of our study help in developing a framework for quantifying the neurological health in clinical setting.

Transcranial Magnetic Stimulation (TMS) involves pulsed magnetic fields that pass through the scalp to stimulate the brain, with incidental stimulation to superficial nerves and muscles. From a research perspective, the tactile sensations can be a problematic confound, particularly when stimulation approaches an unpleasant or painful level. Additionally, tactile sensations contribute to difficult challenges in establishing an appropriate sham control condition. Clinically, some patients find stimulation uncomfortable or intolerable. Clinicians need data on adjustments to stimulation parameters to improve tolerability and efficacy. The primary objective of this study was to characterize the tolerability of TMS by location (over modified Beam F3 prefrontal, THREE-D prefrontal, right orbitofrontal, medial prefrontal, motor, and parietal cortical targets, as well as the knee) and by frequency (1 Hz, 10 Hz, or iTBS), with increasing levels of stimulation intensity. We also characterized sensory thresholds and qualitative aspects of stimulation across locations and frequencies. For location, sites distal to the facial nerves and muscle (Knee, P3, M1, mPFC) were more tolerable, followed by Beam F3, with the THREE-D and AF8 locations as least tolerable. For frequency, we found that 1 Hz was significantly more tolerable than 10 Hz and iTBS. iTBS was more annoying than 10 Hz but only marginally different in tolerability. TMS researchers and clinicians should understand the impact of sensation based on location and frequency, with increasing stimulation intensity. This is a single-session study in generally healthy individuals, and there is a need for additional data to further inform research and clinical practice.

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.

BackgroundChronic insomnia is a highly prevalent and disabling comorbidity in adolescent schizophrenia. Although schizophrenia has been increasingly conceptualized as a disorder of large-scale brain network disconnection, the mechanisms by which neuromodulation acts on overlapping system-level network architecture to improve sleep remain poorly understood. Here, we investigated the network, neurochemical, and transcriptomic mechanisms underlying transcranial direct current stimulation-based sleep improvement in adolescents with schizophrenia. MethodsIn a randomized, double-blind, sham-controlled trial, 78 adolescent schizophrenia with chronic insomnia received either active or sham transcranial direct current stimulation (tDCS). The anode was positioned over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the right DLPFC (20 sessions over 4 weeks). Insomnia Severity Index (ISI) and resting-state functional magnetic resonance imaging (fMRI) were assessed at baseline and post-treatment. We employed a multiscale analytical framework: Shannon-entropy diversity coefficients quantified overlapping system architecture; JuSpace toolbox assessed spatial correspondence with neurotransmitter maps; and the Allen Human Brain Atlas interrogated transcriptomic correlates. ResultsActive tDCS significantly improved insomnia symptoms compared to sham stimulation. This clinical improvement was accompanied by reorganization of overlapping network architecture involving 15 cortical regions with cross-network participation across attention, somatomotor, visual, and default-mode systems. Greater reduction in Shannon-entropy diversity coefficients was correlated with greater insomnia improvement. Spatially, such Shannon-entropy diversity coefficients changes aligned with the distribution of the dopaminergic transporter (DAT), metabotropic glutamate receptor 5 (mGluR5), and vesicular acetylcholine transporter (VAChT). At the molecular level, expression of 104 genes correlated with tDCS-sensitive regions, enriched for ionotropic glutamatergic signaling and AMPA/NMDA receptor complexes, and showed peak expression in cortical excitatory neurons during adolescence. ConclusionstDCS alleviates insomnia in adolescents with schizophrenia by restoring dysfunctional overlapping system architecture, a process spatially constrained by dopaminergic, glutamatergic, and cholinergic systems and supported by an adolescent-relevant glutamate gene network. Our findings reveal a multiscale pathway for neuromodulation and provide a biologically-grounded blueprint for developing sleep-focused personalized interventions in serious mental illness. Trial registrationThis study was registered in the Chinese Clinical Trial Registry (No. ChiCTR2600116100). Registered 5 January 2026 - Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=288899

Changes in basic associative learning processes have been identified in several psychiatric conditions. However, it remains unknown whether these findings result from ongoing psychopathology or represent an underlying transdiagnostic risk factor for multiple clinical states. In this study, 72 participants with subclinical psychopathology, 23 of whom met criteria for the clinical high-risk for psychosis transdiagnostic risk syndrome (CHR+), completed a fear conditioning and generalization paradigm while functional magnetic resonance imaging (fMRI) data were collected. During this procedure, participants were presented with face stimuli that were either paired (CS+) or not paired (CS-) with a mild electrical shock, as well as eight face "morphs" (between the CS+ and CS-) tailored to each participants perceptual discrimination ability. Following the scan session, participants rated the likelihood that each stimulus had been previously followed by a shock. Fear generalization-related neural responses and the memory ratings were then examined using both categorical and individual-level, psychometric modeling approaches. Expected patterns of fear generalization-related responses were observed in the anterior insula and superior frontal gyrus, and in the memory ratings. The psychometric modeling analysis revealed a significantly greater threshold in responses of the left anterior insula, representing a wider fear generalization curve, in the CHR+, compared to the control, group. Moreover, across the whole sample, symptoms of anxiety were associated with a wider fear generalization threshold. Thus, these findings suggest that specific features of one basic associative memory process, fear generalization, may be linked to CHR status and transdiagnostic risk for psychiatric illness.

BackgroundEarly low-level alcohol use predicts subsequent alcohol use and problems. Impulsivity and poor inhibitory control also predict later problematic alcohol use. However, few studies prospectively examine early sipping in combination with modeling impulsivity and inhibitory control change over time as predictors of adolescent alcohol use. MethodsData Release 6.0 from the Adolescent Brain Cognitive Development (ABCD) Study was used (n=11,866; 48% Female). A series of linear mixed-effect models examined trajectories of non-religious sipping at baseline (ages 9-10) and self-reported impulsivity (UPPS-P) and task-based inhibitory control (Flanker task) over time as predictors of past year drinks and problematic alcohol use by ages 15-16. Predictors were run as separate models and a full model with all predictors together. Models were nested within the participant and study site. Interactions with age (to measure change over time from Baseline to Year 6) were included. Corrections for multiple comparisons were employed. ResultsIn individual models, four impulsivity interactions were significant: (1) negative urgency*age ({beta}=.04, FDR-p<.001), (2) positive urgency*age ({beta}=.04, FDR-p<.001), (3) lack of planning*age ({beta}=.04, FDR-p<.001), and (4) sensation seeking*age ({beta}=.04, FDR-p<.001), suggesting that as age increases, the relationship between impulsivity and alcohol use strengthens. Sipping*age ({beta}=.02, FDR-p<.001) interactions also predicted standard drinks. Regarding problematic use, there was a significant interaction in the full model: negative urgency*age ({beta}=-.07, p=.05), indicating that this relationship is more pronounced at earlier ages. ConclusionsTrait impulsivity and sipping in late childhood relate to future alcohol use, and the relationship strengthens with age. Our results found a negative interaction between negative urgency and age on problematic use, potentially indicating negative urgency as a phenotype of vulnerability to experiencing alcohol related problems at younger ages. Findings indicate the importance of understanding facets of impulsivity in the context of adolescent alcohol use for prevention and intervention efforts.

BackgroundSpeech cortical mapping (SCM) conducted with widely available functional MRI (fMRI) can yield divergent results compared to the more commonly used navigated TMS (nTMS). The impact of specific fMRI task paradigms and preprocessing choices on reaching similarity with nTMS has not been explored before. ObjectiveTo test how the fMRI experimental task and spatial smoothing of the data compare with nTMS-based results, to subsequently increase the reliability of object naming fMRI for SCM. MethodsThirteen healthy, right-handed Finnish speakers underwent an nTMS-based SCM experiment in which the left hemisphere was stimulated while the subjects overtly named common visually presented stimuli. Standard as well as magnetoencephalography-informed picture-to-TMS intervals were applied. The same participants completed fMRI with overt naming, silent naming, and observation tasks on the same stimuli, analyzed with 0-, 3-, and 6-mm spatial smoothing. nTMS-based error and non-error sites were converted to volumetric density maps, and error-specific maps were derived by subtracting non-error from error density. Spatial similarity between binarized fMRI maps and nTMS maps was quantified using Jaccard index. Within-session fMRI reliability was estimated with voxel- and subjectwise concordance correlation coefficients across two separate runs conducted on the same day. ResultsSimilarity between fMRI and nTMS maps was overall low but depended significantly on data smoothing. Within subjects, mean error-specific Jaccard index was 0.036, with most individuals showing maximal similarity at 6 mm of smoothing. The fMRI task resulting in highest similarity with the nTMS map varied across participants, but at the group level, silent naming with 6-mm smoothing yielded the best correspondence. In general, within-session fMRI reliability increased with greater smoothing. ConclusionThe amount of applied fMRI data smoothing shapes the agreement of fMRI and nTMS maps during SCM. Silent naming fMRI combined with 6-mm data smoothing yielded the highest overlap with nTMS maps, yet the effect of the experimental task was statistically non-significant and the absolute similarity of the maps remained low. These results underline the different views to brain functions provided by direct perturbation of neural functions vs. blood-oxygenation based fMRI, and offer practical guidance when combining fMRI with nTMS in noninvasive speech cortical mapping. HighlightsO_LICorrespondence of fMRI and TMS speech cortical mapping results varied across individuals C_LIO_LIConcordance between the methods was generally low and depended on the fMRI data smoothing C_LIO_LISilent naming task in fMRI, combined with 6-mm data smoothing, yielded highest similarity to nTMS C_LIO_LIWithin-session fMRI reliability increased with greater smoothing C_LI

IntroductionSleep spindles are electroencephalographic elements characteristic of non-rapid eye movement sleep generated by thalamo-cortical interactions. Spindles have been linked to some of the cognitive benefits afforded by sleep and high spindle activity is associated with increased arousal threshold (deeper sleep). Here, we demonstrate that targeting the thalamus with Transcranial Electrical Stimulation with Temporal Interference (TES-TI) can enhance spindle activity. Methods24 participants (25.5 {+/-} 9.5 years; 69.6% F) underwent thalamic TES-TI stimulation during daytime naps. Three stimulation protocols were tested during stage 2 of non-rapid eye movement sleep (N2): fixed difference frequency of 10 Hz (TES15kHz-TI10Hz), difference frequency matched to individual spindle peak (TES15kHz-TIPeak), and carrier frequency only (TES15kHz). Spectral power in the spindle (sigma) band and integrated spindle activity (ISA) were compared before and during the stimulation, and across stimulation protocols. ResultsTES15kHz-TI10Hz stimulation was associated with a significant increase in sigma band power ({Delta}[x]STIM-PRE = 0.49 log10{micro}V2, p = 0.021) and ISA ({Delta}[x]STIM-PRE = 7.48 {micro}V/s, p = 0.042). Cluster-based analysis localized the increase in sigma power over the frontal and centro-parietal areas (p = 0.022). Linear mixed effects models showed that both sigma band power and ISA during stimulation increased significantly in TES15kHz-TI10Hz compared to the TES15kHz protocol ({beta} = 0.67 log10{micro}V2, p = 0.018; {beta} = 14.70 {micro}V/s, p = 0.0077), while the TES15kHz-TIPeak did not show the same effect. ConclusionsThis study provides evidence supporting the successful use of TES-TI targeting the thalamus to enhance sleep spindle activity. Stimulation at a fixed difference frequency of 10 Hz increased sigma band power and ISA, whereas neither stimulation matched to individual sigma band peak nor TES alone produced comparable effects. These promising results warrant further investigations into the cognitive and clinical impact of TES-TI, a non-invasive neuromodulation tool that can reach deep brain regions. Statement of significanceThis study provides evidence that thalamo-cortical networks, which are central to many physiological and pathological brain activities, can be modulated non-invasively in humans. More specifically, the findings show that transcranial electrical stimulation with temporal interference targeting the thalamus can selectively enhance sleep spindle activity. This work introduces a new strategy for precisely targeting sleep-generating mechanisms regulated by deep brain circuits without surgery or medication. Key next steps include determining how this increase in spindle activity can positively impact cognition and assessing the translational potential of this approach for clinical populations.