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Introduction: Repetitive negative thinking (RNT) is a cognitive process focusing on self-relevant and negative experiences, leading to a poor prognosis of major depressive disorder (MDD). We previously identified that connectivity between the precuneus/posterior cingulate cortex (PCC) and right temporoparietal junction (rTPJ) was positively correlated with levels of RNT. Objective: In this double-blind, randomized, sham-controlled, proof-of-concept trial, we employed real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) to delineate the neural processes that may be causally linked to RNT and could potentially become treatment targets for MDD. Methods: MDD-affected individuals were assigned to either active (n = 20) or sham feedback group (n = 19). RNT was measured by the Ruminative Response Scale-brooding subscale (RRS-B) before and 1 week after the intervention. Results: Individuals in the active but not in the sham group showed a significant reduction in the RRS-B; however, a greater reduction in the PCC-rTPJ connectivity was unrelated to a greater reduction in the RRS-B. Exploratory analyses revealed that a greater reduction in the retrosplenial cortex (RSC)-rTPJ connectivity yielded a more pronounced reduction in the RRS-B in the active but not in the sham group. Conclusions: RtfMRI-nf was effective in reducing RNT. Considering the underlying mechanism of rtfMIR-nf, the RSC and rTPJ could be part of a network (i.e., default mode network) that might collectively affect the intensity of RNT. Understanding the relationship between the functional organization of targeted neural changes and clinical metrics, such as RNT, has the potential to guide the development of mechanism-based treatment of MDD.

BACKGROUND/INTRODUCTION: Sex classification using functional connectivity from resting-state functional magnetic resonance imaging (rs-fMRI) has shown promising results. This suggested that sex difference might also be embedded in the blood-oxygen-level-dependent properties such as the amplitude of low-frequency fluctuation (ALFF) and the fraction of ALFF (fALFF). This study comprehensively investigates sex differences using a reliable and explainable machine learning (ML) pipeline. Five independent cohorts of rs-fMRI with over than 5500 samples were used to assess sex classification performance and map the spatial distribution of the important brain regions. METHODS: Five rs-fMRI samples were used to extract ALFF and fALFF features from predefined brain parcellations and then were fed into an unbiased and explainable ML pipeline with a wide range of methods. The pipeline comprehensively assessed unbiased performance for within-sample and across-sample validation. In addition, the parcellation effect, classifier selection, scanning length, spatial distribution, reproducibility, and feature importance were analyzed and evaluated thoroughly in the study. RESULTS: The results demonstrated high sex classification accuracies from healthy adults (area under the curve >0.89), while degrading for nonhealthy subjects. Sex classification showed moderate to good intraclass correlation coefficient based on parcellation. Linear classifiers outperform nonlinear classifiers. Sex differences could be detected even with a short rs-fMRI scan (e.g., 2 min). The spatial distribution of important features overlaps with previous results from studies. DISCUSSION: Sex differences are consistent in rs-fMRI and should be considered seriously in any study design, analysis, or interpretation. Features that discriminate males and females were found to be distributed across several different brain regions, suggesting a complex mosaic for sex differences in rs-fMRI. IMPACT STATEMENT: The presented study unraveled that sex differences are embedded in the blood-oxygen-level dependent (BOLD) and can be predicted using unbiased and explainable machine learning pipeline. The study revealed that psychiatric disorders and demographics might influence the BOLD signal and interact with the classification of sex. The spatial distribution of the important features presented here supports the notion that the brain is a mosaic of male and female features. The findings emphasize the importance of controlling for sex when conducting brain imaging analysis. In addition, the presented framework can be adapted to classify other variables from resting-state BOLD signals.

Mindfulness training (MT) promotes the development of one’s ability to observe and attend to internal and external experiences with objectivity and nonjudgment with evidence to improve psychological well-being. Real-time functional MRI neurofeedback (rtfMRI-nf) is a noninvasive method of modulating activity of a brain region or circuit. The posterior cingulate cortex (PCC) has been hypothesized to be an important hub instantiating a mindful state. This nonrandomized, single-arm study examined the feasibility and tolerability of training typically developing adolescents to self-regulate the posterior cingulate cortex (PCC) using rtfMRI-nf during MT. Thirty-four adolescents (mean age: 15 years; 14 females) completed the neurofeedback augmented mindfulness training task, including Focus-on-Breath (MT), Describe (self-referential thinking), and Rest conditions, across three neurofeedback and two non-neurofeedback runs (Observe, Transfer). Self-report assessments demonstrated the feasibility and tolerability of the task. Neurofeedback runs differed significantly from non-neurofeedback runs for the Focus-on-Breath versus Describe contrast, characterized by decreased activity in the PCC during the Focus-on-Breath condition (z = −2.38 to −6.27). MT neurofeedback neural representation further involved the medial prefrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex, posterior insula, hippocampus, and amygdala. State awareness of physical sensations increased following rtfMRI-nf and was maintained at 1-week follow-up (Cohens’ d = 0.69). Findings demonstrate feasibility and tolerability of rtfMRI-nf in healthy adolescents, replicates the role of PCC in MT, and demonstrate a potential neuromodulatory mechanism to leverage and streamline the learning of mindfulness practice. (ClinicalTrials.gov identifier #NCT04053582; August 12, 2019).

Resting-state functional connectivity (RSFC) has been proposed as a potential indicator of repetitive negative thinking (RNT) in depression, while inconsistent findings have been reported. This study utilized connectome-based predictive modeling (CPM) to investigate whether RSFC and negative-thinking-state functional connectivity (NTFC) could predict RNT in individuals with Major Depressive Disorder (MDD). Although RSFC distinguished between healthy and depressed individuals, it did not predict trait RNT (as assessed by the Ruminative Responses Scale-Brooding subscale) in depressed individuals. Conversely, NTFC predicted trait RNT in depressed individuals with significant accuracy, but could not differentiate between healthy and depressed individuals. Connectome-wide analysis revealed that negative thinking in depression was associated with higher FC between default mode and executive control regions, which was not observed in RSFC. Our findings suggest that RNT in depression is associated with an active mental process involving multiple brain regions across functional networks that is not represented in the resting state.

Background Depression (MDD) is associated with an unusually large amount of individual disability and societal costs as well as unsatisfactory outcomes with well-established therapies, including psychotropic drugs and different types of psychotherapy. Based on increasing interest in modulation of brain circuits involved in specific symptoms of depression, we chose to target a single measurable and replicable construct of depression, repetitive negative thinking (RNT), a transdiagnostic clinical manifestation that cuts across a variety of internalizing psychiatric disorders, but in the case of depression, it is associated with persistent symptoms, treatment resistance, proneness to relapse after treatment, and more suicidal ideation, behavior, and completed suicides. With the help of using low-intensity transcranial focused ultrasound (LIFU), we will modulate individually-identified neural circuits associated with (a) the generation and maintenance of repetitive negative thinking (RNT), and (b) affective processing of self-referential adjectives. Methods The study will consist of two groups/arms subjected consecutively to either LIFU sonication or sham sonication in a crossover fashion. It will be a single-site, pilot study involving 20 participants with depression (10 with low RNT and 10 with high RNT) and 10 healthy controls. This project has two phases. First, we will use advanced structural-functional connectivity analysis techniques to individually define anatomical tracts that support functional connectivity alterations associated with the intensity of RNT in each MDD patient. Informed by recent neurocircuitry evidence in MDD and obsessive-compulsive disorder we hypothesize that structural pathways linking the thalamus, the orbitofrontal cortex, and the anterior cingulate cortex in the right hemisphere will be associated with RNT. Second, by using the resulting pathways to guide the choice of the target(s) for LIFU neuromodulation, we will probe its on (1) measures of RNT (Brief State Rumination Inventory), (2) functional connectivity between regions known to have an anatomical connection in the individual participant, and (3) neural processing of self-referential affective adjectives. Discussion We anticipate this feasibility study will provide the information necessary for the design of a larger-scale clinical trial to establish 1) a definitive causal relationship between brain circuits and RNT as a symptom, and 2) a novel target to modulate RNT in the clinical setting. Trial registration: In process at ClinicalTrials.gov. FDA Non-Significant Risk determination Q220192 (November 4, 2022).

Background: This study examined whether a combination of the Awareness and Care for my Autistic Traits (ACAT) program and treatment-as-usual (TAU) is more effective than only TAU in increasing the understanding of autistic attributes, reducing treatment stigma, and improving mental health and social adaptation among adolescents with autism spectrum disorder (ASD) and their parents/guardians. Methods: Forty-nine adolescents and their parents/guardians were randomly assigned to either a combination of ACAT and TAU (COMB) group or only TAU group. The COMB group received six weekly 100-min ACAT sessions while the TAU group received no additional intervention. The primary outcome was the change in the understanding of autistic attributes (Autism Knowledge Quiz-Child: AKQ-C), administered to autistic adolescents from pre-to post-intervention. The secondary outcomes included the change in AKQ-parent version (AKQ-P) administered to their parents/guardians, treatment stigma, improving mental health, and social adaptation among autistic adolescents and their parents/guardians. All measures except for the self-rating scales were scored by asessors blind to the group assignment. Results: The individuals (both autistic adolescents and their parents/guardians) in the COMB group, showed an increased score of the AKQ-C and AKQ-P than did those in the TAU group. Autistic adolescents in the COMB group also demonstrated reduced treatment-related stigma and behavioral problems than those in the TAU group, while there were no group differences in the change in social adaptation. For parents/guardians, there were no group differences in the change in treatment-related stigma, mental health, adaptive skills, or attitudes toward their children. Conclusions: The results suggest that the ACAT could be an effective treatment modality for both autistic adolescents and their parents/guardians to increase the understanding of autistic attributes. The ACAT may positively affect self-understanding, reduce treatment stigma, and stabilize behavioral issues for autistic adolescents, but it may not effectively reduce treatment barriers or improve mental health for parents/guardians. Further research should consider whether additional support for parents/guardians could be beneficial. Trial registration: Registration number - UMIN000029851 and date of registration - 06/01/2018.

BACKGROUND: Low intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation (tACS or tDCS), applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional magnetic resonance imaging (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. OBJECTIVE: To develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency, and reproducibility (ContES Checklist). METHODS: A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists (EP) through the International Network of the tES-fMRI (INTF) Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC based on a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed using the checklist. RESULTS: Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (1) technological factors, (2) safety and noise tests, and (3) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. CONCLUSIONS: Use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies, and increase methodological transparency and reproducibility.

Rumination, repetitively thinking about the causes, consequences, and one's negative affect, has been considered as an important factor of depression. The intrusion of ruminative thoughts is not easily controlled, and it may be useful to visualize one's neural activity related to rumination and to use that information to facilitate one's self‐control. Real‐time fMRI neurofeedback (rtfMRI‐nf) enables one to see and regulate the fMRI signal from their own brain. This proof‐of concept study utilized connectivity‐based rtfMRI‐nf (cnf) to normalize brain functional connectivity (FC) associated with rumination. Healthy participants were instructed to brake or decrease FC between the precuneus and the right temporoparietal junction (rTPJ), associated with high levels of rumination, while engaging in a self‐referential task. The cnf group (n = 14) showed a linear decrease in the precuneus‐rTPJ FC across neurofeedback training (trend [112] = −0.180, 95% confidence interval [CI] −0.330 to −0.031, while the sham group (n = 14) showed a linear increase in the target FC (trend [112] = 0.151, 95% CI 0.017 to 0.299). Although the cnf group showed a greater reduction in state‐rumination compared to the sham group after neurofeedback training (p, Regions of interest (ROI) for the connectivity‐based rtfMRI‐nf and the neurofeedback algorithm. (a) ROIs for the connectivity‐based rtfMRI‐nf. (b) Neurofeedback algorithm and display. Red circles and arrows indicate the precuneus ROI and BOLD activities, and blue circles and arrows indicate the right temporoparietal junction (rTPJ) ROI and BOLD activities. The sidebars on the screen were updated every 2‐s with positive feedback (+1: light blue color) or no feedback (0: blank color).

Microstructural alterations in cortico-subcortical connections are thought to be present in obsessive–compulsive disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Here we investigated microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. We analyzed diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA OCD Working Group, in a cross-sectional case-control magnetic resonance study. We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen’s d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Adult OCD patients showed significant FA reduction in the sagittal stratum (d = −0.21, z = −3.21, p = 0.001) and posterior thalamic radiation (d = −0.26, z = −4.57, p z = 2.71, p = 0.006), longer duration of illness (z = −2.086, p = 0.036), and a higher percentage of medicated patients in the cohorts studied (z = −1.98, p = 0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to controls. Our findings of microstructural alterations in projection and association fibers to posterior brain regions in OCD are consistent with models emphasizing deficits in connectivity as an important feature of this disorder.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

Accepted Manuscript, BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD.METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -20.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD., This research was funded by the Max Planck Society (Germany). Additional funding was from the Japan Society for the Promotion of Science (KAKENHI Grant No. 18K15523 [to YA], KAKENHI Grant No. 16K04344 [to YH], KAKENHI Grant Nos. 16K19778 and 18K07608 [to TNakam], and KAKENHI Grant No. 26461762 [to AN]); the Carlos III Health Institute (Grant No. PI14/00419 [to PA], Grant No. PI040829 cofunded by European Regional Development Fund [to LL], Grant No. FI17/00294 [to IM-Z], Grant No. PI16/00950 [to JMM], and Grant Nos. CPII16/00048, PI13/01958, and PI16/00889 cofunded by European Regional Development Funds [to CS-M]); the Ontario Mental Health Foundation (Research Training Fellowship [to SHA]); Alberta Innovates Translational Health Chair in Child and Youth Mental Health (to PDA), the Ontario Brain Institute (to PDA); the National Institute of Mental Health (Grant No. K23MH104515 [to JTB], Grant No. K23-MH092397 [to BPB], Grant No. K23MH082176 [to KDF), Grant No. R21MH101441 [to RM], Grant No. R01MH081864 [to JO and JP], and Grant No. R01MH085900 [to JO and JF], Grant No. R21MH093889 [to HBS]); Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant No. 2011/21357–9 [to MCB], Grant No. 2011/21357–9 [to GFB], Grant No. 2011/21357–9 [to MQH], and Grant No. 2011/21357–9 [to ECM]); the Swiss National Science Foundation (Grant No. 320030_130237 [to SB; principal investigator, Susanne Walitza]); the Hartmann Müller Foundation (Grant No. 1460 [to SB]); the David Judah Fund at the Massachusetts General Hospital (to BPB); EU FP7 Project TACTICS (Grant No. 278948 [to JB]); the National Natural Science Foundation of China (Grant No. 81560233 [to YC] and Grant No. 81371340 [to ZW]); the International OCD Foundation (Grant No. K23 MH115206 [to PG]); the Wellcome Sir Henry Dale Fellowship (Grant No. 211155/Z/18/Z [to TUH]); the Jacobs Foundation (to TUH); the Brain and Behavior Research Foundation (2018 NARSAD Young Investigator Grant No. 27023 [to TUH]); the Agency for Medical Research and Development (Grant No. JP18dm0307002 [to YH]); the Michael Smith Foundation for Health Research (to FJ-F); the Federal Ministry of Education and Research of Germany (Grant No. BMBF-01GW0724 [to NK]); the Deutsche Forschungsgemeinschaft (Grant No. KO 3744/7–1 [to KK]); the Helse Vest Health Authority (Grant Nos. 911754 and 911880 [to GK]); the Norwegian Research Council (Grant No. HELSEFORSK 243675 [to GK]); the Marató TV3 Foundation (Grant Nos. 01/2010 and 091710 [to LL]); the Agency for Management of University and Research Grants (Grant No. 2017 SGR 881 [to LL] and 2017 SGR 1247 from the Generalitat de Catalunya [to JMM]); Fundação para a Ciência e a Tecnologia (Grant No. PDE/BDE/113604/2015 from the PhD-iHES Program [to RM], Grant No. PDE/BDE/113601/2015 from the PhD-iHES Program [to PSM]); the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research (Grant Nos. 22591262, 25461732, and 16K10253 [to TNakao]); the Government of India Department of Science and Technology (DST INSPIRE Faculty Grant No. -IFA12-LSBM-26 [to JCN] and Grant No. SR/S0/HS/0016/2011 [to YCJR]); the Government of India Department of Biotechnology (Grant No. BT/06/IYBA/2012 [to JCN] and Grant No. BT/PR13334/Med/30/259/2009 [to YCJR]); the New York State Office of Mental Health (to HBS); the Italian Ministry of Health (Grant No. RC13-14-15-16A [to GS]); the National Center for Advancing Translational Sciences (Grant No. UL1TR000067/KL2TR00069 [to ERS]); the Canadian Institutes of Health Research (to SES); the Michael Smith Foundation for Health Research (to SES); the British Columbia Provincial Health Services Authority (to SES); the Netherlands Organization for Scientific Research (Grant No. NWO/ZonMW Vidi 917.15.318 [to GAvW]); the Wellcome-DBT India Alliance (Grant No. 500236/Z/11/Z [to GV]); the Shanghai Key Laboratory of Psychotic Disorders (Grant No. 13dz2260500 [to ZW]).

The ventromedial prefrontal cortex (vmPFC) is involved in regulation of negative emotion and decision‐making, emotional and behavioral control, and active resilient coping. This pilot study examined the feasibility of training healthy subjects (n = 27) to self‐regulate the vmPFC activity using a real‐time functional magnetic resonance imaging neurofeedback (rtfMRI‐nf). Participants in the experimental group (EG, n = 18) were provided with an ongoing vmPFC hemodynamic activity (rtfMRI‐nf signal represented as variable‐height bar). Individuals were instructed to raise the bar by self‐relevant value‐based thinking. Participants in the control group (CG, n = 9) performed the same task; however, they were provided with computer‐generated sham neurofeedback signal. Results demonstrate that (a) both the CG and the EG show a higher vmPFC fMRI signal at the baseline than during neurofeedback training; (b) no significant positive training effect was seen in the vmPFC across neurofeedback runs; however, the medial prefrontal cortex, middle temporal gyri, inferior frontal gyri, and precuneus showed significant decreasing trends across the training runs only for the EG; (c) the vmPFC rtfMRI‐nf signal associated with the fMRI signal across the default mode network (DMN). These findings suggest that it may be difficult to modulate a single DMN region without affecting other DMN regions. Observed decreased vmPFC activity during the neurofeedback task could be due to interference from the fMRI signal within other DMN network regions, as well as interaction with task‐positive networks. Even though participants in the EG did not show significant positive increase in the vmPFC activity among neurofeedback runs, they were able to learn to accommodate the demand of self‐regulation task to maintain the vmPFC activity with the help of a neurofeedback signal.

Recent studies suggest that transcranial electrical stimulation (tES) can be performed during functional magnetic resonance imaging (fMRI). The novel approach of using concurrent tES-fMRI to modulate and measure targeted brain activity/connectivity may provide unique insights into the causal interactions between the brain neural responses and psychiatric/neurologic signs and symptoms, and importantly, guide the development of new treatments. However, tES stimulation parameters to optimally influence the underlying brain activity in health and disorder may vary with respect to phase, frequency, intensity and electrode’s montage. Here, we delineate how a closed-loop tES-fMRI study of frontoparietal network modulation can be designed and performed. We also discuss the challenges of running a concurrent tES-fMRI, describing how we can distinguish clinically meaningful physiological changes caused by tES from tES-related artifacts. There is a large methodological parameter space including electrode types, electrolytes, electrode montages, concurrent tES-fMRI hardware, online fMRI processing pipelines and closed-loop optimization algorithms that should be carefully selected for closed-loop tES-fMRI brain modulation. We also provide technical details on how safety and quality of tES-fMRI settings can be tested, and how these settings can be monitored during the study to ensure they do not exceed safety standards. The initial results of feasibility and applicability of closed-loop tES-fMRI are reported and potential hypotheses for the outcomes are discussed.Highlight pointsMethodological details of a closed-loop tES-fMRI study protocol are provided.The protocol is performed successfully on a frontoparietal network without side-effects.The temperature of electrodes in concurrent tES-fMRI remains in the safe range.Properly setup concurrent tES does not introduce MRI artifacts and noise.Simplex optimizer could be used to find an optimal tES stimulation parameter.

Highlights • rtfMRI-nf LA emotional training reduces depressive symptoms. • rtfMRI-nf LA training increases KynA/3-HK, a neuroprotective index. • Baseline KynA/QA is associated with the ability to upregulate the LA. • In partial responder group LA upregulation positively correlates with KynA/QA. • In partial responder group LA upregulation inversely correlates with MADRS. • Modulation of the KP may drive rtfMRI-nf-induced changes in neuroplasticity. • Non-specific effects cannot be ruled out due to the lack of a sham control., Real-time fMRI neurofeedback (rtfMRI-nf) left amygdala (LA) training is a promising intervention for major depressive disorder (MDD). We have previously proposed that rtfMRI-nf LA training may reverse depression-associated regional impairments in neuroplasticity and restore information flow within emotion-regulating neural circuits. Inflammatory cytokines as well as the neuroactive metabolites of an immunoregulatory pathway, i.e. the kynurenine pathway (KP), have previously been implicated in neuroplasticity. Therefore, in this proof-of-principle study, we investigated the association between rtfMRI-nf LA training and circulating inflammatory mediators and KP metabolites. Based on our previous work, the primary variable of interest was the ratio of the NMDA-receptor antagonist, kynurenic acid to the NMDA receptor agonist, quinolinic acid (KynA/QA), a putative neuroprotective index. We tested two main hypotheses. i. Whether rtfMRI-nf acutely modulates KynA/QA, and ii. whether baseline KynA/QA predicts response to rtfMRI-nf. Twenty-nine unmedicated participants who met DSM-5 criteria for MDD based on the Mini-International Neuropsychiatric Interview and had current depressive symptoms (Montgomery-Åsberg Depression Rating Scale (MADRS) score > 6) completed two rtfMRI-nf sessions to upregulate LA activity (Visit1 and 2), as well as a follow-up (Visit3) without rtfMRI-nf. All visits occurred at two-week intervals. At all three visits, the MADRS was administered to participants and serum samples for the quantification of inflammatory cytokines and KP metabolites were obtained. First, the longitudinal changes in the MADRS score and immune markers were tested by linear mixed effect model analysis. Further, utilizing a linear regression model, we investigated the relationship between rtfMRI-nf performance and immune markers. After two sessions of rtfMRI-nf, MADRS scores were significantly reduced (t[58] = −4.07, p = 0.009, d = 0.56). Thirteen participants showed a ≥ 25% reduction in the MADRS score (the partial responder group). There was a significant effect of visit (F[2,58] = 3.17, p = 0.05) for the neuroprotective index, KynA to 3-hydroxykynurenine (3-HK), that was driven by a significant increase in KynA/3-HK between Visit1 and Visit3 (t[58] = 2.50, p = 0.03, d = 0.38). A higher baseline level of KynA/QA (β = 5.23, p = 0.06; rho = 0.49, p = 0.02) was associated with greater ability to upregulate the LA. Finally, for exploratory purposes correlation analyses were performed between the partial responder and the non-responder groups as well as in the whole sample including all KP metabolites and cytokines. In the partial responder group, greater ability to upregulate the LA was correlated with an increase in KynA/QA after rtfMRI-nf (rho = 0.75, p = 0.03). The results are consistent with the possibility that rtfMRI-nf decreases metabolism down the so-called neurotoxic branch of the KP. Nevertheless, non-specific effects cannot be ruled out due to the lack of a sham control. Future, controlled studies are needed to determine whether the increase in KynA/3HK and KynA/QA is specific to rtfMRI-nf or whether it is a non-specific correlate of the resolution of depressive symptoms. Similarly, replication studies are needed to determine whether KynA/QA has clinical utility as a treatment response biomarker.

BackgroundLow intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation (tACS or tDCS), applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional magnetic resonance imaging (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies.ObjectiveTo develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency, and reproducibility (ContES Checklist).MethodsA two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists (EP) through the International Network of the tES-fMRI (INTF) Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC based on a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed using the checklist.ResultsExperts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (1) technological factors, (2) safety and noise tests, and (3) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article.ConclusionsUse of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies, and increase methodological transparency and reproducibility.

Electroencephalography microstates (EEG-ms) capture and reflect the spatio-temporal neural dynamics of the brain. A growing literature is employing EEG-ms-based analyses to study various mental illnesses and to evaluate brain mechanisms implicated in cognitive and emotional processing. The spatial and functional interpretation of the EEG-ms is still being investigated. Previous works studied the association of EEG-ms time courses with blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal and suggested an association between EEG-ms and resting-state networks (RSNs). However, the distinctive association between EEG-ms temporal dynamics and brain neuronal activities is still not clear, despite the assumption that EEG-ms are an electrophysiological representation of RSNs activity. Recent works suggest a role for brain spontaneous EEG rhythms in contributing to and modulating canonical EEG-ms topographies and determining their classes (coined A through D) and metrics. This work simultaneously utilized EEG and fMRI to understand the EEG-ms and their properties further. We adopted the canonical EEG-ms analysis to extract three types of regressors for EEG-informed fMRI analyses: EEG-ms direct time courses, temporal activity per microstate, and pairwise temporal transitions among microstates (the latter two coined activity regressors). After convolving EEG-ms regressors with a hemodynamic response function, a generalized linear model whole-brain voxel-wise analysis was conducted to associate EEG-ms regressors with fMRI signals. The direct time course regressors replicated prior findings of the association between the fMRI signal and EEG-ms time courses but to a smaller extent. Notably, EEG-ms activity regressors were mostly anticorrelated with fMRI, including brain regions in the somatomotor, visual, dorsal attention, and ventral attention fMRI networks with no significant overlap for default mode, limbic or frontoparietal networks. A similar pattern emerged in using the transition regressors among microstates but not in self-transitions. The relatively short duration of each EEG-ms and the significant association of EEG-ms activity regressors with fMRI signals suggest that EEG-ms manifests successive transition from one brain functional state to another rather than being associated with specific brain functional state or RSN networks.

Background Cognitive behavioral therapy (CBT), which includes exposure and response prevention (ERP), is effective in improving symptoms of obsessive-compulsive disorder (OCD). However, whether poor cognitive functions and autism spectrum disorder (ASD) traits affect the therapeutic response of patients with OCD to CBT remains unclear. This study aimed to identify factors predictive of the therapeutic response of Japanese patients with OCD to ERP. Methods Forty-two Japanese outpatients with OCD were assessed using the Wechsler Adult Intelligence Scale-III (WAIS-III), Yale-Brown Obsessive-Compulsive Scale, Patient Health Questionnaire 9-item scale, and Autism Spectrum Quotient (AQ) at pre- and post-treatment. We used multiple regression analyses to estimate the effect on therapeutic response change. The treatment response change was set as a dependent variable in multiple regression analyses. Results Multiple regression analyses showed that among independent variables, communication skill as an AQ sub-scale and Letter Number Sequencing as a WAIS-III sub-test predict the therapeutic response to ERP. Conclusions Our results suggest that diminished working memory (Letter Number Sequencing), poor communication skill may undermine responsiveness to ERP among patients with OCD. Trial registration: UMIN, UMIN00024087. Registered 20 September 2016 - Retrospectively registered (including retrospective data), https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000027729&type=summary&language=J

Objective. Electroencephalography (EEG) microstates (MSs), which reflect a large topographical representation of coherent electrophysiological brain activity, are widely adopted to study cognitive processes mechanisms and aberrant alterations in brain disorders. MS topographies are quasi-stable lasting between 60–120 ms. Some evidence suggests that MS are the electrophysiological signature of resting-state networks (RSNs). However, the spatial and functional interpretation of MS and their association with functional magnetic resonance imaging (fMRI) remains unclear. Approach. In a cohort of healthy subjects (n = 52), we conducted several statistical and machine learning (ML) approaches analyses on the association among MS spatio-temporal dynamics and the blood-oxygenation-level dependent (BOLD) simultaneous EEG-fMRI data using statistical and ML approaches. Main results. Our results using a generalized linear model showed that MS transitions were largely and negatively associated with BOLD signals in the somatomotor, visual, dorsal attention, and ventral attention fMRI networks with limited association within the default mode network. Additionally, a novel recurrent neural network (RNN) confirmed the association between MS transitioning and fMRI signal while revealing that MS dynamics can model BOLD signals and vice versa. Significance. Results suggest that MS transitions may represent the deactivation of fMRI RSNs and provide evidence that both modalities measure common aspects of undergoing brain neuronal activities. These results may help to better understand the electrophysiological interpretation of MS.

Aki Tsuchiyagaito,1–3 Satoshi Horiuchi,4 Toko Igarashi,5 Yoshiya Kawanori,4 Yoshiyuki Hirano,1,3 Hirooki Yabe,2 Akiko Nakagawa1,3 1Research Center for Child Mental Development, Chiba University, Chiba, 2Department of Neuropsychiatry, Fukushima Medical University, Fukushima, 3United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka, 4Faculty of Social Welfare, Iwate Prefectural University, Iwate, 5Graduate School of Education, Joetsu University of Education, Niigata, Japan Background: The Hoarding Rating Scale-Self-Report (HRS-SR) is a five-item scale that assesses the symptoms of hoarding. These symptoms include excessive acquisition, difficulty in discarding, and excessive clutter that causes distress. We conducted three studies to examine the factor structure, reliability, and validity of the Japanese version of the HRS-SR (HRS-SR-J). Methods: Study 1 examined its reliability; 193 college students and 320 adolescents and adults completed the HRS-SR-J and, of the college students, 32 took it again 2weeks later. Study 2 aimed to confirm that its scores in a sample of 210 adolescents and adults are independent of social desirability. Study 3 aimed to validate the HRS-SR-J in the aspects of convergent and discriminant validity in a sample of 550 adults. Results: The HRS-SR-J showed good internal consistency and 2-week test–retest reliability. Based on the nonsignificant correlations between the HRS-SR-J and social desirability, the HRS-SR-J was not strongly affected by social desirability. In addition, it also had a good convergent validity with the Japanese version of the Saving Inventory-Revised (SI-R-J) and the hoarding subscale of the Obsessive-Compulsive Inventory, while having a significantly weaker correlation with the five subscales of the Obsessive-Compulsive Inventory, except for the hoarding subscale. In addition, the strength of the correlation between the HRS-SR-J and the Japanese version of the Patient Health Questionnaire-9 and that between the HRS-SR-J and the Generalized Anxiety Disorder-7 were significantly weaker than the correlation between the HRS-SR-J and the SI-R-J. These results demonstrate that the HRS-SR-J has good convergent and discriminant validity. Conclusion: The HRS-SR-J is a notable self-report scale for examining the severity of hoarding symptoms. Keywords: Japanese version of the Hoarding Rating Scale-Self-Report, Hoarding Rating Scale, hoarding, reliability, validity

Highlights • Introduced connectome-wide approach of neurofeedback target identification. • Identified connectivity related to rumination severity with resting-state data. • Positively correlated precuneus-RTPJ connectivity with rumination severity. • Performed simulation analysis to design the optimal neurofeedback signal. • The two-point method was optimal online connectivity measure robust to motion., Real-time fMRI neurofeedback (rtfMRI-nf) enables noninvasive targeted intervention in brain activation with high spatial specificity. To achieve this promise of rtfMRI-nf, we introduced and demonstrated a data-driven framework to design a rtfMRI-nf intervention through the discovery of precise target location associated with clinical symptoms and neurofeedback signal optimization. Specifically, we identified the functional connectivity locus associated with rumination symptoms, utilizing a connectome-wide search in resting-state fMRI data from a large cohort of mood and anxiety disorder individuals (N = 223) and healthy controls (N = 45). Then, we performed a rtfMRI simulation analysis to optimize the online functional connectivity neurofeedback signal for the identified functional connectivity. The connectome-wide search was performed in the medial prefrontal cortex and the posterior cingulate cortex/precuneus brain regions to identify the precise location of the functional connectivity associated with rumination severity as measured by the ruminative response style (RRS) scale. The analysis found that the functional connectivity between the loci in the precuneus (-6, −54, 48 mm in MNI) and the right temporo-parietal junction (RTPJ; 49, −49, 23 mm) was positively correlated with RRS scores (depressive, p