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Abstract Real-time fMRI neurofeedback (rtfMRI-NF) has emerged as a promising intervention for psychiatric disorders, yet its clinical efficacy remains underexplored due to an incomplete mechanistic understanding. This study aimed to delineate the whole-brain mechanisms underpinning the effects of rtfMRI-NF on repetitive negative thinking in depression. In a double-blind randomized controlled trial, forty-three depressed individuals underwent NF training targeting the functional connectivity (FC) between the posterior cingulate cortex and the right temporoparietal junction, linked to rumination severity. Participants were randomly assigned to active or sham groups, with the sham group receiving synthesized feedback mimicking real NF signal patterns. The active group demonstrated a significant reduction in brooding rumination scores (d = −1.52, p

BackgroundMindfulness training has been shown to promote positive mental health outcomes and related changes in neural networks such as the default mode network, which has a central node in the posterior cingulate cortex (PCC). Previous work from our group reported on the impact of a novel, neurofeedback augmented mindfulness training (NAMT) task on regulation of PCC hemodynamic activity in typically developing adolescents. The present pilot study aimed to expand on this finding by examining the pre-post changes of the NAMT task on resting-state functional connectivity of the PCC.MethodsThirty-one typically developing adolescents (14.77 ± 1.23 years; 45% female) underwent a resting-state functional magnetic resonance imaging scan both before and after completing the NAMT task. A linear mixed effects model was used to assess for changes in functional connectivity of the PCC across the two resting-state runs.ResultsData did not support the hypothesized decrease in connectivity between the PCC seed and other DMN regions from pre- to post-NAMT task. However, we observed a significant increase in functional connectivity between the PCC and a cluster encompassing the left hippocampus and amygdala following completion of the NAMT task (run 1 Fisher’s Z = 0.16; run 2 Fisher’s Z = 0.26).ConclusionAlthough preliminary, this finding suggests NAMT has the potential to strengthen connectivity between default mode and salience regions. We speculate that such changed connectivity may facilitate enhanced self-referential and emotional processing in adolescents.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT04053582.

Abstract Background Autistic people demonstrate focused interests, sensitivity to sensory stimulation, and, compared with the general population, differences in social communication and interaction. We examined whether a combination of the Awareness and Care for My Autistic Traits (ACAT) program and treatment-as-usual is more effective than only treatment-as-usual in increasing the understanding of autistic attributes, reducing treatment stigma, and improving mental health and social adaptation among autistic adolescents and their parents/guardians. Methods Forty-nine adolescents and their parents/guardians were randomly assigned to either a combination of ACAT and treatment-as-usual or only treatment-as-usual. The combined group received six weekly 100-minute ACAT sessions, while the treatment-as-usual group received no additional intervention. The primary outcome was the change in understanding of autistic attributes (Autism Knowledge Quiz-Child), administered from pre- to post-intervention. The secondary outcomes included the change in Autism Knowledge Quiz-Parent, reduced treatment stigma, and improved mental health and social adaptation among autistic adolescents and their parents/guardians. A primary outcome measure scale was scored by assessors who were blind to the group assignment. Results The combined group (both autistic adolescents and their parents/guardians) showed an increase in Autism Knowledge Quiz scores compared to those in the treatment-as-usual group. Autistic adolescents in the combined group also demonstrated a decrease in treatment-related stigma and an improvement in general mental health compared to those in the treatment-as-usual 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, general mental health, adaptive skills, or attitudes toward their children. Conclusions The ACAT program could be an effective treatment modality to increase the understanding of autistic attributes among both autistic adolescents and their parents/guardians. The ACAT program positively affects self-understanding, reduces treatment stigma, and stabilizes behavioral issues for autistic adolescents as a part of mental health measures, but it does 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 : The study was registered in UMIN (UMIN000029851, 06/01/2018).

Abstract One of the most critical challenges in using noninvasive brain stimulation (NIBS) techniques for the treatment of psychiatric and neurologic disorders is inter- and intra-individual variability in response to NIBS. Response variations in previous findings suggest that the one-size-fits-all approach does not seem the most appropriate option for enhancing stimulation outcomes. While there is a growing body of evidence for the feasibility and effectiveness of individualized NIBS approaches, the optimal way to achieve this is yet to be determined. Transcranial electrical stimulation (tES) is one of the NIBS techniques showing promising results in modulating treatment outcomes in several psychiatric and neurologic disorders, but it faces the same challenge for individual optimization. With new computational and methodological advances, tES can be integrated with real-time functional magnetic resonance imaging (rtfMRI) to establish closed-loop tES-fMRI for individually optimized neuromodulation. Closed-loop tES-fMRI systems aim to optimize stimulation parameters based on minimizing differences between the model of the current brain state and the desired value to maximize the expected clinical outcome. The methodological space to optimize closed-loop tES fMRI for clinical applications includes (1) stimulation vs. data acquisition timing, (2) fMRI context (task-based or resting-state), (3) inherent brain oscillations, (4) dose-response function, (5) brain target trait and state and (6) optimization algorithm. Closed-loop tES-fMRI technology has several advantages over non-individualized or open-loop systems to reshape the future of neuromodulation with objective optimization in a clinically relevant context such as drug cue reactivity for substance use disorder considering both inter and intra-individual variations. Using multi-level brain and behavior measures as input and desired outcomes to individualize stimulation parameters provides a framework for designing personalized tES protocols in precision psychiatry.

BackgroundAdolescents have experienced increases in anxiety, depression, and stress during the COVID-19 pandemic and may be at particular risk for suffering from long-term mental health consequences because of their unique developmental stage. This study aimed to determine if initial increases in depression and anxiety in a small sample of healthy adolescents after the onset of the COVID-19 pandemic were sustained at follow-up during a later stage of the pandemic.MethodsFifteen healthy adolescents completed self-report measures at three timepoints (pre-pandemic [T1], early pandemic [T2], and later pandemic [T3]). The sustained effect of COVID-19 on depression and anxiety was examined using linear mixed-effect analyses. An exploratory analysis was conducted to investigate the relationship between difficulties in emotion regulation during COVID-19 at T2 and increases in depression and anxiety at T3.ResultsThe severity of depression and anxiety was significantly increased at T2 and sustained at T3 (depression: Hedges’ g [T1 to T2] = 1.04, g [T1 to T3] = 0.95; anxiety: g [T1 to T2] = 0.79, g [T1 to T3] = 0.80). This was accompanied by sustained reductions in positive affect, peer trust, and peer communication. Greater levels of difficulties in emotion regulation at T2 were related to greater symptoms of depression and anxiety at T3 (rho = 0.71 to 0.80).ConclusionIncreased symptoms of depression and anxiety were sustained at the later stage of the pandemic in healthy adolescents. Replication of these findings with a larger sample size would be required to draw firm conclusions.

Abstract 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 may vary with respect to phase difference, frequency, intensity, and electrode's montage among individuals. Here, we propose a protocol for closed‐loop tES‐fMRI to optimize the frequency and phase difference of alternating current stimulation (tACS) for two nodes (frontal and parietal regions) in individual participants. We carefully considered the challenges in an online optimization of tES parameters with concurrent fMRI, specifically in its safety, artifact in fMRI image quality, online evaluation of the tES effect, and parameter optimization method, and we designed the protocol to run an effective study to enhance frontoparietal connectivity and working memory performance with the optimized tACS using closed‐loop tES‐fMRI. We provide technical details of the protocol, including electrode types, electrolytes, electrode montages, concurrent tES‐fMRI hardware, online fMRI processing pipelines, and the optimization algorithm. We confirmed the implementation of this protocol worked successfully with a pilot experiment.

Abstract 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 ERP-based CBT remains unclear. This study aimed to identify factors predictive of the therapeutic response of Japanese patients with OCD to ERP-based CBT. 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 as an AQ sub-scale and Letter Number Sequencing as a WAIS-III sub-test predict the therapeutic response to ERP-based CBT . Conclusions Our results suggest that diminished working memory (Letter Number Sequencing), poor communication skill (AQ sub-scale) may undermine responsiveness to ERP-based CBT among patients with OCD. Trial registration UMIN, UMIN00024087 . Registered 20 September 2016 - Retrospectively registered (including retrospective data).

Abstract Background One aim of an autism spectrum disorder (ASD) diagnosis is to obtain special support for the disorder, though this does not guarantee practical support. We developed a psychoeducational program using cognitive-behavioral therapy (CBT) and Aware and Care for my Autistic Traits (ACAT) for Japanese adolescents with high-functioning ASD and their parents. Methods This multisite study is a randomized controlled trial. In total, 24 participants will be assigned to the ACAT group and 24 to the treatment-as-usual (TAU) group. The ACAT group will receive a weekly 100-min session for 6 weeks, regular medical care, and one follow-up session. In this ongoing clinical trial, we will compare the scores of the measures recorded in the pre- and post-intervention stages between the ACAT and TAU groups. A total of 41 patients out of a target of 48 have participated in the trial to date. The primary outcome measure is the Autism Knowledge Questionnaire. Secondary outcome measures include Barriers to Access to Care Evaluation 3rd Edition, the Strengths and Difficulties Questionnaire, the Vineland Adaptive Behavior Scales second edition, the Parenting Resilience Elements Questionnaire, the General Health Questionnaire 12, and the Depression Self-Rating Scale for Children assessments, as well as an electroencephalographic recording. Discussion It is expected that participants in the ACAT group will significantly increase their self-understanding and awareness of ASD symptoms compared to those in the TAU group. Additionally, the ACAT group is expected to exhibit improved social adaptation and mental health if children and parents are able to better understand the ASD characteristics through sessions. This intervention will contribute to the establishment of an effective evidence-based treatment strategy for adolescents with ASD. Trial registration UMIN Register 000029851 . Registered on January 06, 2018

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.

Mindfulness training (MT) reduces self-referential processing and promotes interoception, the perception of sensations from inside the body, by increasing one’s awareness of and regulating responses to them. The posterior cingulate cortex (PCC) and the insular cortex (INS) are considered hubs for self-referential processing and interoception, respectively. Although MT has been consistently found to decrease PCC, little is known about how MT relates to INS activity. Understanding links between mindfulness and interoception may be particularly important for informing mental health in adolescence, when neuroplasticity and emergence of psychopathology are heightened. We examined INS activity during real-time functional magnetic resonance imaging neurofeedback-augmented mindfulness training (NAMT) targeting the PCC. Healthy adolescents (N = 37; 16 female) completed the NAMT task, including Focus-on-Breath (MT), Describe (self-referential processing), and Rest conditions, across three neurofeedback runs and two non-neurofeedback runs (Observe, Transfer). Regression coefficients estimated from the generalized linear model were extracted from three INS subregions: anterior (aINS), mid (mINS), and posterior (pINS). Mixed model analyses revealed the main effect of run for Focus-on-Breath vs. Describe contrast in aINS [R2 = 0.39] and pINS [R2 = 0.33], but not mINS [R2 = 0.34]. Post hoc analyses revealed greater aINS activity and reduced pINS activity during neurofeedback runs, and such activities were related to lower self-reported life satisfaction and less pain behavior, respectively. These findings revealed the specific involvement of insula subregions in rtfMRI-nf MT.

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 2 weeks 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

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

Electroencephalography (EEG) measures the brain’s electrophysiological spatio-temporal activities with high temporal resolution. Multichannel and broadband analysis of EEG signals is referred to as EEG microstates (EEG-ms) and can characterize such dynamic neuronal activity. EEG-ms have gained much attention due to the increasing evidence of their association with mental activities and large-scale brain networks identified by functional magnetic resonance imaging (fMRI). Spatially independent EEG-ms are quasi-stationary topographies (e.g., stable, lasting a few dozen milliseconds) typically classified into four canonical classes (microstates A through D). They can be identified by clustering EEG signals around EEG global field power (GFP) maxima points. We examined the EEG-ms properties and the dynamics of cohorts of mood and anxiety (MA) disorders subjects (n = 61) and healthy controls (HCs; n = 52). In both groups, we found four distinct classes of EEG-ms (A through D), which did not differ among cohorts. This suggests a lack of significant structural cortical abnormalities among cohorts, which would otherwise affect the EEG-ms topographies. However, both cohorts’ brain network dynamics significantly varied, as reflected in EEG-ms properties. Compared to HC, the MA cohort features a lower transition probability between EEG-ms B and D and higher transition probability from A to D and from B to C, with a trend towards significance in the average duration of microstate C. Furthermore, we harnessed a recently introduced theoretical approach to analyze the temporal dependencies in EEG-ms. The results revealed that the transition matrices of MA group exhibit higher symmetrical and stationarity properties as compared to HC ones. In addition, we found an elevation in the temporal dependencies among microstates, especially in microstate B for the MA group. The determined alteration in EEG-ms temporal dependencies among the cohorts suggests that brain abnormalities in mood and anxiety disorders reflect aberrant neural dynamics and a temporal dwelling among ceratin brain states (i.e., mood and anxiety disorders subjects have a less dynamicity in switching between different brain states).

Cognitive behavioral therapy (CBT) is an effective treatment for obsessive–compulsive disorder (OCD) and is also applicable to patients with both OCD and autism spectrum disorder (ASD). However, previous studies have reported that CBT for patients with both OCD and ASD might be less effective than for patients with OCD alone. In addition, there is no evidence as to why autistic traits might be risk factors. Therefore, we investigated whether comorbidity between ASD and OCD may significantly affect treatment outcome and discovered predictors of CBT outcomes using structural magnetic resonance imaging (MRI) data. A total of 39 patients, who were diagnosed with OCD, were enrolled in this study. Of these, except for 2 dropout cases, 15 patients were diagnosed with ASD, and 22 patients were diagnosed with OCD without ASD. Both groups took CBT for 11–20 sessions. First, to examine the effectiveness of CBT for OCD patients with and without ASD, we compared CBT outcomes between the two groups. Second, to investigate how the structural abnormality profile of the brain at pretreatment influenced CBT outcomes, we performed a structural MRI comparison focusing on the gray matter volume of the whole brain in both patients with only OCD, and those with both OCD and ASD. In order to discover neurostructural predictors of CBT outcomes besides autistic traits, we divided our samples again into two groups of those who did and those who did not remit after CBT, and repeated the analysis taking autistic traits into account. The results showed that OCD patients with ASD responded significantly less well to CBT. The OCD patients with ASD had much less gray matter volume in the left occipital lobe than OCD patients without ASD. The non-remission group had a significantly smaller volume of gray matter in the left dorsolateral prefrontal cortex (DLPFC) compared with the remission group, after having partialed out autistic traits. These results indicate that the abnormalities in DLPFC negatively affect the CBT outcome, regardless of the severity of the autistic traits.