Yukako Nakagami

The dorsal midbrain-striatal dopaminergic stream encodes salience in animals, while it’s unknown in humans. The midbrain-striatal dopaminergic hyperactivity is postulated to attribute aberrantly-heightened salience to ordinary stimuli, forming delusion and hallucination. While animal studies implicate the ventral midbrain-striatal stream, patient studies suggest the dorsal stream, leaving the precise localization of aberrant salience unclear. We investigated these issues by examining midbrain-striatal functional connectivity. Resting-state functional MRI was acquired from 116 patients with schizophrenia (SCZ) and 224 age- and sex-matched healthy controls (HC). Subjective aberrant salience was assessed using the Aberrant Salience Inventory (ASI). Functional connectivity was computed between six striatal seeds (bilateral ventral limbic, dorsal executive, and dorsal sensorimotor striata) and the dopaminergic midbrain voxels (ventral tegmental area and substantia nigra). We tested (1) the presence of a ventral-to-dorsal connectivity gradient along anterior-to-posterior and inferior-to-superior axes; (2) the main effects of diagnosis and ASI and their interaction on connectivity; and (3) their associations with psychotic symptoms. Both anterior-to-posterior and inferior-to-superior connectivity gradients were confirmed. A significant main effect of diagnosis was observed in connectivity between the left anterior midbrain and ventral limbic striatum, which was reduced in SCZ than in HC. A significant diagnosis-by-ASI sensory subscale interaction was found for connectivity between the left anteroinferior midbrain and the dorsal sensorimotor striatum. This ASI subscale was significantly correlated with positive symptoms (all P < 0.05 family-wise error fully corrected). These findings demonstrate the ventral-to-dorsal midbrain-striatal gradients in humans and indicate a more complex localization of aberrant salience than previously assumed.

Background: Insomnia symptoms associated with late chronotypes are prevalent among young adults, and frequently lead to sleep deprivation, morning-awakening difficulties, and excessive daytime sleepiness. These conditions are associated with psychological distress, impaired academic functioning, and reduced self-esteem. Although chronobiological behavioral interventions are effective, their accessibility remains limited. To bridge this gap, we developed a smartphone application delivering digital brief behavioral treatment for insomnia (BBT-I). We also designed a four-week program integrating the app with light therapy (LT) via wearable glasses named “Digital BBT-I + LT”. This randomized controlled trial will evaluate the efficacy of digital BBT-I with LT and digital BBT-I alone compared with a waitlist control group. Methods: This three-arm parallel-group randomized controlled trial will target young adults with insomnia symptoms and late chronotypes. Participants will be randomized to receive digital BBT-I with adjunctive LT, digital BBT-I alone, or a waitlist control condition. The primary outcome will be insomnia symptom severity, assessed using the Insomnia Severity Index. Evaluations will be conducted at baseline, weekly during the four-week intervention period (days 8, 15, 22, and 29), and at the 3-month follow-up. Discussion: Late chronotypes and insomnia significantly impair sleep and mental health in young adults. Despite the recognized importance of chronobiology-based treatments, they are rarely adopted as standard care. This highlights the need for scalable digital interventions, such as digital BBT-I. By rigorously assessing these strategies, this trial aims to provide clinical evidence regarding accessible interventions to improve sleep and mental health outcomes in this population.

Objective: This study was undertaken to assess clinicians' knowledge of epilepsy surgery across Asia–Oceania and identify individual‐ and country‐ or region‐level factors associated with this knowledge, to inform strategies addressing the epilepsy surgery treatment gap. Methods: We conducted a multinational, cross‐sectional, web‐based survey of clinicians involved in epilepsy care across 18 countries or regions in Asia–Oceania (May–September 2024). The primary outcome was an epilepsy surgery knowledge score (range = 0–12), derived from 12 multiple‐choice items covering indications for surgery, referral timing, understanding of surgical procedures, misconceptions about antiseizure medication efficacy, and perceived contraindications (e.g., electroencephalographic/magnetic resonance imaging findings, eloquent cortex, memory risk, psychiatric comorbidity, and intellectual disability). Linear mixed‐effects models were used to identify individual‐level predictors of knowledge, with country or region modeled as a random intercept. Ancillary analyses examined correlations between country‐ or region‐level knowledge effects and academic activity related to epilepsy. Results: A total of 809 clinicians were included, with respondents primarily from India ( n = 204), China ( n = 194), and Japan ( n = 93). The mean knowledge score was 7.3 ± 2.9, with item‐level correct response rates ranging from 11.2% to 87.6%. Higher knowledge was independently associated with being an epileptologist or neurosurgeon, working at a center with an epilepsy surgery program, and higher epilepsy case volume. Lower knowledge was observed among clinicians outside core neurological specialties. Significant country‐ or region‐level variation persisted after adjustment and correlated with national academic activity in epilepsy surgery and epilepsy awareness. Significance: Clinician knowledge of epilepsy surgery varies substantially across Asia–Oceania. Although targeted education is necessary, structural factors such as the availability of epilepsy surgery programs and national academic engagement also appear critical for translating knowledge into access. Multilevel strategies that integrate education with health‐system strengthening are needed to meaningfully reduce the epilepsy surgery knowledge and treatment gaps.

Lee E, et al. J Korean Med Sci. 2026 May;41:e139. https://doi.org/10.3346/jkms.2026.41.e139

Objective: Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the ATN1 gene. The juvenile onset type often presents with epilepsy, including progressive myoclonic epilepsy (PME). However, evidence on epilepsy in DRPLA remains limited. This systematic review and meta‐analysis aimed to summarize clinical characteristics of DRPLA‐related epilepsy. Methods: We systematically searched MEDLINE (PubMed), CENTRAL, Embase, Ichushi, and ClinicalTrials.gov for studies on DRPLA‐related epilepsy, following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines. The review protocol was registered with the Open Science Framework. Any study design reporting at least one case of DRPLA‐related epilepsy was eligible, including case reports, case series, cohort studies, and clinical trials. Eligible studies underwent screening and full‐text assessment, followed by inclusion in descriptive and meta‐analytic syntheses. Meta‐analyses included only studies reporting ≥5 DRPLA patients. Results: A total of 181 studies encompassing 1191 patients met the eligibility criteria. DRPLA patients with epilepsy had a younger onset age (16.9 [95% confidence interval (CI) = 13.76–20.76] vs. 45.5 years [95% CI = 42.77–48.47]) and more CAG repeats (66.7 [95% CI = 63.63–69.84] vs. 59.2 [95% CI = 55.67–62.92]) than those without epilepsy. DRPLA patients with epilepsy showed a higher likelihood of paternal versus maternal inheritance (odds ratio = 2.47 [95% CI = .97–6.27]). Focal seizures were frequently observed (40.0%–76.5%) alongside myoclonic and generalized tonic–clonic seizures. Electroencephalographic findings included slow bursts (38.0%), photoparoxysmal responses (36.6%), and interictal epileptiform discharges (77.5%). Giant somatosensory‐evoked potentials, typically seen in PME, were observed in only two patients and absent in 27. Among antiseizure medications, perampanel and levetiracetam were more frequently reported as effective than sodium channel blockers. Significance: This review synthesizes fragmented evidence on DRPLA‐related epilepsy and highlights key clinical and electrophysiological patterns. Despite limitations from small‐scale studies, these findings support more informed clinical care and underscore the need for larger cohort studies.

Aim: The aim of this study was to investigate whether psychiatrists around the world believe they might encounter cases of hikikomori (prolonged social isolation), and how they formulate and treat such cases.Methods: A hikikomori case vignette was sent to psychiatrists of 34 countries around the world. Participants rated for the vignette: frequency of similar cases in one's practicing country; and aspects of formulation, diagnosis, suicide risk, and treatment plan.Results: In total, 344 complete responses from 34 countries were returned. Eight countries/areas had 10 or more respondents: Japan (61), South Korea (54), Nepal (48), Iran (40), Thailand (32), India (23), Hong Kong (12), and UK (10); the remainder were placed in the “others” group (64). Respondents from all countries except Thailand felt that similar cases were seen. Diverse patterns of response were obtained regarding formulation and treatment. Japan, South Korea, and “others” favored psychosocial aspects in the formulation, while Iran, Nepal, and India favored biological factors. Most respondents felt the case could be treated by an outpatient visit, while others preferred hospitalization. Psychotherapy was rated highly as an intervention; Iran, South Korea, and “others” also rated pharmacotherapy highly.Conclusion: Despite its limitations as an exploratory study, we found evidence that hikikomori‐like cases might exist around the world. However, opinions on how such cases should be formulated and treated vary significantly among countries. We believe this reflects how the experience of hikikomori is dependent on the related sociocultural context. Further comparative work, preferably with standardized assessment tools, will help to clarify how society might influence the individual experiences of practitioner and hikikomori patients.

Objectives: The diagnosis of early‐onset Alzheimer's disease (EOAD) can cause emotional stress not only to the patients themselves but also to their spouses. This study aimed to evaluate the risk of psychiatric disorders in spouses of EOAD patients, using psychotropic drug initiation as a surrogate indicator.Methods: A cohort study was conducted using a Japanese claims database, with spouses of EOAD patients (exposed spouses) matched with spouses of non‐EOAD individuals (reference spouses) up to a 1:10 ratio. Primary outcome was the initiation of mood disorder drugs, and secondary outcomes were the initiation of drugs for anxiety disorders, sleep disorders, and schizophrenia spectrum disorders. Four study cohorts were created according to each outcome analysis. Multivariable Cox regression models were used to estimate adjusted hazard ratios (aHRs) and their 95% confidence intervals (CIs) for study outcomes.Results: The analysis of mood disorder drugs included 395 exposed spouses and 3711 reference spouses. The proportion of patients excluded from the analysis due to prescription of mood disorder drugs during the baseline period was 4.3% higher among exposed spouses than reference spouses. There was no major difference between groups with respect to mood disorder drug initiation after 1 year (aHR, 2.08 [95% CI, 0.61 to 7.13]). In subgroup analysis of females and dependents, exposed spouses showed a higher rate of initiation (females: aHR, 6.39 [95% CI, 1.24 to 32.80]; dependents: aHR, 6.47 [95% CI, 1.25 to 33.55]). No substantial differences in secondary outcomes were observed in any comparison.Conclusions: This study does not conclusively demonstrate an increase in mood disorder drug initiation among spouses of EOAD patients overall; however, initiation rates may be higher among female or dependent spouses. Our findings also suggest that exposed spouses experience significant psychological stress prior to their partners' EOAD diagnoses.

Background: Internet-based cognitive behavioral therapy (iCBT) shows promise in the prevention of depression. However, the specific iCBT components that contribute to its effectiveness remain unclear. Objective: We aim to evaluate the effects of iCBT components in preventing depression among university students. Methods: Using a smartphone cognitive behavioral therapy (CBT) app, we randomly allocated university students to the presence or absence of 5 different iCBT components: self-monitoring, behavioral activation, cognitive restructuring, assertiveness training, and problem-solving. The active intervention lasted 8 weeks but the app remained accessible through the follow-up. The primary outcome was the onset of a major depressive episode (MDE) between baseline and the follow-up after 52 weeks, as assessed with the computerized World Health Organization Composite International Diagnostic Interview. Secondary outcomes included changes in the 9-item Patient Health Questionnaire, 7-item General Anxiety Disorder, and CBT Skills Scale. Results: During the 12-month follow-up, 133 of 1301 (10) participants reported the onset of an MDE. There were no significant differences in the incidence of MDEs between the groups with or without each component (hazard ratios ranged from 0.85, 95% CI 0.60‐1.20, for assertiveness training to 1.26, 95% CI 0.88‐1.79, for self-monitoring). Furthermore, there were no significant differences in the changes on the 9-item Patient Health Questionnaire, 7-item General Anxiety Disorder, or for CBT Skills Scale between component allocation groups. However, significant reductions in depression and anxiety symptoms were observed among all participants at the 52-week follow-up. Conclusions: In this study, we could not identify any specific iCBT components that were effective in preventing depression or the acquisition of CBT skills over the 12-month follow-up period, but all participants with and without intervention of each iCBT component demonstrated significant improvements in depressive and anxiety symptoms. Further research is needed to explore the potential impact of frequency of psychological assessments, nonspecific intervention effects, natural change in the mental state, and the baseline depression level.

BACKGROUND Internet-based cognitive-behavioral therapy (iCBT) shows promise in the prevention of depression. However, the specific iCBT components that contribute to its effectiveness remain unclear. OBJECTIVE To evaluate the effects of iCBT components in preventing depression among university students. METHODS Using a smartphone CBT app, we randomly allocated university students to the presence or absence of five different iCBT components: self-monitoring (SM), behavioral activation (BA), cognitive restructuring (CR), assertiveness training (AT), and problem-solving (PS). The active intervention lasted eight weeks but the app remained accessible through the follow-up. The primary outcome was the onset of a major depressive episode (MDE) between baseline and 52 weeks follow-up, as assessed with the computerized WHO Composite International Diagnostic Interview (CIDI). Secondary outcomes included changes in the Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder-7 (GAD-7), and CBT Skills Scale. RESULTS During the 12-month follow-up, 133 of 1301 participants (10.2%) reported onset of MDE. There were no significant differences in the incidence of MDE between the groups with or without each component (Hazard ratios ranged from 0.85 [95% confidence interval: 0.60-1.20] for AT to 1.26 [0.88-1.79] for SM). Furthermore, there were no significant differences in the changes on the PHQ-9, GAD-7 or for CBT Skills Scale between component allocation groups. However, significant reductions in depression and anxiety symptoms were observed among all participants at the 52-week follow-up. CONCLUSIONS In this study, all participants with and without intervention of iCBT components demonstrated significant improvements in depressive and anxiety symptoms and we could not identify any specific iCBT components that were effective in preventing depression or the acquisition of CBT skills over the 12-month follow-up period. Further research is needed to explore the potential impact of frequency of psychological assessments, non-specific intervention effects, natural change in the mental state, and the baseline depression level. CLINICALTRIAL UMINCTR-000031307 INTERNATIONAL REGISTERED REPORT RR2-10.1186/s13063-018-2719-z

Subthreshold depression impairs young people's quality of life and places them at greater risk of developing major depression. Cognitive behavioral therapy (CBT) is an evidence-based approach for addressing such depressive states. This study identified subtypes of university students with subthreshold depression and revealed discrete profiles of five CBT skills: self-monitoring, cognitive restructuring, behavioral activation, assertive communication, and problem solving. Using data from the Healthy Campus Trial (registration number: UMINCTR-000031307), a hierarchical clustering analysis categorized 1,080 students into three clusters: Reflective Low-skilled, Non-reflective High-skilled, and Non-reflective Low-skilled students. Non-reflective Low-skilled students were significantly more depressed than other students (p < .001). The severity of depression seemed to be related to the combination of self-monitoring skills and other CBT skills. Considering the high prevalence of poor self-monitoring skills in persons with autism, the most severe depression was observed in the significant association between Non-reflective Low-skilled students and autistic traits (p = .008). These findings suggest that subthreshold depression can be categorized into three subtypes based on CBT skill profiles. The assessment of autistic traits is also suggested when we provide CBT interventions for Non-reflective Low-skilled students.