Published papers

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: The American Society of Clinical Oncology (ASCO) Clinical Practice guidelines recommend that physicians, nurses, social workers, and other health care providers should be prepared to discuss the risk of infertility with patients. We conducted an educational program for non-physician health care providers regarding fertility preservation and evaluated the effects of the educational program. Methods: The 4-h educational program consisted of lectures about infertility as a potential risk of cancer treatment, fertility preservation, and psychosocial support. Knowledge, confidence, institutional change, and self-practice were assessed pre-program, immediately post-program, and 6 months post-program. Results: Of 124 participants who joined the program, 74 completed and returned the follow-up survey 6 months after the program. Sixty-one percent of the participants were nurses, 27% were social workers, and 4% were psychologists. The scores for confidence and knowledge increased between pre- and immediate post-program periods (p < 0.01), and between pre- and 6-month post-program periods (p < 0.01). The knowledge score was 52, 76, and 71% at the 3 points respectively. The participants became more likely to disseminate fertility preservation counseling at their institutions (p < 0.01) and use informational resources (p < 0.01). Overall, self-practice and institutional support did not change. Conclusions: The study revealed that this educational program is applicable for non-physicians to learn about fertility preservation. The participants improved significantly in confidence and knowledge, but not in counseling skills.

© 2018 Sado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective Dementia has become a global critical issue. It is estimated that the global cost of dementia was 818 billion USD in 2015. The situation in Japan, which is the most aged country in the world, should be critical. However, the societal cost of dementia in Japan has not yet been estimated. This study was designed to estimate cost of dementia from societal perspective. Design We estimated the cost from societal perspective with prevalence based approach. Setting, participants and measures Main data sources for the parameters to estimate the costs are the National Data Base, a nationwide representative individual-level database for healthcare utilization, the Survey of Long-Term Care Benefit Expenditures, a nationwide survey based on individual-level secondary data for formal long-term care utilization, and the results of an informal care time survey for informal care cost. We conducted the analyses with ‘probabilistic modeling’ using the parameters obtained to estimate the costs of dementia. We also projected future costs. Results The societal costs of dementia in Japan in 2014 were estimated at JPY 14.5 trillion (se 66.0 billion). Of these, the costs for healthcare, long-term care, and informal care are JPY 1.91 trillion (se 4.91 billion), JPY 6.44 trillion (se 63.2 billion), and JPY 6.16 trillion (se 12.5 billion) respectively. The cost per person with dementia appeared to be JPY5.95 million (se 27 thousand). The total costs would reach JPY 24.3 trillion by 2060, which is 1.6 times higher than that in 2014. Conclusions The societal cost of dementia in Japan appeared to be considerable. Interventions to mitigate this impact should be considered.

© 2019 Background: Neurophysiology including P300, that is a typical index of event-related potential, may be potential biomarkers for bipolar disorder (BD) and it can be useful towards elucidating the pathophysiology of BD. However, previous findings from P300 studies were inconsistent due to the heterogeneity of research methods, which make it difficult to understand the neurobiological significance of them. The aim of this study is to conduct a meta-analysis on P300 in patients with BD. Method: A literature search was conducted using PubMed to identify studies that compared P300 event-related potential between patients with BD and healthy controls (HCs). We analyzed P300 indices such as amplitude and latency of P3a and P3b in auditory or visual paradigms. Further, moderator analyses were conducted to investigate the influence of patient characteristics (i.e. history of psychosis, diagnostic subcategories [BD-I/BD-II], and phase of illness [euthymic, manic, or depressive]) on P300 indices. Result: Out of 124 initial records, we included 30 articles (BD: N = 1331; HCs: N = 1818). Patients with BD showed reduced P3a and P3b amplitude in both paradigms and delayed P3b latency in auditory paradigms compared to HCs. There was no influence on the history of psychosis, diagnostic subcategories, or phase of illness on P300 indices. Limitation: The difference in medication use was difficult to control and it may affect the results. Conclusion: This meta-analysis provides evidence for P300 abnormalities in patients with BD compared to HCs. Our results suggest that P300 may be trait markers rather than state markers in this illness.

© 2020 The Authors Introduction: Depressive and neurocognitive disorders are debilitating conditions that account for the leading causes of years lived with disability worldwide. However, there are no biomarkers that are objective or easy-to-obtain in daily clinical practice, which leads to difficulties in assessing treatment response and developing new drugs. New technology allows quantification of features that clinicians perceive as reflective of disorder severity, such as facial expressions, phonic/speech information, body motion, daily activity, and sleep. Methods: Major depressive disorder, bipolar disorder, and major and minor neurocognitive disorders as well as healthy controls are recruited for the study. A psychiatrist/psychologist conducts conversational 10-min interviews with participants ≤10 times within up to five years of follow-up. Interviews are recorded using RGB and infrared cameras, and an array microphone. As an option, participants are asked to wear wrist-band type devices during the observational period. Various software is used to process the raw video, voice, infrared, and wearable device data. A machine learning approach is used to predict the presence of symptoms, severity, and the improvement/deterioration of symptoms. Discussion: The overall goal of this proposed study, the Project for Objective Measures Using Computational Psychiatry Technology (PROMPT), is to develop objective, noninvasive, and easy-to-use biomarkers for assessing the severity of depressive and neurocognitive disorders in the hopes of guiding decision-making in clinical settings as well as reducing the risk of clinical trial failure. Challenges may include the large variability of samples, which makes it difficult to extract the features that commonly reflect disorder severity. Trial Registration: UMIN000021396, University Hospital Medical Information Network (UMIN).

© 2018 International Psychogeriatric Association. In Japan, 4.6 million people are living with dementia and the number is expected to rise to 7 million by 2025. Amyloid-β (Aβ) positron emission tomography (PET) is used for cognitively normal Japanese people with or without subjective cognitive decline (SCD) for the purpose of clinical trials or diagnosis. Nevertheless, no empirical studies have been conducted on the safety of disclosing amyloid status to such populations. We conducted amyloid PET imaging on 42 participants (Aβ positive (n = 10) and negative (n = 32)). State anxiety and depression were measured at pre- and post-disclosure, and test-related distress at post-disclosure. Mean state anxiety and depression scores were below the cut-off through pre- and post-disclosure in the Aβ positive and negative groups. State anxiety and depression did not change over time and were not different between groups. Mean test-related distress scores were within normal limits at post-disclosure in both groups. No significant difference was found between groups. Disclosing Aβ positive results did not cause greater mood disturbance than negative results in a short period of time. The short-term psychological safety of disclosing Aβ PET results to asymptomatic Japanese adults with SCD was indicated.

© 2018 The Authors. Purpose: In recent years, the relationship between dry eye disease (DED) and psychiatric disorders has been gaining attention. The relationship between dry eye symptoms and psychiatric symptoms has been reported in multiple retrospective studies. However, in previous studies there have been limitations to these observations, such as a lack of close examination of either DED or mood symptoms. Methods: In this study, we evaluated the psychological state and social functionality of DED patients by administering validated psychiatric tests as well as ophthalmologic examinations twice during the course of DED treatment. Forty subjects (61.3 ± 18.1-years old) received the primary psychiatric assessments and 26 received the secondary psychiatric assessments. Results: In a cross-sectional examination, we found patients with depressive and/or anxiety symptoms had higher Dry Eye Related Quality of Life Score (DEQ) scores, whereas the objective symptoms of DED did not differ between groups. We also found a positive relationship between depression/anxiety scores and DED subjective symptoms. On the other hand, in longitudinal examination, we found psychiatric symptoms had no impact on subjective and objective DED symptoms throughout the course of DED symptoms. Conclusions: We found depression and anxiety were related to the subjective symptoms of DED but not the objective symptoms. Translational Relevance: It is important to pay attention to psychiatric symptoms in patients with DED and an investigation into appropriate treatment strategies for patients with DED in combination with psychiatric symptoms is needed in the future.

© 2020 Daté et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objectives As the population of patients with cognitive decline grows, physicians and caregivers need brief screening tools. Comprehensive neurocognitive batteries require special training and time for evaluation. We focused on accessibility and compared the diagnostic power of several easy questions. Design “Attended With” (AW) and “Head-Turning Sign” (HTS) factors and participants’ replies to following questions were recorded: “Do you feel that you have more difficulties in your daily life than you used to?”, [no consciousness (C-) or consciousness+ (C+)], “Could you tell me about your daily pleasures or pastimes?” [no pleasure (P-) or pleasure + (P+)], “What are notable current/recent news/topics?” [no news (N-) or news+ (N+)]. Setting This took place in our Memory Clinic between May 2016 and July 2019. Participants We enrolled 162 consecutive cases (44 cognitive normal (CN), 55 amnestic mild cognitive impairment (aMCI), and 48 Alzheimer’s disease (AD)). Measurements The sensitivity and specificity of each battery were calculated, and on account of those numbers, the population attributable risk percent % (PAR%) of (AW and HTS+), (C- and P-), (C- and N-), (P- and N-) as analysis of combination of questions, respectively, were calculated. Results AW had high sensitivity, 87.4, 95.8% (CN vs aMCI + AD, CN + aMCI vs AD) but the sensitivity of HTS was only 46.4, 57.7%, and HTS showed high specificity, 100.0, 71.8%. C- had high sensitivity, 80.6, 87.5%, whereas P- and N- had high specificity, both 83.9% in CN vs aMCI + AD, 88.1% and 75.9% in CN + aMCI vs AD, respectively. In combination analysis, the PAR% of (C- and N-) were as high as (AW and HTS+). Conclusions The combination of (C- and N-) is as powerful as (AW and HTS+) in screening AD. Our findings provide novel insights for screening utility of brief questions “Consciousness of Impairment” and “Recent News.”

© 2020 The Authors Psychiatry and Clinical Neurosciences © 2020 Japanese Society of Psychiatry and Neurology Aim: Suicide attempters have a high risk of repeated suicide attempts and completed suicide. There is evidence that assertive case management can reduce the incidence of recurrent suicidal behavior among suicide attempters. This study evaluated the effect of an assertive-case-management training program. Methods: This multicenter, before-and-after study was conducted at 10 centers in Japan. Participants were 274 medical personnel. We used Japanese versions of the Attitudes to Suicide Prevention Scale, the Gatekeeper Self-Efficacy Scale, the Suicide Intervention Response Inventory (SIRI), and the Attitudes Toward Suicide Questionnaire. We evaluated the effects with one-sample t-tests, and examined prognosis factors with multivariable analysis. Results: There were significant improvements between pre-training and post-training in the Attitudes to Suicide Prevention Scale (mean: −3.07, 95% confidence interval [CI]: −3.57 to −2.57, P < 0.001), the Gatekeeper Self-Efficacy Scale (mean: 10.40, 95%CI: 9.48 to 11.32, P < 0.001), SIRI-1 (appropriate responses; mean: 1.15, 95%CI: 0.89 to 1.42, P < 0.001), and SIRI-2 (different to the expert responses; mean: −4.78, 95%CI: −6.18 to −3.38, P < 0.001). Significant improvements were found on all Attitudes Toward Suicide Questionnaire subscale scores, except Unjustified Behavior. The effect of training was influenced by experience of suicide-prevention training and experience of working with suicidal patients. Conclusion: The training program (which was developed to implement and disseminate evidence-based suicide-prevention measures) improved attitudes, self-efficacy, and skills for suicide prevention among medical personnel. Specialized suicide-prevention training and experience with suicidal patients are valuable for enhancing positive attitudes and self-efficacy; furthermore, age and clinical experience alone are insufficient for these purposes.

© 2020 Yamamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background There are no reliable and validated objective biomarkers for the assessment of depression severity. We aimed to investigate the association between depression severity and timing-related speech features using speech recognition technology. Method Patients with major depressive disorder (MDD), those with bipolar disorder (BP), and healthy controls (HC) were asked to engage in a non-structured interview with research psychologists. Using automated speech recognition technology, we measured three timing-related speech features: speech rate, pause time, and response time. The severity of depression was assessed using the Hamilton Depression Rating Scale 17-item version (HAMD-17). We conducted the current study to answer the following questions: 1) Are there differences in speech features among MDD, BP, and HC? 2) Do speech features correlate with depression severity? 3) Do changes in speech features correlate with within-subject changes in depression severity? Results We collected 1058 data sets from 241 individuals for the study (97 MDD, 68 BP, and 76 HC). There were significant differences in speech features among groups; depressed patients showed slower speech rate, longer pause time, and longer response time than HC. All timing-related speech features showed significant associations with HAMD-17 total scores. Longitudinal changes in speech rate correlated with changes in HAMD-17 total scores. Conclusions Depressed individuals showed longer response time, longer pause time, and slower speech rate than healthy individuals, all of which were suggestive of psychomotor retardation. Our study suggests that speech features could be used as objective biomarkers for the assessment of depression severity.

PURPOSE: The assessment of anterior eye diseases and the understanding of psychological functions of blinking can benefit greatly from a validated blinking detection technology. In this work, we proposed an algorithm based on facial recognition built on current video processing technologies to automatically filter and analyze blinking movements. We compared electrooculography (EOG), the gold standard of blinking measurement, with manual video tape recording counting (mVTRc) and our proposed automated video tape recording analysis (aVTRa) in both static and dynamic conditions to validate our aVTRa method. METHODS: We measured blinking in both static condition, where the subject was sitting still with chin fixed on the table, and dynamic condition, where the subject's face was not fixed and natural communication was taking place between the subject and interviewer. We defined concordance of blinks between measurement methods as having less than 50 ms difference between eyes opening and closing. RESULTS: The subjects consisted of seven healthy Japanese volunteers (3 male, four female) without significant eye disease with average age of 31.4±7.2. The concordance of EOG vs. aVTRa, EOG vs. mVTRc, and aVTRa vs. mVTRc (average±SD) were found to be 92.2±10.8%, 85.0±16.5%, and 99.6±1.0% in static conditions and 32.6±31.0%, 28.0±24.2%, and 98.5±2.7% in dynamic conditions, respectively. CONCLUSIONS: In static conditions, we have found a high blink concordance rate between the proposed aVTRa versus EOG, and confirmed the validity of aVTRa in both static and dynamic conditions.

© 2020 The Author(s). Published by Cambridge University Press. Background Virtual reality exposure therapy (VRET) is currently being used to treat social anxiety disorder (SAD); however, VRET's magnitude of efficacy, duration of efficacy, and impact on treatment discontinuation are still unclear. Methods We conducted a meta-analysis of studies that investigated the efficacy of VRET for SAD. The search strategy and analysis method are registered at PROSPERO (#CRD42019121097). Inclusion criteria were: (1) studies that targeted patients with SAD or related phobias; (2) studies where VRET was conducted for at least three sessions; (3) studies that included at least 10 participants. The primary outcome was social anxiety evaluation score change. Hedges' g and its 95% confidence intervals were calculated using random-effect models. The secondary outcome was the risk ratio for treatment discontinuation. Results Twenty-two studies (n = 703) met the inclusion criteria and were analyzed. The efficacy of VRET for SAD was significant and continued over a long-term follow-up period: Hedges' g for effect size at post-intervention,-0.86 (-1.04 to-0.68); three months post-intervention,-1.03 (-1.35 to-0.72); 6 months post-intervention,-1.14 (-1.39 to-0.89); and 12 months post-intervention,-0.74 (-1.05 to-0.43). When compared to in vivo exposure, the efficacy of VRET was similar at post-intervention but became inferior at later follow-up points. Participant dropout rates showed no significant difference compared to in vivo exposure. Conclusion VRET is an acceptable treatment for SAD patients that has significant, long-lasting efficacy, although it is possible that during long-term follow-up, VRET efficacy lessens as compared to in vivo exposure.

© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4–10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.

© 2018 Wiley Periodicals, Inc. Polarized light imaging (PLI) enables detecting the orientation of myelinated axon bundles in brain slices at microscopic resolution without histological staining. However, standard PLI requires labor-intensive procedures such as mounting brain cryosections on slide glasses. We developed an optical system that does not require a mounting procedure for PLI. Specifically, we developed an optical system to perform PLI in reflection mode (rPLI) instead of employing transmitted light as in standard PLI. We integrated this rPLI system with a conventional vibratome slicer whose cutting blade surface is a mirror. This combination allowed PLI measurements directly during the slicing procedure at room temperature. Thus, mounting procedure for PLI is not necessary. As a proof-of-concept experiment, a perfusion-fixed brain of a mouse was embedded in gelatin-containing agar and cut serially at 40~200 μm intervals. The slicing procedure was temporarily halted after each cut to capture the PLI images of the slice on the reflecting blade surface while the slice was still held up by the agar block. The orientation of the fiber bundle estimated with this method agreed with the results obtained from previous reports. Combination of a popular vibratome slicer and our rPLI system that uses versatile and inexpensive optical components would increase popularity of PLI and facilitates connectome studies at microscopic resolution. Research Highlights: Polarized light imaging (PLI) of brain slices was realized by using reflected light (rPLI) instead of transmitted light. The rPLI method allows detecting the myelinated fiber bundle orientation during slice preparation.

© Shigetsugu Nakao, Atsuo Nakagawa, Yoshiyo Oguchi, Dai Mitsuda, Noriko Kato, Yuko Nakagawa, Noriko Tamura, Yuka Kudo, Takayuki Abe, Mitsunori Hiyama, Satoru Iwashita, Yutaka Ono, Masaru Mimura. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 21.09.2018. This is an open-access article distributed under the terms of the Creative Commons Attribution License. Background: Meta-analyses of several randomized controlled trials have shown that cognitive behavioral therapy (CBT) has comparable efficacy to antidepressant medication, but therapist availability and cost-effectiveness is a problem. Objective: This study aimed to evaluate the effectiveness of Web-based CBT blended with face-to-face sessions that reduce therapist time in patients with major depression who were unresponsive to antidepressant medications. Methods: A 12-week, assessor-masked, parallel-group, waiting- list controlled, randomized trial was conducted at 3 medical institutions in Tokyo. Outpatients aged 20-65 years with a primary diagnosis of major depression who were taking ≥1 antidepressant medications at an adequate dose for ≥6 weeks and had a 17-item GRID-Hamilton Depression Rating Scale (HAMD) score of ≥14 were randomly assigned (1:1) to blended CBT or waiting-list groups using a computer allocation system, stratified by the study site with the minimization method, to balance age and baseline GRID-HAMD score. The CBT intervention was given in a combined format, comprising a Web-based program and 12 45-minute face-to-face sessions. Thus, across 12 weeks, a participant could receive up to 540 minutes of contact with a therapist, which is approximately two-thirds of the therapist contact time provided in the conventional CBT protocol, which typically provides 16 50-minute sessions. The primary outcome was the alleviation of depressive symptoms, as measured by a change in the total GRID-HAMD score from baseline (at randomization) to posttreatment (at 12 weeks). Moreover, in an exploratory analysis, we investigated whether the expected positive effects of the intervention were sustained during follow-up, 3 months after the posttreatment assessment. Analyses were performed on an intention-to-treat basis, and the primary outcome was analyzed using a mixed-effects model for repeated measures. Results: We randomized 40 participants to either blended CBT (n=20) or waiting-list (n=20) groups. All patients completed the 12-week treatment protocol and were included in the intention-to-treat analyses. Participants in the blended CBT group had significantly alleviated depressive symptoms at week 12, as shown by greater least squares mean changes in the GRID-HAMD score, than those in the waiting list group (−8.9 points vs −3.0 points; mean between-group difference=−5.95; 95% CI −9.53 to −2.37; P<.001). The follow-up effects within the blended CBT group, as measured by the GRID-HAMD score, were sustained at the 3-month follow-up (week 24) and posttreatment (week 12): posttreatment, 9.4 (SD 5.2), versus follow-up, 7.2 (SD 5.7); P=.009. Conclusions: Although our findings warrant confirmation in larger and longer term studies with active controls, these suggest that a combined form of CBT is effective in reducing depressive symptoms in patients with major depression who are unresponsive to antidepressant medications.

© The Author(s) (2018). Since prior diffusion tensor imaging (DTI) studies reported no significant differences in white matter organizations between individuals with autism spectrum disorder (ASD) and their unaffected siblings, the neural correlates for developing a clinical diagnosis among people with endophenotypes remain undetermined. We obtained DTI data from a total of 60 participants consisting of 30 people with endophenotypes and 30 people without. We first followed a conventional approach by comparing individuals with ASD and their unaffected siblings. Using region-of-interest approach, we then performed bootstrapping to examine whether the differences in white matter organizations between individuals with ASD and their unaffected siblings were substantially large, considering the distribution of differences between typically developing (TD) siblings. Conventional approaches revealed no significant differences in white matter organizations between individuals with ASD and their unaffected siblings. Bootstrapping revealed a significantly large difference in axial diffusivity in the left stria terminalis between individuals with ASD and their unaffected siblings after accounting for the distribution of differences in axial diffusivity among TD siblings (99.998 percentile). The results remained significant after controlling for multiple comparisons with Bonferroni method. We assumed that one aspect of this tract was associated with the development of a clinical diagnosis.

© 2020 Elsevier Inc. Previous diffusion tensor imaging (DTI) studies have reported white matter alterations in patients with schizophrenia. Notably, one third of this population does not respond to first-line antipsychotics and is thus referred to as treatment-resistant schizophrenia (TRS). Despite potentially distinct neural bases between TRS and non-TRS, few studies have compared white matter integrity between these groups. In order to reflect clinical picture of TRS, we enrolled TRS patients who had severe symptoms. According to the consensus criteria for TRS. TRS was defined by severe positive symptomatology despite optimal antipsychotic treatment. Fractional anisotropy (FA), an index of white matter integrity, was examined by DTI and analyzed with tract-based spatial statistics in 24 TRS patients (mean PANSS = 108.9), 28 non-TRS patients (mean PANSS = 50.0), and 27 healthy controls (HCs) for group comparison. Additionally, correlation analyses were conducted between FA values and symptomatology. The TRS group had lower FA values in multiple tracts (cerebral peduncle, corona radiata, corpus callosum, external and internal capsules, posterior thalamic radiation, sagittal stratum, superior longitudinal fasciculus, tapetum, and uncinate fasciculus) compared to the HC group as well as the non-TRS group (p <.05; family-wise error-corrected), while no differences were found between the non-TRS and HC groups. In the TRS group, FA values in most of the tracts (other than the left anterior limb of internal capsule, left cerebral peduncle, and right uncinate fasciculus) were negatively correlated with the Positive and Negative Syndrome Scale total scores, and negative and general symptom scores. No such relationships were found in the non-TRS group. The identified white matter integrity deficits may reflect the pathophysiology of TRS.

© Copyright 2020, Mary Ann Liebert, Inc., publishers. Microstructural white matter (WM) disruption and resulting abnormal structural connectivity form a potential underlying pathology in traumatic brain injury (TBI). Herein, to determine the potential mechanism of cognitive deterioration in TBI, we examined the association of damage to specific WM tracts with cognitive function in TBI patients. We recruited 18 individuals with mild-to-moderate/severe TBI in the chronic phase and 17 age-matched controls. We determined the pattern of WM aberrations in TBI using tract-based spatial statistics (TBSS) and then examined the relationship between cognitive impairment and WM damage using the threshold-free cluster enhancement correction in TBSS. TBSS analysis showed that TBI patients exhibited WM aberrations in a wide range of brain regions. In the majority of these regions, lower fractional anisotropy (FA) largely overlapped with increased radial diffusivity, but not with axial diffusivity. Further, voxel-wise correction in TBSS demonstrated that higher FA values were associated with better performance in the phonemic verbal fluency task (VFT) in widespread WM regions, but not with the semantic VFT. Despite variation in the magnitude and location of brain injury between individual cases, chronic TBI patients exhibited widespread WM aberrations. We confirmed the findings of previous studies that WM integrity is lower across the spectrum of TBI severity in chronic subjects compared to controls. Further, phonemic VFT may be a more sensitive cognitive measure of executive dysfunction associated with WM aberrations in TBI compared with semantic VFT.

© 2018 Wiley Periodicals, Inc. Functional magnetic resonance imaging (fMRI) based on the blood oxygenation level-dependent (BOLD) signal has been used to infer sites of neuronal activation in the brain. A recent study demonstrated, however, unexpected BOLD signal generation without neuronal excitation, which led us to hypothesize the presence of another cellular source for BOLD signal generation. Collective assessment of optogenetic activation of astrocytes or neurons, fMRI in awake mice, electrophysiological measurements, and histochemical detection of neuronal activation, coherently suggested astrocytes as another cellular source. Unexpectedly, astrocyte-evoked BOLD signal accompanied oxygen consumption without modulation of neuronal activity. Imaging mass spectrometry of brain sections identified synthesis of acetyl-carnitine via oxidative glucose metabolism at the site of astrocyte-, but not neuron-evoked BOLD signal. Our data provide causal evidence that astrocytic activation alone is able to evoke BOLD signal response, which may lead to reconsideration of current interpretation of BOLD signal as a marker of neuronal activation.

© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. Tau deposits is a core feature of neurodegenerative disorder following traumatic brain injury (TBI). Despite ample evidence from post-mortem studies demonstrating exposure to both mild-repetitive and severe TBIs are linked to tau depositions, associations of topology of tau lesions with late-onset psychiatric symptoms due to TBI have not been explored. To address this issue, we assessed tau deposits in long-term survivors of TBI by PET with 11C-PBB3, and evaluated those associations with late-life neuropsychiatric outcomes. PET data were acquired from 27 subjects in the chronic stage following mild-repetitive or severe TBI and 15 healthy control subjects. Among the TBI patients, 14 were diagnosed as having late-onset symptoms based on the criteria of traumatic encephalopathy syndrome. For quantification of tau burden in TBI brains, we calculated 11C-PBB3 binding capacity (cm3), which is a summed voxel value of binding potentials (BP*ND) multiplied by voxel volume. Main outcomes of the present study were differences in 11C-PBB3 binding capacity between groups, and the association of regional 11C-PBB3 binding capacity with neuropsychiatric symptoms. To confirm 11C-PBB3 binding to tau deposits in TBI brains, we conducted in vitro PBB3 fluorescence and phospho-tau antibody immunofluorescence labelling of brain sections of chronic traumatic encephalopathy obtained from the Brain Bank. Our results showed that patients with TBI had higher 11C-PBB3 binding capacities in the neocortical grey and white matter segments than healthy control subjects. Furthermore, TBI patients with traumatic encephalopathy syndrome showed higher 11C-PBB3 binding capacity in the white matter segment than those without traumatic encephalopathy syndrome, and regional assessments revealed that subgroup difference was also significant in the frontal white matter. 11C-PBB3 binding capacity in the white matter segment correlated with the severity of psychosis. In vitro assays demonstrated PBB3-positive tau inclusions at the depth of neocortical sulci, confirming 11C-PBB3 binding to tau lesions. In conclusion, increased 11C-PBB3 binding capacity is associated with late-onset neuropsychiatric symptoms following TBI, and a close correlation was found between psychosis and 11C-PBB3 binding capacity in the white matter.

© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Neuropsychiatric symptoms (NPS) inevitably occur during the course of Alzheimer’s disease (AD) including psychosis, aggression, and depression. The effectiveness of pharmacological treatments for NPS has been limited because of their lack of efficacy, discontinuation due to undesirable adverse events, or poor adherence. In recent consensus guidelines, non-pharmacological treatments for NPS have been prioritized as first-line management strategies. Pharmacological treatments for severe NPS should be administrated as a second-line approach, and have been suggested to be started at a lower dosage followed by titration to a minimum effective dosage and for a limited time period. However, recent studies have shown that some patients receiving pharmacological treatments do not exhibit treatment efficacy in comparison with placebo. The concurrence of several sub-symptoms in NPS makes it difficult to target one symptom exclusively. Therefore, the current review focuses on a strategy for such refractory NPS in patients with AD. Recent randomized controlled trials have shown that the severity of NPS gradually reduces in a time-dependent manner regardless of active treatments. Therefore, clinicians should consider potential causes of NPS sub-symptoms from multifactorial aspects and select alternative treatments (e.g. neuromodulation or relocation into specialized care units) during the long-term disease course.