Is there a spinal tap responder in progressive supranuclear palsy? The first prospective study.

OBJECTIVE: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease, and sometimes shows idiopathic normal pressure hydrocephalus (iNPH)-like presentations. We aimed to evaluate spinal tap responsiveness in patients with PSP, including the effect of sham spinal tap. METHODS: Eleven patients with PSP, ten with probable/definite iNPH, and eight control patients were prospectively enrolled. All participants underwent sham spinal tap and spinal tap procedures. Gait was evaluated using wearable inertial sensors. We defined "tap responders" as individuals with a 10% or more improvement from baseline in any of the gait parameters (timed up-and-go test total time, stride length, and velocity during straight walking under single-task and cognitive dual-task conditions). We compared the ratio of responders in patients with PSP to patients with iNPH and controls. RESULTS: The ratio of tap responders and the ratio of sham tap responders in patients with PSP were significantly higher than those in control patients, and not different from those in patients with iNPH. PSP patients with iNPH-like MRI features tended to respond to the spinal tap compared to those without such imaging features. Notably, one patient with PSP, who responded to the spinal tap beyond the effect of sham spinal tap, was treated by the shunt operation. CONCLUSION: This is the first prospective study to demonstrate tap and shunt responsiveness in patients with PSP while highlighting the placebo effects of the spinal tap in patients with PSP or iNPH. Our findings suggest that some PSP patients have impaired cerebrospinal fluid circulation, contributing to a distinct component of the clinical spectrum.

Decreased short-latency afferent inhibition in individuals with mild cognitive impairment: A TMS-EEG study.

TMS combined with EEG (TMS-EEG) is a tool to characterize the neurophysiological dynamics of the cortex. Among the TMS paradigms, short-latency afferent inhibition (SAI) allows the investigation of inhibitory effects mediated by the cholinergic system. The aim of this study was to compare cholinergic function in the DLPFC between individuals with mild cognitive impairment (MCI) and healthy controls (HC) using TMS-EEG with the SAI paradigm. In this study, 30 MCI and 30 HC subjects were included. The SAI paradigm consisted of 80 single pulse TMS and 80 SAI stimulations applied to the left DLPFC. N100 components, global mean field power (GMFP) and total power were calculated. As a result, individuals with MCI showed reduced inhibitory effects on N100 components and GMFP at approximately 100 ms post-stimulation and on ß-band activity at 200 ms post-stimulation compared to HC. Individuals with MCI showed reduced SAI, suggesting impaired cholinergic function in the DLPFC compared to the HC group. We conclude that these findings underscore the clinical applicability of the TMS-EEG method as a powerful tool for assessing cholinergic function in individuals with MCI.

The relationship between cognitive reserve focused on leisure experiences and cognitive functions in bipolar patients.

Bipolar disorder (BP) is characterized by cognitive decline. Individual differences exist in maintaining cognitive function due to daily physical activity and sleep. We examined the relationship between leisure experiences as proxies for cognitive reserve (CR) and cognitive function in patients with bipolar disorder after adjusting for daily physical activity and sleep. The CR of patients with BP (n = 24) and healthy study controls (HC) (n = 24) was assessed using premorbid IQ, years of education, and leisure activity history. Performance-based neuropsychological tests were performed to evaluate cognitive function. A self-reported scale was used to assess resilience. Physical activity and sleep were measured using an activity meter. Verbal fluency, story memory, and verbal memory were significantly positively correlated with the kinds of leisure experiences in patients with BP. A hierarchical regression analysis accounting for confounding factors showed that verbal fluency and memory were associated with the kinds of leisure experiences. Neither years of education nor resilience were significantly associated with neuropsychological scores. Various leisure experiences in patients with BP are associated with higher language-related cognitive functioning. Engaging in various leisure experiences may affect higher cognitive functions related to language.

The effect of damage to the white matter network and premorbid intellectual ability on postoperative verbal short-term memory and functional outcome in patients with brain lesions.

Cognitive reserve is the capacity to cope with cognitive decline due to brain damage caused by neurological diseases. Premorbid IQ has been investigated as a proxy for cognitive reserve. To date, no study has focused on the effects of premorbid IQ in patients with brain tumors, considering the damage to white matter tracts. We investigated whether a higher premorbid IQ has a beneficial impact on postoperative verbal short-term memory and functional outcomes in patients with brain tumors. A total of 65 patients with brain tumors (35 right and 30 left hemisphere lesions) and 65 healthy subjects participated in the study. We used multiple regression analysis to examine whether white matter tract damage and premorbid IQ affect postoperative verbal short-term memory, and the interaction effects of premorbid IQ with damage to white matter tract on postoperative verbal short-term memory. Path analysis was used to investigate the relationship between damage to the white matter tract and premorbid IQ on postoperative functional ability. Our results showed that damage to the left arcuate fasciculus affected postoperative functional ability through verbal short-term memory, working memory, and global cognition in patients with left hemisphere lesions. In the right hemisphere lesion group, high premorbid IQ had a positive effect on functional ability by mediating verbal short-term memory, verbal working memory, and global cognition. We found that damage to the eloquent pathway affected postoperative verbal short-term memory regardless of the premorbid IQ level. However, a higher premorbid IQ was associated with better postoperative verbal short-term memory and functional outcomes when the brain lesions were not located in a crucial pathway. Our findings suggest that premorbid IQ and damage to the white matter tracts should be considered predictors of postoperative functional outcomes.

Decrease in gamma-band auditory steady-state response in patients with treatment-resistant schizophrenia.

BACKGROUND: Thirty percent of patients with schizophrenia do not respond to non-clozapine antipsychotics and are termed treatment-resistant schizophrenia (TRS). The 40-Hz auditory steady-state response (ASSR) is a well-known to be reduced in patients with schizophrenia compared to healthy controls (HCs), suggesting impaired gamma oscillation in schizophrenia. Given no ASSR study on TRS, we aimed to examine the neurophysiological basis of TRS employing 40-Hz ASSR paradigm. METHOD: We compared ASSR measures among HCs, patients with non-TRS, and patients with TRS. TRS criteria were defined by a score of 4 or higher on two items of the Positive and Negative Syndrome Scale (PANSS) positive symptoms despite standard antipsychotic treatment. Participants were examined for ASSR with 40-Hz click-train stimulus, and then time-frequency analysis was performed to calculate evoked power and phase-locking factor (PLF) of 40-Hz ASSR. RESULTS: A total of 79 participants were included: 27 patients with TRS (PANSS = 92.6 ± 15.8); 27 patients with non-TRS (PANSS = 63.3 ± 14.7); and 25 HCs. Evoked power in 40-Hz ASSR was lower in the TRS group than in the HC group (F2,79 = 8.37, p = 0.015; TRS vs. HCs: p = 0.012, d = 1.1) while no differences in PLF were found between the groups. CONCLUSION: These results suggest that glutamatergic and GABAergic neurophysiological dysfunctions are involved in the pathophysiology of TRS. Our findings warrant more comprehensive and longitudinal studies for deep phenotyping of TRS.

The Relationship between Daily Behavior Changes and Vaccine Attitudes at the Early Stage of the COVID-19 Pandemic among Japanese People from Different Demographics: A Retrospective and Exploratory Examination Using a Free-Response Survey.

This study investigated how daily behaviors of Japanese people changed during the early stages of the COVID-19 pandemic and whether the change was mediated by demographics. It also examined whether the magnitude of behavior change in a demographic group is related to their attitudes towards the COVID-19 vaccine. 301 Japanese responded to an online survey in February 2021, in which they first wrote some activities they frequently performed before the virus outbreak and then wrote about activities in their current life. The number of gathered answers were 1858 for 'before' and 1668 for 'after', and they were grouped into 19 behavior categories. Overall, behaviors such as traveling, eating out, and shopping were much less frequently described in the 'after' condition; while housework, food delivery, and pandemic prevention were mentioned more. However, the change pattern was significantly influenced by demographics of age, gender, having children or not, and household income. Especially women, younger generations, and people without children showed the greatest extent of behavior change compared with the other demographic cohorts. These groups were reported to be vaccine-hesitant in the literature. This study suggests that individuals with hesitant attitudes towards vaccines are more willing to change their behaviors to control viral transmission.

The relationship between leisure activities and mental health: The impact of resilience and COVID-19.

Engaging in leisure activities promotes mental health. The effect is likely associated with resilience as the broaden-and-build theory suggests positive emotions elicited from leisure increase mental resources for stress coping. The present research examined whether participating in different leisure activities at a given time increases the level of resilience, which in turn reduces psychological problems. It also investigated the changes in people's leisure activities due to the COVID-19 outbreak and the impact of these changes on their mental health. Japanese participants (N = 300) responded to two online surveys conducted before (January 2020) and after the outbreak (February 2021). They selected the leisure activities they had engaged in from 100 choices and reported their levels of resilience and depressive symptoms. An analysis of covariates revealed that the total number of selected activities significantly reduced in the second survey, but the levels of resilience and depressive symptoms remained constant. Regression analysis showed that the reduction in leisure activities did not predict depressive symptoms. However, structural equation modeling established that the relationship between leisure and depression was mediated by resilience, supporting the initial hypothesis. Importantly, this relationship slightly differed by age group, likely because popular activities and their psychological impacts vary depending on age.

Premorbid intellectual ability in schizophrenia influence family appraisal related to cognitive impairments: a cross-sectional study on cognitive impairment and family assessments.

BACKGROUND: Patients with schizophrenia are unaware of their cognitive impairments. Misperception of cognitive impairment is an important factor associated with real-world functional outcomes in patients with schizophrenia. The patient's family member plays a crucial role in detecting patients' cognitive impairments when the patients are unaware of their own cognitive impairments. Previous studies have reported that not only the patient's subjective rating, but also the patient's family members' rating of their cognitive impairment may not be precise. However, it is unclear why family ratings are inaccurate, and which factors impact family ratings. This study investigated whether family ratings differed significantly from the patients' subjective ratings of the patients' cognitive impairments and sought to determine the reason for the differences between the family ratings and the patients' neurocognitive performances. We investigated the relationship between patients' subjective ratings, family ratings for patients' cognitive impairments, neuropsychological performance, and other aspects, including premorbid IQ and clinical symptoms. METHOD: We evaluated 44 patients with schizophrenia for cognitive function using neuropsychological tests; in addition, both the patients and their families rated the patients' cognitive impairments through questionnaires. We used the Mann-Whitney U test to examine whether the family ratings differed significantly from the patients' self-reported ratings of their cognitive impairment. We conducted multiple regression analysis and structural equation modeling to determine why the patients' subjective ratings and the family ratings were not definitively associated with the patients' neurocognitive performances. We performed multiple regression analysis with a stepwise method with neurocognitive performance, premorbid IQ, positive symptoms, and negative symptoms as independent variables and family ratings of patients' cognitive impairments as dependent variables. RESULTS: We found that the family ratings differed significantly from the patients' subjective self-reported ratings of their cognitive impairments. Our results showed that the premorbid IQ of patients is the strongest predictor of family ratings. Furthermore, among the neurocognitive domains, only the processing speed of patients was associated with family ratings. CONCLUSIONS: We found that the family ratings were not consistent with the patients' subjective self-reported ratings and the family ratings were most affected by the patients' premorbid intellectual abilities. These results suggest that the families' current assessments of the patients' current cognitive impairments were affected by the patients' premorbid intellectual ability rather than the patients' current neurocognitive performance. Patients' processing speed predicted family ratings; however, family members' ratings were not related to verbal learning/memory, executive function, and language of patients. Therefore, our findings highlight that patients' family ratings may differ from patients' subjective ratings, results of performance-based neuropsychological tests, and clinician ratings.

The efficacy of memantine in the treatment of civilian posttraumatic stress disorder: an open-label trial.

Background: Currently, there is a paucity of pharmacological treatment options for posttraumatic stress disorder (PTSD), and the development of a novel pharmacotherapeutic approach has become a matter of great interest. Objective: We conducted a 12-week open-label clinical trial to examine the efficacy and safety of memantine, an N-methyl-D-aspartate receptor antagonist, in the treatment of civilian PTSD. Method: Thirteen adult patients with DSM-IV PTSD, all civilian women, were enrolled. They were monitored at an ambulatory care facility every week until 4 weeks and then every 4 weeks until 12 weeks. Memantine was added to each patient's current medication, with the initial dosage of 5 mg/day and then titrated. Concomitant medications were essentially kept unchanged during the trial. The primary outcome was PTSD diagnosis and severity assessed with the Posttraumatic Diagnostic Scale (PDS). Results: Of the 13 cases, one dropped out and two were discarded due to the protocol deviation, and the analysis was done for the remaining 10. Mean PDS total scores decreased from 32.3 ± 9.7 at baseline to 12.2 ± 7.9 at endpoint, which was statistically significant with a large effect (paired t-test: p = .002, d = 1.35); intrusion, avoidance, hyperarousal symptoms were all significantly improved from baseline to endpoint. Six patients no longer fulfilled the diagnostic criteria of PTSD at endpoint. Some adverse, but not serious, effects possibly related to memantine were observed, including sleep problems, sleepiness, sedation, weight change and hypotension. Conclusions: Memantine significantly reduced PTSD symptoms in civilian female PTSD patients and the drug was well tolerated. Future randomized controlled trials are necessary to verify the efficacy and safety of memantine in the treatment of PTSD.

Antecedentes: Actualmente, hay escasez de opciones de tratamiento farmacológico para el trastorno de estrés postraumático (TEPT), y el desarrollo de un enfoque farmacoterapéutico nuevo se ha transformado en materia de gran interés.Objetivo: Llevamos a cabo un ensayo clínico abierto de 12 semanas para examinar la eficacia y seguridad de memantina, un antagonista del receptor de N-metil-d-aspartato, en el tratamiento del TEPT en civiles.Método: Se inscribieron trece pacientes adultas con TEPT según DSM-IV, todas mujeres civiles. Fueron monitoreadas en un centro de atención ambulatoria semanalmente por 4 semanas, y luego cada 4 semanas hasta las 12 semanas. Se agregó memantina al tratamiento farmacológico actual de cada paciente, con dosis inicial de 5 mg/día y titulación posterior. Los fármacos concomitantes fueron mantenidos esencialmente sin cambios durante el estudio. El objetivo primario fue el diagnóstico de TEPT y su severidad, evaluada con la Escala de Diagóstico Postraumático (PDS, por su sigla en inglés).Resultados: De los 13 casos, uno abandonó y 2 fueron descartados debido a desvío del protocolo, y el análisis fue realizado con los 10 restantes. El puntaje total promedio de PDS disminuyó de 32.3 ± 9.7 en el basal a 12.2 ± 7.9 al término, lo que fue estadísticamente significativo con un tamaño de efecto grande (prueba t pareada: p=.002, d=1.35); los síntomas de intrusión, evitación e hiperactivación mejoraron todos en forma al término respecto a la basal. Seis pacientes dejaron de cumplir los criterios de TEPT al término. Se observaron algunos efectos adversos, pero no serios, posiblemente relacionados a memantina, que incluyeron problemas del sueño, somnolencia, sedación, cambios en el peso e hipotensión.Conclusiones: La memantina redujo significativamente los síntomas de TEPT en pacientes mujeres civiles con TEPT y el fármaco fue bien tolerado. Se requieren ensayos controlados aleatorizados en el futuro para verificar la eficacia y seguridad de la memantina en el tratamiento del TEPT.

Childhood maltreatment history and attention bias variability in healthy adult women: role of inflammation and the BDNF Val66Met genotype.

Childhood maltreatment has been associated with greater attention bias to emotional information, but the findings are controversial. Recently, a novel index of attention bias, i.e., attention bias variability (ABV), has been developed to better capture trauma-related attentional dysfunction. However, ABV in relation to childhood trauma has not been studied. Here, we examined the association of childhood maltreatment history with attention bias/ABV in 128 healthy adult women. Different types of childhood maltreatment were assessed with the Childhood Trauma Questionnaire. Attention bias/ABV was measured by the dot-probe task. Possible mechanisms whereby childhood maltreatment affects attention bias/ABV were also explored, focusing on blood proinflammatory markers and the BDNF Val66Met polymorphism. We observed a significant positive correlation between childhood emotional abuse and ABV (P = 0.002). Serum high-sensitivity tumor necrosis factor-α levels were significantly positively correlated with ABV (P < 0.001), but not with childhood maltreatment. Jonckheere-Terpstra trend test showed a significant tendency toward greater ABV with increasing numbers of the BDNF Met alleles (P = 0.021). A two-way analysis of variance further revealed that the genotype-by-emotional abuse interaction for ABV was significant (P = 0.022); individuals with the Val/Met and Met/Met genotypes exhibited even greater ABV when childhood emotional abuse was present. These results indicate that childhood emotional abuse can have a long-term negative impact on emotional attention control. Increased inflammation may be involved in the mechanism of ABV, possibly independently of childhood maltreatment. The BDNF Met allele may dose-dependently increase ABV by interacting with childhood emotional abuse.

Association of CRP genetic variation with symptomatology, cognitive function, and circulating proinflammatory markers in civilian women with PTSD.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with increased inflammation. C-reactive protein (CRP) is a marker of systemic inflammation, and recently, single nucleotide polymorphisms (SNPs) in the CRP gene have been associated with increased blood CRP protein levels and illness severity in PTSD patients. However, the mechanism by which the CRP SNPs are involved in PTSD remains unclear. Here we investigated the association of CRP genetic variation with blood proinflammatory protein levels, symptomatology, and cognitive function, and further explored the moderating effect of childhood maltreatment history, in adult patients with PTSD. METHODS: Fifty-seven Japanese civilian women with PTSD and 73 healthy control women were enrolled. Three SNPs in the CRP gene, namely rs2794520, rs1130864, and rs3093059, were genotyped, and analyses focused on rs2794520 (T/C). Serum levels of high-sensitivity CRP (hsCRP), high-sensitivity tumor necrosis factor-α (hsTNF-α), and interleukin-6 were measured. PTSD symptoms were evaluated by the Posttraumatic Diagnostic Scale. Cognitive function was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status. Childhood maltreatment history was assessed by the Childhood Trauma Questionnaire. RESULTS: Patients with the rs2794520 CC/CT genotype, compared to those with the TT genotype, showed significantly higher levels of hsCRP (p=0.009) and hsTNF-α (p=0.001), more severe PTSD symptoms (p=0.036), and poorer cognitive function (p=0.018). A two-way analysis of variance revealed a significant genotype-by-maltreatment interaction for more severe PTSD avoidance symptom (p=0.012). LIMITATIONS: The relatively small sample size limited our findings. CONCLUSIONS: These findings may provide an insight into the etiology of PTSD from the inflammatory perspective.

Effects of multisession transcranial direct current stimulation as an augmentation to cognitive tasks in patients with neurocognitive disorders in Japan: a study protocol for a randomised controlled trial.

INTRODUCTION: Transcranial direct current stimulation (tDCS) is a potentially novel strategy for cognitive enhancement in patients with disorders. We present a study protocol for a randomised controlled trial designed to evaluate the safety and efficacy of tDCS combined with cognitive tasks on cognition in such patients. METHOD AND ANALYSIS: This is a two-arm, parallel-design, randomised, sham-controlled trial, in which participants and raters will be blinded at a single centre. Stratified randomisation will be conducted, and a randomisation sequence will be generated through the Electronic Data Capture system. Patients who met the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for neurocognitive disorders will be recruited and randomised to receive either active (2 mA for 20 min) or sham (stimulation ramped up and down for 1 min) stimulation in 10 sessions over five consecutive days. A direct current will be transferred by a 35 cm2 saline-soaked sponge electrode. An anode will be placed over the left dorsolateral prefrontal cortex, and a cathode will be placed over the right supraorbital cortex. Calculation tasks will be conducted in both arms as a cognitive task for 20 min during the stimulation. This task consists of basic arithmetic questions, such as single-digit addition, subtraction, multiplication and division. The primary outcome will be the mean change in the Alzheimer Disease Assessment Scale-cognition at Day 5 after baseline. Depressive symptoms, as measured by the geriatric depression scale, and quality of life, as measured by the Medical Outcomes Study 36-item Short-Form Health Survey, will also be assessed. Data will be collected at baseline, within 3 days following the final stimulation and 1 month thereafter. The estimated sample size is 46 per group based on the assumptions that an estimated mean difference is -1.61 and SD is 2.7. Mixed models for repeated measures will be used for the statistical analysis. ETHICS AND DISSEMINATION: The National Center of Neurology and the Psychiatry Clinical Research Review Board (CRB3180006) approved this study. The results of this study will be published in a scientific peer-reviewed journal. TRIAL REGISTRATION DETAILS: Japan Registry of Clinical Trials jRCTs032180016.

Possible Long-Term Effects of Childhood Maltreatment on Cognitive Function in Adult Women With Posttraumatic Stress Disorder.

Accumulated evidence shows that individuals with posttraumatic stress disorder (PTSD) have compromised cognitive function. PTSD is associated with childhood maltreatment, which also can negatively affect cognitive function. It is therefore possible that cognitive dysfunction in adult patients with PTSD can be due at least partly to childhood maltreatment, although little is documented on this issue. Here we aimed to examine the possible effect of childhood maltreatment on cognitive function in adult patients with PTSD. A total of 50 women with DSM-IV PTSD and 94 healthy control women were enrolled. Most of the patients developed PTSD after experiencing interpersonal violence during adulthood. History of childhood maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ). Cognitive functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Compared to controls, patients reported significantly more experiences of all types of childhood maltreatment as assessed by the CTQ and showed significantly poorer performance on immediate memory, language, attention, and the total score of RBANS. In patients, sexual abuse scores were significantly negatively correlated with RBANS language (p < 0.001) and total score (p = 0.005). Further analyses revealed that PTSD patients with childhood sexual abuse had even poorer cognitive function than those without the abuse. In controls, no significant correlation was found between CTQ and RBANS scores. These results suggest that childhood maltreatment, specifically sexual abuse, may lead to persistent cognitive impairment in individuals with PTSD. Our findings might underscore the importance of early detection and intervention of childhood maltreatment, which will be achieved by careful observation of, and listening to, maltreated children in education and welfare scenes as well as clinical settings.

The BDNF Val66Met polymorphism affects negative memory bias in civilian women with PTSD.

Memory abnormalities are considered a core feature of posttraumatic stress disorder (PTSD). Studies attempting to quantify such memory dysfunction in PTSD have reported that individuals with this disorder exhibit selective memory bias toward negative material. The low expression Met allele of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with the aetiology of PTSD and with memory abnormalities. It is therefore possible that the BDNF Val66Met polymorphism can moderate the relationship between PTSD and memory bias. Here we examined this association in 50 civilian women with PTSD and 70 non-trauma-exposed healthy control women. All subjects were genotyped for the BDNF Val66Met (rs6265) polymorphism. Negative memory bias was assessed using a recognition memory task. Patients showed significantly greater negative memory bias compared to controls. In patients, negative memory bias significantly increased with increasing numbers of Met alleles; while no significant relationship was seen in controls. Further pairwise analyses revealed that patients with the Met allele had significantly greater negative memory bias than controls. These results suggest that the relationship between PTSD and negative memory bias can be moderated by the BDNF Val66Met polymorphism. More studies are needed to further clarify the relationship between this polymorphism and memory abnormalities in PTSD.

Combined Treatment with Two Water Extracts of Eleutherococcus senticosus Leaf and Rhizome of Drynaria fortunei Enhances Cognitive Function: A Placebo-Controlled, Randomized, Double-Blind Study in Healthy Adults.

We previously found that the water extract of Eleutherococcus senticosus leaves (ES extract) enhanced cognitive function in normal mice. Our study also revealed that the water extract of rhizomes of Drynaria fortunei (DR extract) enhanced memory function in Alzheimer's disease model mice. In addition, our previous experiments suggested that a combined treatment of ES and DR extracts synergistically improved memory and anti-stress response in mice. Although those two botanical extracts are expected to be beneficial for neuropsychological function, no clinical data has ever been reported. Therefore, we performed a placebo-controlled, randomized, double-blind study to evaluate cognitive enhancement and anti-stress effects by the intake of a combined extract in healthy volunteers. The intake period was 12 weeks. The Japanese version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test was used for neurocognitive assessment. The combined treatment of ES and DR extracts significantly increased the figure recall subscore of RBANS (p = 0.045) in an intergroup comparison. Potentiation of language domain ((p = 0.040), semantic fluency (p = 0.021) and figure recall (p = 0.052) was shown by the extracts (in intragroup comparison). In anti-stress response, the anxiety/uncertainly score was improved by the extract in an intragroup comparison (p = 0.022). No adverse effects were observed. The combined treatment of ES and DR extracts appear to safely enhance a part of cognitive function in healthy adults.

Brain Development of Children With Single Ventricle Physiology or Transposition of the Great Arteries: A Longitudinal Observation Study.

To define the correlation between neuroanatomic and developmental outcomes of children with single ventricle (SV) or transposition of the great arteries (TGA), a prospective longitudinal study was performed in preschool and school-age children. Twenty-seven children with congenital heart disease (9, TGA; 18, SV) were included. Participants underwent 3-dimensional magnetic resonance imaging (MRI) and neurodevelopmental assessment at around 3 years (preschool age) and at 9 years (school age), and 48 healthy controls underwent MRI, and their data were used to derive best-fit models for normal brain volumes for comparisons with congenital heart disease patients. Total brain volume (TBV) and regional brain volumes remained significantly smaller in SV children than in TGA children at both time points, though the growth slope of TBV was not significantly different between the SV and TGA groups. Although the psychomotor developmental index at preschool was significantly lower in SV patients, the full-scale IQ at school age was not significantly lower in SV patients. There was a strong correlation between full-scale IQ and TBV (r = 0.49, P = 0.005). Despite the current best practices, persistently lower TBV was seen in SV patients until 9 years of age. For both the SV and TGA groups, TBV at 3 years was a strong predictor of TBV at 9 years. Since there was a correlation between TBV and IQ at 9 years, identification of factors that affect brain growth until 3 years will be imperative to improve patients' cognitive function at school age.

Levels of glutamatergic neurometabolites in patients with severe treatment-resistant schizophrenia: a proton magnetic resonance spectroscopy study.

Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy (1H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS.

Proinflammatory status-stratified blood transcriptome profiling of civilian women with PTSD.

Etiology of posttraumatic stress disorder (PTSD) remains largely unknown. Studies have shown that a significant subset of patients with PTSD exhibit increased inflammation, suggesting that the understanding of this disorder could be facilitated by classifying these patients by inflammatory status. Here we performed a microarray-based blood transcriptome analysis on proinflammatory status-stratified Japanese civilian women with PTSD most of whom developed the disorder after experiencing interpersonal violence. By utilizing our previously identified cut-off serum interleukin-6 (IL-6) level that approximately corresponded to the median IL-6 level of our PTSD patients, we classified patients into those with high IL-6 levels and those with normal IL-6 levels (n = 16 for each). Transcriptome profiles of these 2 groups were compared with the profile of 16 age-matched healthy control women. Differentially expressed genes between high IL-6 patients and controls showed significant enrichment in a number of gene ontology terms and pathways primarily involved in immune/inflammatory responses, and their protein-protein interaction network was significantly enriched. In contrast, differentially expressed genes between normal IL-6 patients and controls showed significant enrichment in several gene ontology terms related to ion transport and neural function. The microarray data were confirmed by reverse transcription quantitative PCR. These findings illustrate the heterogeneous molecular mechanisms of PTSD within this relatively homogeneous sample in terms of sex, trauma type, and ethnicity, suggesting that peripheral proinflammatory status such as IL-6 levels could be a useful subtyping marker for this disorder. With further research, it is hoped that our findings will be translated into personalized medicine.

Cortisol-related hippocampal-extrastriate functional connectivity explains the adverse effect of cortisol on visuospatial retrieval.

Cortisol is known to affect visuospatial memory through its major binding site in the brain, the hippocampus. The synchronization of neural activity between the hippocampus, prefrontal cortex (PFC), and visual cortex is presumed to be essential for the formation of visuospatial memory because of their visuospatial learning-dependent neuroplasticity. However, it remains unclear how hippocampal connectivity with the PFC and visual cortex is involved in the relationship between cortisol and visuospatial memory in humans. We thus investigated whether functional connectivity (FC) of the hippocampus, specifically its rostral and caudal subdivisions, mediates the relationship between visuospatial memory and endogenous cortisol. One-hundred sixty-six healthy young adults underwent standard neuropsychological tests to assess visuospatial construction (a complex figure copying test) and retrieval (the corresponding recall test) and collected their saliva at 6-time points across 2 consecutive days for measurement of daily cortisol concentrations (dCOR). Ninety of them received resting-state fMRI scans. Greater dCOR was significantly associated with better figure copying performance, but contrastingly with poorer figure recall. In proportion to dCOR, the rostral hippocampus (rHC) showed significantly increased FC with the PFC (including its dorsolateral and medial parts) and the inferior lateral occipital cortex (iLOC), while the caudal hippocampus had increased FC with the anterior middle temporal cortex. Of the cortisol-related hippocampal connectivity, the rHC-iLOC FC was specifically correlated with figure recall and showed complete mediation for the negative relationship of dCOR with figure recall. These results suggest that cortisol might have enhancing effects on visuospatial encoding as well as impairing effects on visuospatial retrieval, possibly due to its occupancy patterns of corticosteroid receptors. Cortisol's adverse effects on visuospatial retrieval might be explained through cortisol-related rostral hippocampal connectivity with the iLOC, which is a part of the extrastriate cortex implicated in visuospatial perception. Thorough dissection of hippocampal-prefrontal-extrastriate connectivity might facilitate the understanding of neural mechanisms underlying cortisol's contrasting effects on encoding (or consolidation) and retrieval of visuospatial information.

Kihito, a Traditional Japanese Kampo Medicine, Improves Cognitive Function in Alzheimer's Disease Patients.

BACKGROUND AND AIMS: We previously reported that the administration of traditional Japanese medicines, kihito (Gui-Pi-Tang in Chinese) and kamikihito (Jia-Wei-Gui-Pi-Tang in Chinese), to Alzheimer's disease (AD) model mice improved memory impairment. There are a few reports that show kihito and kamikihito have a beneficial effect on the cognitive function of AD patients in clinical studies. However, these studies are not comparative and are retrospective studies; thus, more evidence is needed. Therefore, we conducted an open-label, crossover designed clinical trial to investigate the effect of kihito on cognitive function of AD patients. METHODS: The inclusion criteria for eligible patients were as follows: (1) imaging diagnosis (magnetic resonance imaging and single-photon emission computed tomography) of AD, (2) a treatment regimen including acetylcholinesterase inhibitors (ChEIs), and (3) a Mini-Mental State Examination (MMSE) score ≥15. The exclusion criteria were as follows: (1) change in ChEI dosage, (2) memantine usage, and (3) MMSE score < 15. To prevent bias in age and baseline cognitive function, patients were divided into two groups: the first group received 2.5 g of kihito extract 3 times/day during the first half of the study (weeks 0-16) and the second group received the same dose of kihito during the second half of the study (weeks 17-32). ChEI dosage did not change during the study period. Patients underwent a cognitive function test during weeks 0, 16, and 32. Cognitive function was evaluated by Japanese versions of the Mini-Mental State Examination (MMSE-J) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS-J) test. RESULTS: Ten patients completed the clinical trial (4 males, 6 females, average age 71.7 years). MMSE-J scores significantly increased during the kihito intake period. RBANS-J test scores had a slight improvement during the kihito intake period compared with the ChEI alone treatment period, but no significant changes were observed. CONCLUSION: Kihito improves cognitive function in AD patients.