PET-detectable tau pathology correlates with long-term neuropsychiatric outcomes in patients with traumatic brain injury.

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.

Dysconnectivity of the Agency Network in Schizophrenia: A Functional Magnetic Resonance Imaging Study.

Background: Self-disturbances in schizophrenia have recently been explained by an abnormality in the sense of agency (SoA). The cerebral structures of SoA in healthy people are considered to mainly include the insula and inferior parietal lobule. In contrast, the functional lesion of aberrant SoA in schizophrenia is not yet fully understood. Considering the recent explanation of establishing SoA from the standpoint of associative learning, the "agency network" may include not only the insula and inferior parietal lobule but also the striatum. We hypothesized that aberrant SoA in schizophrenia is based on a deficit in the "agency network." Methods: Functional magnetic resonance imaging data were acquired while patients with schizophrenia (n = 15) and matched controls (n = 15) performed our adaptation method of agency attribution task on a trial-by-trial basis to assess participants' explicit experience of the temporal causal relationship between an action and an external event with temporal biases. Analysis of functional connectivity was done using the right supramarginal gyrus and the right middle frontal gyrus as seed regions. Results: In healthy controls, analyses revealed increased activation of the right inferior parietal lobule (mainly the supramarginal gyrus), right insula, and right middle frontal gyrus as an activation of the agency condition. We defined activated Brodmann areas shown in the agency condition of healthy controls as the seed region for connectivity analysis. The connectivity analysis revealed lower connectivity between the head of the left caudate nucleus and right supramarginal gyrus in the patients compared to healthy controls. Conclusions: This dysconnectivity of the agency network in schizophrenia may lead to self-disturbance through deficits in associative learning of SoA. These findings may explain why pathological function of the striatum in schizophrenia leads to self-disturbance.

Impairment in judgement of the moral emotion guilt following orbitofrontal cortex damage.

Although neuroimaging studies have provided evidence for an association between moral emotions and the orbitofrontal cortex, studies on patients with focal lesions using experimental probes of moral emotions are scarce. Here, we addressed this topic by presenting a moral emotion judgement task to patients with focal brain damage. Four judgement tasks in a simple pairwise choice paradigm were given to 72 patients with cerebrovascular disease. These tasks consisted of a perceptual line judgement task as a control task; the objects' preference task as a basic preference judgement task; and two types of moral emotion judgement task, an anger task and a guilt task. A multiple linear regression analysis was performed on each set of task performance scores to take into account potential confounders. Performance on the guilt emotion judgement task negatively correlated with the orbitofrontal cortex damage, but not with the other variables. Results for the other judgement tasks did not reach statistical significance. The close association between orbitofrontal cortex damage and a decrease in guilt emotion judgement consistency might suggest that the orbitofrontal cortex plays a key role in the sense of guilt, a hallmark of morality.

Semantic memory deficits are associated with pica in individuals with acquired brain injury.

Although pica is one of the most prominent signs in individuals with severe cognitive impairment, the mechanisms and neural basis for pica have not been well elucidated. To address this issue, patients with acquired brain injury who showed pica and hyperorality were investigated. Eleven patients with pica, i.e., individuals who eat non-food items, and eight patients with hyperorality but who never eat non-food items were recruited. The cognitive and behavioral assessments and neural substrates of the two groups were compared. For basic cognitive and behavioral functions, two kinds of mental state examination-the mini-mental state examination and the new clinical scale for rating of mental states of the elderly-were administered. For pica-related behavioral features, frontal release signs, semantic memory deficits, and changes in eating behaviors were compared. Compared with the hyperorality group, the pica group had more severe semantic memory deficits and fewer frontal release signs, whereas there was no significant difference in changes in eating behaviors. Individuals in the pica group always had a lesion in the posterior part of the middle temporal gyrus. These findings suggest that semantic memory deficits following temporal lobe damage are associated with pica.

Updating the neuropsychological test system in Japan for the elderly and in a modern touch screen tablet society by resetting the cut-off values.

AIM: Covert hepatic encephalopathy is frequently seen in cirrhotic patients. This condition can be diagnosed by a computerized neuropsychological test system (NPT); however, NPT has not been updated for approximately two decades in Japan. The aim of this study is to update the NPT to be more suitable for both the elderly and modern society by resetting of cut-off values. METHODS: We enrolled 367 healthy subjects aged between 40 and 79 years old between 2003 and 2010. The NPT consists of the following eight tests: number connection tests (NCT)-A and -B, a figure position test, a digit symbol test, a block design test, and reaction time tests (RTT)-A, -B, and -C. All subjects were classified into eight groups (5-year quartile ranges from 40 to 79 years old), and the cut-off value for each test was compared to the former cut-off value (NPT version 1). RESULTS: In all eight tests, most of the cut-off values were different from those in NPT version 1. The difference was minimal in RTT-A, RTT-B, and RTT-C. However, the difference was evident in the NCT-A, NCT-B, digit symbol test, and block design test. In particular, a 57.8-s decrease in the cut-off value was seen in the 65-69-year-old group for the NCT-B test (71.3 s vs. 129.1 s). CONCLUSIONS: We updated the NPT by covering subjects aged 40-79 years and resetting the cut-off values. Thus, the updated NPT is an elderly and modern subject-compliant application. This update may improve the diagnostic ability of covert hepatic encephalopathy in contemporary cirrhotic patients.

Disappearance of treatment-resistant depression after damage to the orbitofrontal cortex and subgenual cingulate area: a case study.

BACKGROUND: Although post-stroke depression is a well-characterized disorder, there is less understanding of how pre-existence of depression is affected by a stroke. CASE PRESENTATION: We describe a patient with treatment-resistant major depression, which had been ongoing for 14 years but disappeared shortly after onset of a subarachnoid hemorrhage. Her cognitive function and functional status were mostly unaffected by the stroke. However, she no longer excessively regretted past events. Lesions were found in the orbitofrontal cortex, which is involved in feeling regret, and in the adjacent subgenual cingulate area, which is metabolically hyperactive in treatment-resistant depression and is the target for deep-brain stimulation for relief of treatment-resistant depression. The lesions from the stroke may have caused the disappearance of the patient's treatment-resistant depression by alleviating excessive regret and decreasing the elevated activity in these areas. CONCLUSIONS: This patient's clinical course may shed light on the neuropsychological and neurophysiological mechanisms of major depression of the melancholic subtype.

Strength of Intentional Effort Enhances the Sense of Agency.

Sense of agency (SoA) refers to the feeling of controlling one's own actions, and the experience of controlling external events with one's actions. The present study examined the effect of strength of intentional effort on SoA. We manipulated the strength of intentional effort using three types of buttons that differed in the amount of force required to depress them. We used a self-attribution task as an explicit measure of SoA. The results indicate that strength of intentional effort enhanced self-attribution when action-effect congruency was unreliable. We concluded that intentional effort importantly affects the integration of multiple cues affecting explicit judgments of agency when the causal relationship action and effect was unreliable.

The Japanese version of the Rapid Dementia Screening Test is effective compared to the clock-drawing test for detecting patients with mild Alzheimer's disease.

BACKGROUND: The Japanese version of the Rapid Dementia Screening Test (RDST-J) and the clock-drawing test (CDT) are both brief psychometric screening tools used to detect the severity of Alzheimer's disease. It remains unclear, however, which is more effective when screening for mild Alzheimer's disease. METHODS: We administered the RDST-J and CDT to 250 patients with very mild to severe Alzheimer's disease and to 49 healthy volunteers. Patients with a Mini-Mental State Examination score of 12-26 had Clinical Dementia Rating (CDR) scores from 0.5 to 3. Patients were divided into four groups according to CDR score. We performed one-way factorial anova between the four groups and control subjects based on the CDT and RDST-J scores. RESULTS: Data analysis revealed that RDST-J could distinguish patients with CDR 0.5 from the controls, but CDT could not. Furthermore, the sensitivity of a RDST-J score ≥8 was 57.1%, with a specificity of 81.0%, and the sensitivity of a RDST-J score ≥9 was 79.6%, with a specificity of 55.1% for discriminating CDR 0.5 from controls. CONCLUSIONS: RDST-J is a more effective tool than CDT for distinguishing CDR 0.5 from controls.

Behavioral evidence of delayed prediction signals during agency attribution in patients with schizophrenia.

Self-disturbance, a core feature of schizophrenia, recently has been explained from the standpoint of an abnormal sense of agency (SoA). Previous studies showed that aberrant SoA in schizophrenia arise from imprecise predictions about the sensory consequences of actions. However, the nature of the malfunctioning predictions remains unclear. We examined the temporally "delayed" nature of inadequate predictions. We studied 30 patients with schizophrenia and 30 healthy controls. Our original SoA task evaluates explicit experience of the temporal causal relationship between an intentional action and an effect on a computer screen under the presence of temporal biases. We introduced an adaptation with a "trial-by-trial" method that prolonged or shortened the temporal biases. We hypothesized that delayed prediction signals in schizophrenia could lead to a match in timing between predictions and actual outcomes, resulting in self-agency. The adjustment courses to changing temporal biases were evaluated. Patients with schizophrenia continued to feel self-agency even when the adjusted temporal bias was longer than 1000ms. This result indicated that patient's prediction would be delayed in each trial. Our study empirically showed behavioral evidence for "delayed" prediction signals in a SoA paradigm for the first time.

Utility of Scalp Hair Follicles as a Novel Source of Biomarker Genes for Psychiatric Illnesses.

BACKGROUND: Identifying beneficial surrogate genetic markers in psychiatric disorders is crucial but challenging. METHODS: Given that scalp hair follicles are easily accessible and, like the brain, are derived from the ectoderm, expressions of messenger RNA (mRNA) and microRNA in the organ were examined between schizophrenia (n for first/second = 52/42) and control subjects (n = 62/55) in two sets of cohort. Genes of significance were also analyzed using postmortem brains (n for case/control = 35/35 in Brodmann area 46, 20/20 in cornu ammonis 1) and induced pluripotent stem cells (n = 4/4) and pluripotent stem cell-derived neurospheres (n = 12/12) to see their role in the central nervous system. Expression levels of mRNA for autism (n for case/control = 18/24) were also examined using scalp hair follicles. RESULTS: Among mRNA examined, FABP4 was downregulated in schizophrenia subjects by two independent sample sets. Receiver operating characteristic curve analysis determined that the sensitivity and specificity were 71.8% and 66.7%, respectively. FABP4 was expressed from the stage of neurosphere. Additionally, microarray-based microRNA analysis showed a trend of increased expression of hsa-miR-4449 (p = .0634) in hair follicles from schizophrenia. hsa-miR-4449 expression was increased in Brodmann area 46 from schizophrenia (p = .0007). Finally, we tested the expression of nine putative autism candidate genes in hair follicles and found decreased CNTNAP2 expression in the autism cohort. CONCLUSIONS: Scalp hair follicles could be a beneficial genetic biomarker resource for brain diseases, and further studies of FABP4 are merited in schizophrenia pathogenesis.

[Mirror neuron system dysfunction in schizophrenia and its clinical implication].

Since the discovery of mirror neuron system, several neurophysiological and neuroimaging studies showed that the mirror neuron system might have a role in understanding other people's actions and intentions with automatic simulation of their actions. Moreover, some studies suggested that mirror neurons have a broader role in social cognition including understanding others' emotions and empathy. It has not been proved, however, whether the mirror neuron system is necessarily involved in empathy processes. In the domain of social cognition deficits, it is important to investigate the involvement of mirror neuron system dysfunction in psychosis such as schizophrenia. Using magnetoencephalography, we examined whether antipsychotic-free schizophrenia patients displayed mirror neuron system dysfunction during observation of biological motion (jaw movement). Compared with normal controls, the patients with schizophrenia had fewer components of both the waveform and equivalent current dipole, suggesting aberrant brain activity resulting from dysfunction of the right inferior parietal cortex. They also lacked the changes of alpha band and gamma band oscillation seen in normal controls, and had weaker phase locking factors and gamma-synchronization predominantly in right parietal cortex. This finding demonstrated that untreated patients with schizophrenia exhibited aberrant mirror neuron system function based on the right inferior parietal cortex, which is characterized by dysfunction of gamma-synchronization.

Emergence of realism: Enhanced visual artistry and high accuracy of visual numerosity representation after left prefrontal damage.

Over the last two decades, evidence of enhancement of drawing and painting skills due to focal prefrontal damage has accumulated. It is of special interest that most artworks created by such patients were highly realistic ones, but the mechanism underlying this phenomenon remains to be understood. Our hypothesis is that enhanced tendency of realism was associated with accuracy of visual numerosity representation, which has been shown to be mediated predominantly by right parietal functions. Here, we report a case of left prefrontal stroke, where the patient showed enhancement of artistic skills of realistic painting after the onset of brain damage. We investigated cognitive, functional and esthetic characteristics of the patient׳s visual artistry and visual numerosity representation. Neuropsychological tests revealed impaired executive function after the stroke. Despite that, the patient׳s visual artistry related to realism was rather promoted across the onset of brain damage as demonstrated by blind evaluation of the paintings by professional art reviewers. On visual numerical cognition tasks, the patient showed higher performance in comparison with age-matched healthy controls. These results paralleled increased perfusion in the right parietal cortex including the precuneus and intraparietal sulcus. Our data provide new insight into mechanisms underlying change in artistic style due to focal prefrontal lesion.

Predictors of repeated sick leave in the workplace because of mental disorders.

INTRODUCTION: Mental disorders create a considerable burden to society. Previous studies have shown that productivity loss constitutes the largest proportion of the total societal burden. For depression and anxiety disorders, in particular, more than half of the associated productivity loss occurs in the workplace. Many previous studies have clarified the risk factors for the relapse/recurrence of mental disorders in health care settings. However, the risk factors for repeated sick leave among mental disorders prevalent in the workplace have not yet been adequately evaluated. OBJECTIVE: The objective of this study was to investigate which variables could predict repeated sick leave for workers with a history of sick leave because of mental disorders. METHODS: Data regarding 194 subjects employed at a manufacturing company were obtained. Mental disorders were defined as disorders listed in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The duration between the return to work (RTW) and the repeated sick leave was regarded as a dependent variable. The subjects' age at the RTW, sex, age at the time of employment, job tenure, diagnosis, number of previous sick leave days, duration of most recent sick leave, and employee rank were examined as explanatory variables. Univariate analyses using a log-rank test and a multivariate analysis using the Cox proportional hazard model were conducted. RESULTS: The results of the univariate analyses showed that the number of previous sick-leave episodes was a significant predictor of repeated sick leave. A multivariate analysis revealed that age at RTW and the number of previous sick-leave episodes were significant variables. CONCLUSION: Age and the number of previous sick-leave episodes appeared to be predictors of repeated sick leave. Therefore, effective intervention to prevent repeated sick leave for those with high risk is quite crucial. Analyses including various work-related factors with subjects from multiple companies should be conducted in future studies.

Increased l1 retrotransposition in the neuronal genome in schizophrenia.

Recent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.

Reverse Fox test for detecting visuospatial dysfunction corresponding to parietal hypoperfusion in mild Alzheimer's disease.

BACKGROUND/AIM: We developed a novel visuospatial clinical task to detect parietal dysfunction in mild Alzheimer's disease (AD). METHODS: A total of 65 outpatients, including 47 with mild AD and 18 cognitively and neuroradiologically normal individuals with subjective memory impairment (NL), performed the "Reverse Fox" test and underwent brain single photon emission tomography. Patients with AD were divided into subgroups according to the results of the Reverse Fox test (successful vs unsuccessful). RESULTS: Success in the Reverse Fox test was achieved by 31.9% of patients with AD and 94.4% of NL. The unsuccessful AD subgroup had reduced perfusion of the medial parietal and bilateral temporoparietal regions compared with the successful AD subgroup. CONCLUSIONS: Failure in the Reverse Fox test was related to parietal hypoperfusion in patients with mild AD. Our findings suggest that the Reverse Fox test may be one of the useful supporting tools for detecting mild AD at outpatient clinic.

Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[¹8F]FMeNER-D2.

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹8F]FMeNER-D2 to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED50) and concentration (EC50) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

Progression of logopenic variant primary progressive aphasia to apraxia and semantic memory deficits.

BACKGROUND: Due to the nature of neurodegenerative disorders, patients with primary progressive aphasia develop cognitive impairment other than aphasia as the disorder progresses. The progression of logopenic variant primary progressive aphasia (lvPPA), however, has not been well described. In particular, praxic disorders and semantic memory deficits have rarely been reported. CASE PRESENTATIONS: We report three patients in the initial stage of lvPPA who subsequently developed apraxia in the middle stage and developed clinically evident semantic memory deficits in the advanced stages. CONCLUSIONS: The present case series suggests that some patients with lvPPA develop an atypical type of dementia with apraxia and semantic memory deficits, suggesting that these cases should be classified as a type of early-onset Alzheimer's disease.

An open-label study of algorithm-based treatment versus treatment-as-usual for patients with schizophrenia.

OBJECTIVE: The use of an algorithm may facilitate measurement-based treatment and result in more rational therapy. We conducted a 1-year, open-label study to compare various outcomes of algorithm-based treatment (ALGO) for schizophrenia versus treatment-as-usual (TAU), for which evidence has been very scarce. METHODS: In ALGO, patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were treated with an algorithm consisting of a series of antipsychotic monotherapies that was guided by the total scores in the positive and negative syndrome scale (PANSS). When posttreatment PANSS total scores were above 70% of those at baseline in the first and second stages, or above 80% in the 3rd stage, patients proceeded to the next treatment stage with different antipsychotics. In contrast, TAU represented the best clinical judgment by treating psychiatrists. RESULTS: Forty-two patients (21 females, 39.0 ± 10.9 years-old) participated in this study. The baseline PANSS total score indicated the presence of severe psychopathology and was significantly higher in the ALGO group (n = 25; 106.9 ± 20.0) than in the TAU group (n = 17; 92.2 ± 18.3) (P = 0.021). As a result of treatment, there were no significant differences in the PANSS reduction rates, premature attrition rates, as well as in a variety of other clinical measures between the groups. Despite an effort to make each group unique in pharmacologic treatment, it was found that pharmacotherapy in the TAU group eventually became similar in quality to that of the ALGO group. CONCLUSION: While the results need to be carefully interpreted in light of a hard-to-distinguish treatment manner between the two groups and more studies are necessary, algorithm-based antipsychotic treatments for schizophrenia compared well to treatment-as-usual in this study.

Neural substrates for judgment of self-agency in ambiguous situations.

The sense of agency is the attribution of oneself as the cause of one's own actions and their effects. Accurate agency judgments are essential for adaptive behaviors in dynamic environments, especially in conditions of uncertainty. However, it is unclear how agency judgments are made in ambiguous situations where self-agency and non-self-agency are both possible. Agency attribution is thus thought to require higher-order neurocognitive processes that integrate several possibilities. Furthermore, neural activity specific to self-attribution, as compared with non-self-attribution, may reflect higher-order critical operations that contribute to constructions of self-consciousness. Based on these assumptions, the present study focused on agency judgments under ambiguous conditions and examined the neural correlates of this operation with functional magnetic resonance imaging. Participants performed a simple but demanding agency-judgment task, which required them to report on whether they attributed their own action as the cause of a visual stimulus change. The temporal discrepancy between the participant's action and the visual events was adaptively set to be maximally ambiguous for each individual on a trial-by-trial basis. Comparison with results for a control condition revealed that the judgment of agency was associated with activity in lateral temporo-parietal areas, medial frontal areas, the dorsolateral prefrontal area, and frontal operculum/insula regions. However, most of these areas did not differentiate between self- and non-self-attribution. Instead, self-attribution was associated with activity in posterior midline areas, including the precuneus and posterior cingulate cortex. These results suggest that deliberate self-attribution of an external event is principally associated with activity in posterior midline structures, which is imperative for self-consciousness.