Brain-derived neurotrophic factor from microglia regulates neuronal development in the medial prefrontal cortex and its associated social behavior.

Microglia and brain-derived neurotrophic factor (BDNF) are essential for the neuroplasticity that characterizes critical developmental periods. The experience-dependent development of social behaviors-associated with the medial prefrontal cortex (mPFC)-has a critical period during the juvenile period in mice. However, whether microglia and BDNF affect social development remains unclear. Herein, we aimed to elucidate the effects of microglia-derived BDNF on social behaviors and mPFC development. Mice that underwent social isolation during p21-p35 had increased Bdnf in the microglia accompanied by reduced adulthood sociability. Additionally, transgenic mice overexpressing microglial Bdnf-regulated using doxycycline at different time points-underwent behavioral, electrophysiological, and gene expression analyses. In these mice, long-term overexpression of microglial BDNF impaired sociability and excessive mPFC inhibitory neuronal circuit activity. However, administering doxycycline to normalize BDNF from p21 normalized sociability and electrophysiological function in the mPFC, whereas normalizing BDNF from later ages (p45-p50) did not normalize electrophysiological abnormalities in the mPFC, despite the improved sociability. To evaluate the possible role of BDNF in human sociability, we analyzed the relationship between adverse childhood experiences and BDNF expression in human macrophages, a possible proxy for microglia. Results show that adverse childhood experiences positively correlated with BDNF expression in M2 but not M1 macrophages. In summary, our study demonstrated the influence of microglial BDNF on the development of experience-dependent social behaviors in mice, emphasizing its specific impact on the maturation of mPFC function, particularly during the juvenile period. Furthermore, our results propose a translational implication by suggesting a potential link between BDNF secretion from macrophages and childhood experiences in humans.

Juvenile social isolation immediately affects the synaptic activity and firing property of fast-spiking parvalbumin-expressing interneuron subtype in mouse medial prefrontal cortex.

A lack of juvenile social experience causes various behavioral impairments and brain dysfunction, especially in the medial prefrontal cortex (mPFC). Our previous studies revealed that juvenile social isolation for 2 weeks immediately after weaning affects the synaptic inputs and intrinsic excitability of fast-spiking parvalbumin-expressing (FSPV) interneurons as well as a specific type of layer 5 (L5) pyramidal cells, which we termed prominent h-current (PH) cells, in the mPFC. However, since these changes were observed at the adult age of postnatal day 65 (P65), the primary cause of these changes to neurons immediately after juvenile social isolation (postnatal day 35) remains unknown. Here, we investigated the immediate effects of juvenile social isolation on the excitability and synaptic inputs of PH pyramidal cells and FSPV interneurons at P35 using whole-cell patch-clamp recording. We observed that excitatory inputs to FSPV interneurons increased immediately after juvenile social isolation. We also found that juvenile social isolation increases the firing reactivity of a subtype of FSPV interneurons, whereas only a fractional effect was detected in PH pyramidal cells. These findings suggest that juvenile social isolation primarily disturbs the developmental rebuilding of circuits involving FSPV interneurons and eventually affects the circuits involving PH pyramidal cells in adulthood.

A case report of mania with abnormal cerebral blood flow and cognitive impairment 24 years after head trauma.

BACKGROUND: Mania usually occurs secondary to organic etiologies such as head trauma within a short time of the primary condition's onset; however, there have been a few cases reported in the literature of long time spans before the manifestation of mania. The orbitofrontal cortex has been reported to be associated with manic states in bipolar disorder and with mania-inducing lesions. Head trauma commonly disrupts various cognitive functions, including attention and information processing. Traumatic brain injury patients have been shown to have greater posterior cingulate cortex and precuneus functional connectivity to the rest of the default mode network. We describe a case of secondary mania after head trauma 24 years ago with low blood flow in the orbitofrontal cortex, high blood flow in the posterior cingulate cortex, and impaired cognitive functioning, including impaired attention and lowered processing speed. CASE PRESENTATION: We describe a 30-year-old Japanese man with secondary mania and a medical history of head trauma 24 years ago. After head trauma at 6 years of age, the patient first showed apathy as a sign of frontal lobe impairment. After recovering, he experienced no psychiatric problems during adolescence, although he did show disinhibited behavior. At the onset of mania, low blood flow in the OFC and high blood flow in the PCC were observed as well as impaired cognitive function, including inattention and lowered processing speed. Abnormal cerebral blood flow was less prominent and cognitive dysfunction was partially recovered following recovery from mania, but his processing speed remained low. CONCLUSIONS: Although functional recovery from head trauma in childhood is better than that in adulthood, the brain may remain vulnerable for a long time. The risk of psychotic symptoms such as mania should be considered, even if sufficient superficial brain functional recovery is shown.

Social Isolation During the Critical Period Reduces Synaptic and Intrinsic Excitability of a Subtype of Pyramidal Cell in Mouse Prefrontal Cortex.

Juvenile social experience is crucial for the functional development of forebrain regions, especially the prefrontal cortex (PFC). We previously reported that social isolation for 2 weeks after weaning induces prefrontal cortex dysfunction and hypomyelination. However, the effect of social isolation on physiological properties of PFC neuronal circuit remained unknown. Since hypomyelination due to isolation is prominent in deep-layer of medial PFC (mPFC), we focused on 2 types of Layer-5 pyramidal cells in the mPFC: prominent h-current (PH) cells and nonprominent h-current (non-PH) cells. We found that a 2-week social isolation after weaning leads to a specific deterioration in action potential properties and reduction in excitatory synaptic inputs in PH cells. The effects of social isolation on PH cells, which involve reduction in functional glutamatergic synapses and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate charge ratio, are specific to the 2 weeks after weaning and to the mPFC. We conclude that juvenile social experience plays crucial roles in the functional development in a subtype of Layer-5 pyramidal cells in the mPFC. Since these neurons project to subcortical structures, a deficit in social experience during the critical period may result in immature neural circuitry between mPFC and subcortical targets.

Guanfacine monotherapy for ADHD/ASD comorbid with Tourette syndrome: a case report.

BACKGROUND: Patients with attention deficit/hyperactivity disorder (ADHD) often experience comorbid conditions, such as autism spectrum disorder (ASD) and Tourette syndrome (TS). Although pharmacotherapies are effective for treating ADHD, they are likely to elicit a variety of adverse effects. It is, thus, important to select an effective and well-tolerated pharmacotherapeutic treatment for patients with ADHD/ASD comorbid with TS. CASE PRESENTATION: We report the case of a 10-year-old boy with ADHD/ASD comorbid with TS who was treated with guanfacine (GUAN). He experienced several side effects of atomoxetine (ATX) and methylphenidate (MPH) before being treated with GUAN. In the presented case, symptoms of ADHD as well as tic symptoms were improved by treatment with GUAN. CONCLUSION: GUAN might be effective and well tolerated in the treatment of patients with ADHD/ASD comorbid with TS who experience side effects of ATX and MPH.

Detection of brain amyloid-ß deposits due to the repetitive head trauma in a former karate player.

Head trauma is a well-established epidemiological risk factor for Alzheimer's disease, but a study of early detection of its pathology has not yet been performed in human patients in vivo. To address this issue, we performed 11 C-labelled Pittsburgh compound B-positron emission tomography on a right-handed 30-year-old man with cognitive deterioration after repetitive head trauma during karate matches. Structural magnetic resonance imaging was also performed on this patient. The same positron emission tomography analysis was performed on elderly healthy controls (15 men, mean age: 70.7 ± 6.2 years). To analyze grey matter volume, structural magnetic resonance imaging was performed on age-matched healthy controls (15 men, mean age: 28.5 ± 3.6 years). The cognitive deterioration in our patient was fixed and partially improved in the 10 years after the repetitive head trauma. However, Pittsburgh compound B-non-displaceable binding potential was significantly elevated in the patient. Volume reduction was shown in the medial temporal region, cerebellum, and the basal frontal cortex, while amyloid-ß increase was shown in the bilateral prefrontal cortex. This is the first study to show an early degenerative process due to head trauma in the prefrontal cortex, where structural damage is not yet visible. Early recognition of the degenerative pathology due to repetitive head trauma by amyloid and possibly tau imaging would help clinicians determine how to treat those with early symptoms.

Reduced prefrontal hemodynamic response in adult attention-deficit hyperactivity disorder as measured by near-infrared spectroscopy.

AIM: Recent developments in near-infrared spectroscopy (NIRS) have enabled non-invasive clarification of brain functions in psychiatric disorders. In pediatric attention-deficit hyperactivity disorder (ADHD), reduced prefrontal hemodynamic responses have been observed with NIRS repeatedly. However, there are few studies of adult ADHD by multi-channel NIRS. Therefore, in this study, we used multi-channel NIRS to examine the characteristics of prefrontal hemodynamic responses during the Stroop Color-Word Task (SCWT) in adult ADHD patients and in age- and sex-matched control subjects. METHODS: Twelve treatment-naïve adults with ADHD and 12 age- and sex-matched healthy control subjects participated in the present study after giving consent. We used 24-channel NIRS to measure the oxygenated hemoglobin (oxy-Hb) changes at the frontal lobes of participants during the SCWT. We compared the oxy-Hb changes between adults with ADHD and control subjects by t-tests with Bonferroni correction. RESULTS: During the SCWT, the oxy-Hb changes observed in the ADHD group were significantly smaller than those in the control group in channels 11, 16, 18, 21, 22, 23, and 24, corresponding to the prefrontal cortex. At channels 16, 21, 23, and 24 of the ADHD group, there were negative correlations between the symptomatic severity and the oxy-Hb changes. CONCLUSION: The present study suggests that adults with ADHD have reduced prefrontal hemodynamic response as measured by NIRS.

Social isolation impairs remyelination in mice through modulation of IL-6.

Recent studies have revealed that social experience affects myelination. These findings have important implications for disorders that feature abnormal myelination, such as multiple sclerosis (MS), as previous studies have shown that psychosocial stress exacerbates the pathobiology of MS. However, most studies have focused on psychosocial stress during the demyelination phase of MS and have not investigated the effects of social experience on remyelination. Thus, the current study sought to determine whether social experience can alter remyelination after myelin depletion. Myelin in the mouse medial prefrontal cortex was depleted with cuprizone, and the effects of subsequent social isolation on remyelination were evaluated. Remyelination was severely impaired in socially isolated mice. Social isolation also increased IL-6 levels in the medial prefrontal cortex, and administration of an IL-6 inhibitor (ND50 = 0.01-0.03 µg for 0.25 ng/ml IL-6) ameliorated remyelination impairments. Consistent with this result, IL-6 administration (ED50 = 0.02-0.06 ng/ml) disturbed remyelination. In addition, neuron-oligodendrocyte coculture experiments showed that IL-6 treatment (ED50 ≤ 0.02 ng/ml) markedly impeded myelination, which was recovered with IL-6 inhibitor administration (ND50 = 0.01-0.03 µg for 0.25 ng/ml IL-6). This study provides the first direct evidence, to our knowledge, that social experience influences remyelination via modulation of IL-6 expression. These findings indicate that psychosocial stress may disturb remyelination through regulation of IL-6 expression in patients with such demyelinating diseases that involve remyelination as MS.-Makinodan, M., Ikawa, D., Miyamoto, Y., Yamauchi, J., Yamamuro, K., Yamashita, Y., Toritsuka, M., Kimoto, S., Okumura, K., Yamauchi, T., Fukami, S., Yoshino, H., Wanaka, A., Kishimoto, T. Social isolation impairs remyelination in mice through modulation of IL-6.

Microglia-derived neuregulin expression in psychiatric disorders.

Several studies have revealed that neuregulins (NRGs) are involved in brain function and psychiatric disorders. While NRGs have been regarded as neuron- or astrocyte-derived molecules, our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia. Previous studies have indicated that microglia are activated in the brains of individuals with autism spectrum disorder (ASD). Therefore, we investigated microglial NRG mRNA expression in multiple lines of mice considered models of ASD. Intriguingly, microglial NRG expression significantly increased in BTBR and socially-isolated mice, while maternal immune activation (MIA) mice exhibited identical NRG expression to controls. Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain. To translate these findings for application in clinical psychiatry, we measured levels of NRG1 splice-variant expression in clinically available PBMCs of patients with ASD. Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD (as assessed using the Autistic Diagnostic Interview-Revised test: ADI-R). These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD.

Pharmacotherapy for the treatment of aggression in pediatric and adolescent patients with autism spectrum disorder comorbid with attention-deficit hyperactivity disorder: A questionnaire survey of 571 psychiatrists.

AIM: Both attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are frequently accompanied by serious aggression that requires psychiatric treatment. However, little is known about the experiences psychiatrists have had using pharmacotherapy to treat aggression in patients who have both ASD and ADHD (ASD/ADHD). The purpose of this study was to examine the experiences of Japanese child and adolescent psychiatrists in prescribing medication for aggression in patients with ASD/ADHD. METHODS: A prospective questionnaire was mailed to 2001 psychiatrists affiliated with the Japanese Society for Child and Adolescent Psychiatry. Multivariate logistic regression analysis was used to identify factors predicting the outcome of pharmacotherapeutic treatment of aggression in pediatric and adolescent patients with ASD/ADHD. RESULTS: Of 2001 psychiatrists, 571 (28.5%) completed the full questionnaire (final sample). Of these, 488 (85.4%) prescribed psychotropic medication in treating pediatric and adolescent patients with ASD/ADHD, 299 (61.3%) of them doing so to treat aggression. Prescribers' duration of practice (odds ratio, 1.055; P = 0.038) and patient symptoms of residual impulsivity (odds ratio, 2.479; P = 0.039) increased the odds of prescribing psychotropic medications to treat aggression in these patients. The respondents reported a similar effect for patients with ADHD/ASD compared with those with ADHD only in treating aggression. CONCLUSION: Japanese psychiatrists tended to prescribe psychotropic medication for aggression in pediatric and adolescent patients with ASD/ADHD. Future studies examining aggression in pediatric and adolescent patients with ASD/ADHD should aim to accumulate evidence for the use of psychotropic medications, which could help clinicians make better decisions.

Persistence of impulsivity in pediatric and adolescent patients with obsessive-compulsive disorder.

AIM: Increasing clinical evidence points to impulsivity as a symptom of obsessive-compulsive disorder (OCD). However, little is known about its persistence over time. METHODS: In this study, we evaluated the performance of 12 pediatric patients with OCD on the Stroop color-word task, which assesses impulsivity, and compared this with age- and sex-matched controls. In parallel, we measured changes in hemodynamic responses during the task, using near-infrared spectroscopy. As patients in the OCD group were naïve to treatment, we compared results before and after 3-year medication with serotonin reuptake inhibitors. RESULTS: We report that, compared with controls, the OCD group had significantly poorer performance and less activation in the prefrontal cortex during the Stroop color-word task. Surprisingly, while serotonin-reuptake-inhibitors treatment reduced OCD symptomology, it did not improve the diminished hemodynamic responses or task performance of these patients. CONCLUSION: Our findings suggest that a persistent deficit exists in the inhibitory control of pediatric patients with OCD; they also provide insight into the pathophysiology of OCD.

Event-Related Potentials Correlate with the Severity of Child and Adolescent Patients with Attention Deficit/Hyperactivity Disorder.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) symptoms can continue through adolescence and adulthood, including difficulty in staying focused, paying attention, and controlling behavior, as well as hyperactivity. While children and adolescents with ADHD have functional impairments at multiple dimensions, there are no objective biological indicators to assess the severity of ADHD. Event-related potentials (ERPs) are widely used as a noninvasive method for evaluating sensory and cognitive processes involved in attention tasks. Previous studies have shown that P300 amplitude or latency, a main component in ERPs, is altered in patients with ADHD. However, little is known about the relationship between P300 and the severity of ADHD symptoms. METHOD: We sought to measure both P300 amplitude and latency in ERPs during auditory oddball tasks in 44 patients with ADHD (mean age ± SD 10.28 ± 3.43 years) and 15 age- and gender-matched normally developing children (11.40 ± 3.02 years). In ADHD patients, we also assessed symptom severity using the ADHD rating scale-IV-Japanese version. RESULT: In ADHD groups, P300 amplitude and latency were attenuated and prolonged compared to controls at the frontocentral, centroparietal, and parietal positions. Furthermore, levels of P300 latency at these positions are positively correlated with the inattention subscale scores measured by the ADHD rating scale-IV-Japanese version. CONCLUSIONS: The present study revealed that the degree of P300 latency might reflect the severity of ADHD symptoms with children and adolescents, suggesting that ERPs are a useful technique to evaluate the severity of ADHD symptoms.

Lithium carbonate as a treatment for paliperidone extended-release-induced leukopenia and neutropenia in a patient with schizoaffective disorder; a case report.

BACKGROUND: Antipsychotic drug treatment can potentially lead to adverse events such as leukopenia and neutropenia. Although these events are rare, they represent serious and life-threatening hematological side effects. CASE PRESENTATION: We present a case study of a patient with schizoaffective disorder in a 50-year-old woman. We report a case of paliperidone extended-release (ER)-induced leukopenia and neutropenia in a female patient with schizoaffective disorder. Initiating lithium carbonate treatment and decreasing the dose of valproic acid improved the observed leukopenia and neutropenia. This treatment did not influence psychotic symptoms. CONCLUSION: The combination of paliperidone ER and valproic acid induces increased paliperidone ER plasma levels. Lithium carbonate was successfully used to treat paliperidone ER-induced leukopenia and neutropenia.

[The Pharmacotherapy of Autism Spectrum Disorder with ADHD Symptoms].

Diagnostic and treatment guidelines for childhood attention deficit/hyperactivity disorder (ADHD) were first released in Japan in 2003. Since then, there has been numerous changes in how ADHD is treated, such as the approval of slow-release methylphenidate and atomoxetine for use from childhood to adulthood. Demand regarding adult ADHD has also risen, as the symptoms of ADHD can persist into adulthood, and due to problems with high prevalence rates and comorbidities. Moreover, the DSM-5 recognized the coexistence of ADHD and autis- tic spectrum disorder (ASD), which further raised the level of concern. Yet at present, treat- ment guidelines have not been established for ASD with ADHD symptoms, so it is hoped such guidelines will be created quickly. This article provides a brief summary of recent findings on pharmacological therapy for ASD with ADHD symptoms.

Prefrontal dysfunction in pediatric Tourette's disorder as measured by near-infrared spectroscopy.

BACKGROUND: Tourette's disorder (TD) is a chronic childhood-onset disorder characterized by the presence of multiple motor and vocal tics. Despite strong evidence that the pathophysiology of TD involves structural and functional disturbances of the basal ganglia and cortical frontal areas, in vivo imaging studies have produced conflicting results. Recent developments in near-infrared spectroscopy (NIRS) technology have enabled noninvasive assessment of brain function in people with psychiatric disorders. METHODS: We asked 10 individuals with pediatric TD and 10 healthy controls who were age- and sex- matched to perform the Stroop color-word task during NIRS. We used prefrontal probes and a 24-channel NIRS machine to measure the relative concentrations of oxyhemoglobin (oxy-Hb) every 0.1 s during the task. RESULTS: We found that oxy-Hb changes in the prefrontal cortex were significantly smaller in the TD group compared with the control group, especially in the left dorsolateral prefrontal cortex. CONCLUSIONS: Our data suggest that individuals with pediatric TD have a reduced prefrontal hemodynamic response as measured by NIRS.

Increased prefrontal hemodynamic change after atomoxetine administration in pediatric attention-deficit/hyperactivity disorder as measured by near-infrared spectroscopy.

AIM: Atomoxetine, approved in Japan for the treatment of pediatric attention-deficit/hyperactivity disorder (ADHD) in April 2009, is a nonstimulant that is thought to act presynaptically via the inhibition of norepinephrine reuptake. Near-infrared spectroscopy is a non-invasive optical tool that can be used to study oxygenation and hemodynamic changes in the cerebral cortex. The present study examined the effects of a clinical dose of atomoxetine on changes in prefrontal hemodynamic activity in children with ADHD, as measured by near-infrared spectroscopy using the Stroop Color-Word Task. METHODS: Ten children with ADHD participated in the present study. We used 24-channel near-infrared spectroscopy to measure the relative concentrations of oxyhemoglobin in the frontal lobes of participants in the drug-naïve condition and those who had received atomoxetine for 8 weeks. Measurements were conducted every 0.1 s during the Stroop Color-Word Task. We used the ADHD Rating Scale-IV-Japanese version (Home Version) to evaluate ADHD symptoms. RESULTS: We found a significant decrease in ADHD Rating Scale-IV-Japanese version scores, from 30.7 to 22.6 (P=0.003). During the Stroop Color-Word Task, we found significantly higher levels of oxyhemoglobin changes in the prefrontal cortex of participants in the atomoxetine condition compared with those in the drug-naïve condition. CONCLUSIONS: This increase in oxyhemoglobin changes might indicate an intensified prefrontal hemodynamic response induced by atomoxetine. Near-infrared spectroscopy is a sensitive tool for measuring the pharmacological effects of atomoxetine in children with ADHD.

Levetiracetam improves disinhibitory behavior in nonconvulsive status epilepticus.

BACKGROUND: Nonconvulsive status epilepticus (NCSE) is a severe medical condition and heterogeneous disorder defined by different seizure types and diverse etiologies. NCSE occurs commonly in the elderly and is potentially misdiagnosed as a psychiatric disorder. Current treatment options for NCSE are still unsatisfactory. CASE PRESENTATION: We report a case of NCSE in a 55-year-old epileptic male patient with a history of infectious encephalitis, disinhibitory behavior, and a suspected diagnosis of frontotemporal dementia. Add-on levetiracetam (LEV) to carbamazepine treatment improved clinical manifestations and abnormal electroencephalographic discharge. CONCLUSION: With disinhibitory behavior in the elderly, the possibility of NCSE should be considered. Moreover, LEV may be an effective and well-tolerated pharmacotherapy for elderly NCSE patients.

Paliperidone extended release for the treatment of pediatric and adolescent patients with Tourette's disorder.

OBJECTIVE: A subgroup of patients with Tourette's disorder (TD) has symptoms refractory to haloperidol, a standard therapeutic drug for TD. METHODS: We report on three cases of pediatric and adolescent patients who were treated with paliperidone extended release. RESULTS: In two cases, TD symptoms were remarkably improved by switching from haloperidol to paliperidone extended release, and in another case, paliperidone extended release showed significant efficacy in treating TD symptoms as the first-line drug. In all cases, no significant adverse side effects were detected. CONCLUSION: Paliperidone extended release may be a strong candidate for the treatment of pediatric and adolescent patients with TD.

Preliminary observations on the associations between sensory processing abnormalities and event-related potentials in adults with autism spectrum disorder.

Aim: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is thought to involve a variety of neurophysiological characteristics. Event-related potentials (ERPs) reflect cognitive functions in the brain's cognitive processing. In this study, we investigated differences in P300 and N100 of ERPs between ASD and typically developing groups and focused on the relationship between the components of ERPs and measures of autistic traits and sensory processing characteristics. Methods: ERPs were measured in 96 subjects in the ASD group and 62 subjects in the age- and sex-adjusted typically developing group. Correlations between each component and the scores of the Autism-Spectrum Quotient Japanese version (AQ-J) and the Adolescent and Adult Sensory Profile (AASP) were also evaluated. Results: The ASD group showed a significant decrease in the amplitude of N100 at C3. Furthermore, a negative correlation was found between lower amplitude at C3 of N100 and low registered sensory scores in both groups. Conclusion: Our findings imply that the N100 amplitude at C3 could be a potential indicator for examining the neurophysiological traits of ASD; however, these results should be interpreted with caution due to their preliminary nature. These tentative insights into sensory processing anomalies may be discernible in specific subsets of the ASD population, providing a foundation for future investigative pathways.