BACKGROUND: Heart rate variability (HRV), a well-established indicator of autonomic nervous system function, has been proposed as a clinical biomarker for psychiatric disorders. However, its potential is limited compared to electroencephalography (EEG) markers, possibly due to the influence of confounding factors such as cardiovascular functions. This suggests a need for autonomic metrics more specific to the central nervous system. This study investigated central autonomic control by applying 40 Hz auditory stimulation, which can transmit information beyond the auditory pathway to deep brain structures. METHODS: A total of 165 participants, including individuals with major depressive disorder (MDD), bipolar disorder, schizophrenia spectrum disorders, and healthy controls, underwent HRV and EEG measurements during resting state and 20-Hz and 40-Hz auditory stimulation. RESULTS: The 40-Hz stimulation led to a noticeable rise in the standard deviation of normal-to-normal intervals in HRV. There was a significant difference in low-, but not high-, frequency HRV among the diagnostic groups. Further exploratory analyses showed that during 40-Hz stimulation, patients with MDD experienced a larger decrease in low-frequency HRV compared to healthy individuals. In line with previous findings, patients with schizophrenia spectrum disorders showed a significant reduction in 40-Hz auditory steady-state response and significantly reduced resting theta. CONCLUSIONS: These findings propose a novel metric, gamma (40-Hz) stimulated HRV, as a potential biomarker for impaired autonomic activation in MDD. Beyond the conventional framework, the combined approach of HRV and EEG using 40-Hz auditory stimulation may yield a series of biomarkers indicative of divergent brain functions between mood and psychotic disorders.

Based on the pathophysiological changes observed in schizophrenia, the gamma-aminobutyric acid (GABA) hypothesis may facilitate the development of targeted treatments for this disease. This hypothesis, mainly derived from postmortem brain results, postulates dysfunctions in a subset of GABAergic neurons, particularly parvalbumin-containing interneurons. In the cerebral cortex, the fast spike firing of parvalbumin-positive GABAergic interneurons is regulated by the Kv3.1 and Kv3.2 channels, which belong to a potassium channel subfamily. Decreased Kv3.1 levels have been observed in the prefrontal cortex of patients with schizophrenia, prompting the investigation of Kv3 channel modulators for the treatment of schizophrenia. However, biomarkers that capture the dysfunction of parvalbumin neurons are required for these modulators to be effective in the pharmacotherapy of schizophrenia. Electroencephalography and magnetoencephalography studies have demonstrated impairments in evoked gamma oscillations in patients with schizophrenia, which may reflect the dysfunction of cortical parvalbumin neurons. This review summarizes these topics and provides an overview of how the development of therapeutics that incorporate biomarkers could innovate the treatment of schizophrenia and potentially change the targets of pharmacotherapy.

Impaired gamma oscillations found in a 40-Hz auditory steady-state response (ASSR) in patients with schizophrenia are the robust findings that can be used for future biomarker-based therapeutics. To apply these significant observations into the clinical practice, a clinical system for evoked response audiometry (ERA) may be available. In this study, the delayed 40-Hz ASSR, which was reported as a potent biomarker for schizophrenia, was examined using the ERA system in patients with schizophrenia and its clinical relevance was investigated. The phase of ASSR was significantly delayed in patients with schizophrenia compared with the healthy subjects. The delayed phase was associated with severity of the disease symptoms in the patients. A phase delay with aging was found in healthy subjects, but not in patients with schizophrenia. These findings show availability of the ERA system to identify the delayed 40-Hz ASSR and its clinical implication in patients with schizophrenia. Further applications of the ERA system in clinical psychiatry are warranted in developing biological assessments of schizophrenia with 40-Hz ASSR.

Gamma oscillations probed using auditory steady-state response (ASSR) are promising clinical biomarkers that may give rise to novel therapeutic interventions for schizophrenia. Optimizing clinical settings for these biomarker-driven interventions will require a quick and easy assessment system for gamma oscillations in psychiatry. ASSR has been used in clinical otolaryngology for evoked response audiometry (ERA) in order to judge hearing loss by focusing on the phase-locked response detectability via an automated analysis system. Herein, a standard ERA system with 40- and 46-Hz ASSRs was applied to evaluate the brain pathophysiology of patients with schizophrenia. Both ASSRs in the ERA system showed excellent detectability regarding the phase-locked response in healthy subjects and sharply captured the deficits of the phase-locked response caused by aberrant gamma oscillations in individuals with schizophrenia. These findings demonstrate the capability of the ERA system to specify patients who have aberrant gamma oscillations. The ERA system may have a potential to serve as a real-world clinical medium for upcoming biomarker-driven therapeutics in psychiatry.

Spontaneous brain activity occurs at rest, as represented by the default mode network. A resting paradigm is suitable for investigating brain function of patients with psychiatric diseases who may have difficulties adhering to goal-oriented tasks. Evidence accumulated in neuroimaging studies using functional magnetic resonance imaging has shown that the resting cerebral blood flow is impaired in psychiatric diseases. Near-infrared spectroscopy (NIRS), a simple neuroimaging modality, is an optimal tool for the resting paradigm, because it can offer a comfortable environment for measurement. Recent NIRS studies have demonstrated some promising data of altered resting activity in the prefrontal cortex of patients with schizophrenia, which may be exploited to develop further applications of NIRS in clinical psychiatry. Based on these findings, we emphasize the benefits of NIRS for assessing the prefrontal pathophysiology during the resting state and some methodological issues to be noted while analyzing cerebral blood flow using NIRS; moreover, we focus on interpreting these changes based on the complex nature of the spontaneous brain activity during resting state.

双極性障害患者を対象に、衝動性、攻撃性、絶望感を評価するとともに、Stop-signal taskによって測定されるStop-signal reaction time(SSRT)で実行機能を評価した。DSM-IVにより双極性障害と診断された患者群60例と健常対照群56例を対象とした。患者群はHAM-D-17スコアが7点以下の寛解群28例と8点以上のうつ状態群32例に分類した。寛解群、うつ状態群、健常対象群の3群で衝動性、攻撃性、絶望感のスコアを比較したところ、衝動性、攻撃性のスコアに関しては、寛解群およびうつ状態群ともに健常対照群と比較して有意に高く、寛解群とうつ状態群の間には有意差はなかった。絶望感スコアでは寛解群、うつ状態群ともに健常群よりも有意に高く、寛解群に比べてうつ状態群が有意に高いことが明らかになった。また自殺企図歴のある双極性障害患者においてSSRTが示す衝動性とBuss-Perry Aggression Questionaire(BAQスコア)が示す攻撃性の間に負の相関が見られた。

新たな統合失調症候補遺伝子の検索を目的として,ヒト死後脳を用いたDNA chip解析を行った.さらにその結果に基づき,血液サンプルを用いた遺伝子相関研究を行った.統合失調症患者および健常対照者の死後剖検脳・前頭前野眼窩部からRNAを抽出し,18Sと28SのリボソーマルRNAの安定性を調べた.SCAM-1遺伝子,ATM遺伝子,CASP1遺伝子,AKAP11遺伝子,UPF3A遺伝子,SLC25A1遺伝子を選び,それらの遺伝子多型について検討した.統合失調症とコントロールあるいは日本人の遺伝子多型データベースと比較検討し,いずれも多型頻度において差をみとめず,統合失調症の病因に大きく関与している可能性が低いことが示唆された

セロトニントランスポーター(5HTT)遺伝子多型(5HTT-LPR),ドーパミンD4受容体(DRD4)遺伝子多型(-521C/T),A型モノアミン酸化酵素(MAOA)遺伝子多型(MAOA-uVNTR),カテコール-ο-メチルトランスフェラーゼ(COMT)遺伝子多型(158Val/Met)と自殺との相関研究を行った.更に,これら遺伝子多型間の相互作用と自殺との関連についても検討した.その結果,5HTT-LPR,MAOA-uVNTR,DRD4:-521C/T多型では,自殺既遂者群163例(男112例,女51例)と健常対照群169例における遺伝子型ならびに遺伝子頻度の分布に有意差を認めなかったが,COMT:158Val/Met多型では,男性においてのみ遺伝子型の分布に有意差がみられ,遺伝子頻度でも高活性を示すとされるG(Val)アレルが自殺既遂者群で少ない傾向が認められたことから,男性では高COMT活性が自殺に抑制的に働いていることが示唆された.更に,上記多型間の相互作用を検討したところ,男性においてのみ,5HTT-LPRとMAOA-uVNTR及び5HTT-LPRとCOMT:158Val/Met多型で,遺伝子型の組合せの分布に有意差が認められた

We measured the auditory steady state response (ASSR) using electroencephalography (EEG) and the cerebral blood flow at rest using near-infrared spectroscopy（NIRS）to identify a biomarker for the pathophysiology of the prefrontal cortex in schizophrenia. In the analysis of the cerebral blood flow during resting-state, we applied the methods of the amplitude of low frequency fluctuations (ALFF) and fractional ALFF (fALFF), which have been used in fMRI studies to quantify the resting-state blood flow, to the NIRS data. We found that both ALFF and fALFF were decreased in the medial prefrontal cortex of the chronic patients with schizophrenia, and that the ALFF was negatively associated with the symptoms of auditory hallucinations in the patients.

For an objective evaluation of symptoms particularly such as suicidality in major depressive disorder (MDD) and bipolar disorder(BD), near-infrared spectroscopy (NIRS) was used. MDD with a history of suicidal behavior showed smaller hemodynamic response in the left precentral gyrus. the reduced response in the left inferior frontal gyrus was negatively correlated with impulsivity level and hemodynamic responses in the right middle frontal gyrus were negatively associated with hopelessness and aggression in MDD with a history of suicidal behavior. BD with a history of suicidal behavior exhibits reduced activation in frontotemporal region and delayed activation timing of the NIRS signal in the prefrontal region. BD showed characteristic inactivation pattern of the right superior temporal gyri during an inhibitory control task.

In this study, we found that haloperidol, a typical APD and risperidone, an atypical APD differentially modulated cortical Kv3.1 and Kv3.2 channels. While both haloperidol and risperidone significantly increased Kv3.1 protein levels in rat prefrontal cortex, Kv3.2 protein levels showed an increase and a decrease in the same region by haloperidol and risperidone, respectively. A similar pattern of Kv3.2 change was found in cerebellum, however, no significant changes were found in Kv3.2 protein levels in hippocampus, thalamus and striatum. These result were reported in Annual Meeting of the Japanese Society of Psychiatry and Neurology.

We investigated the factors associated with lithium responsiveness and suicidality in mood disorders (bipolar disorder, depression) by brain function evaluated by the near-infrared spectroscopy and various clinical data. The small number of cases with lithium responsiveness do not reach the statistical significance. On the other hand, we obtained significant results about suicidality as follows. 1) Discrepancies between self- and observer-rated depression severities are associated with vulnerability to suicide in patients with major depressive disorder, and prefrontal cortex activation is associated with these discrepancies. 2) Right temporal activation differs between melancholia and nonmelancholic depression. 3) Patients with bipolar disorders have persistent hypofunction of the frontotemporal cortical regions and the hemodynamic response in the left temporal regions is associated with symptom severity.

DNA chip解析により、13qに位置し、転写因子をコードするKLF5遺伝子の発現量が、統合失調症死後脳前頭前野においてコントロール群よりも減少していることを見出した。さらに、その結果に基づき、378名の健常者および328名の統合失調症患者の血液サンプルを用いてKLF5遺伝子と統合失調症との相関研究をおこなったころ、KLF5遺伝子プロモーター上のSNPと統合失調症との有意な相関をみとめた。また、その相関をみとめた-1593T/C SNPについて統合失調症死後脳における発現量を検討したところ、-1593T/C SNPはKLF5遺伝子の発現量に影響を及ぼしていることを見出した。さらに統合失調症の血液サンプルを用いた遺伝子配列解析をおこなったところ、一つの一塩基変異はコントロール群においてはみられず、統合失調症においてのみみられた。 さらにKLF5遺伝子の脳における発現分布について免疫組織学的な検討をおこなったところ、グルタミン酸ニューロンに多く発現していることを見出した。これまでにKLF5遺伝子は、MAPキナーゼカスケートに位置することが報告されており、MAPキナーゼカスケードは脳においてはシナプス可塑性に重要であることが知られている。これらのことは、KLF5遺伝子がグルタミン酸ニューロンのシナプス可塑性にかかわる可能性を示している。本研究において、KLF5遺伝子が統合失調症と相関したことは、統合失調症においてはグルタミン酸神経伝達に障害があるのではないかというグルタミン酸神経伝達仮説を支持するものであり、その障害にKLF5遺伝子が関わっていることを示唆するものである。以上の結果は、現在欧文雑誌に掲載予定である。

1. We studied the clinical and psychological characteristics associated with suicidality based on the history of lethal suicide attempt in 76 patients mainly with mood disorders. Hopelessness rather than depression, aggression in less than 40 years old patients and neuroticism were associated with suicidality. The perspectives on death were not associated with suicidality. 2. We performed the profiling of mRNA expressions in amygdala of suicide brains. The 21 increased and the 9 decreased expressions of genes were identified. Among the genes with increased expressions, the polymorphisms of 14-3-3 ε gene were associated with suicide. Any polymorphisms in genes with the decreased expressions were not associated with suicide. 3. Among the functional gene polymorphisms which affect a hypothalamic-pituitary-adrenal system (HPA system), we found the significant associations of OPRM1 Asn40Asp, ACE I/D and ADEA2A C-1291G polymorphism with suicide. 4. For functional MRI, we made a neuropsychological task which activates emotion. A stronger activation in amygdala and posterior cingulate gyrus was shown in case of recognition in emotionally negative words, compared with emotionally neutral words. We made the tasks comprising the recall of past negative or positive episodes and the imagination of future negative or positive episodes. The activations were found in the medial frontal cortex, dorsolateral prefrontal cortex posterior cingulate gyrus.