Multivariate sharp-wave ripples in schizophrenia during awake state.

AIMS: Schizophrenia (SZ) is a brain disorder characterized by psychotic symptoms and cognitive dysfunction. Recently, irregularities in sharp-wave ripples (SPW-Rs) have been reported in SZ. As SPW-Rs play a critical role in memory, their irregularities can cause psychotic symptoms and cognitive dysfunction in patients with SZ. In this study, we investigated the SPW-Rs in human SZ. METHODS: We measured whole-brain activity using magnetoencephalography (MEG) in patients with SZ (n = 20) and sex- and age-matched healthy participants (n = 20) during open-eye rest. We identified SPW-Rs and analyzed their occurrence and time-frequency traits. Furthermore, we developed a novel multivariate analysis method, termed "ripple-gedMEG" to extract the global features of SPW-Rs. We also examined the association between SPW-Rs and brain state transitions. The outcomes of these analyses were modeled to predict the positive and negative syndrome scale (PANSS) scores of SZ. RESULTS: We found that SPW-Rs in the SZ (1) occurred more frequently, (2) the delay of the coupling phase (3) appeared in different brain areas, (4) consisted of a less organized spatiotemporal pattern, and (5) were less involved in brain state transitions. Finally, some of the neural features associated with the SPW-Rs were found to be PANSS-positive, a pathological indicator of SZ. These results suggest that widespread but disorganized SPW-Rs underlies the symptoms of SZ. CONCLUSION: We identified irregularities in SPW-Rs in SZ and confirmed that their alternations were strongly associated with SZ neuropathology. These results suggest a new direction for human SZ research.

The Characteristics of Power Spectral Density in Bipolar Disorder at the Resting State.

Bipolar disorder (BD) is a common psychiatric disorder, but its pathophysiology is not fully elucidated. The current study focused on its electrophysiological characteristics, especially power spectral density (PSD). Resting state with eyes opened magnetoencephalography data were collected from 21 patients with BD and 22 healthy controls. The whole brain's PSD was calculated from source reconstructed waveforms at each frequency band (delta: 1-3 Hz, theta: 4-7 Hz, alpha: 8-12 Hz, low beta: 13-19 Hz, high beta: 20-29 Hz, and gamma: 30-80 Hz). We compared PSD values on the marked vertices at each frequency band between healthy and patient groups using a Mann-Whitney rank test to examine the relationship between significantly different PSD and clinical measures. The PSD in patients with BD was significantly decreased in lower frequency bands, mainly in the default mode network (DMN) areas (bilateral medial prefrontal cortex, bilateral precuneus, left inferior parietal lobe, and right temporal cortex in the alpha band) and salience network areas (SAL; left anterior insula [AI] at the delta band, anterior cingulate cortex at the theta band, and right AI at the alpha band). No significant differences in PSD were observed at low beta and high beta. PSD was not correlated with age or other clinical scales. Altered PSDs of the DMN and SAL were observed in the delta, theta, and alpha bands. These alterations contribute to the vulnerability of BD through the disturbance of self-referential mental activity and switching between the default mode and frontoparietal networks.

Disrupted local beta band networks in schizophrenia revealed through graph analysis: A magnetoencephalography study.

AIMS: Schizophrenia (SZ) is characterized by psychotic symptoms and cognitive impairment, and is hypothesized to be a 'dysconnection' syndrome due to abnormal neural network formation. Although numerous studies have helped elucidate the pathophysiology of SZ, many aspects of the mechanism underlying psychotic symptoms remain unknown. This study used graph theory analysis to evaluate the characteristics of the resting-state network (RSN) in terms of microscale and macroscale indices, and to identify candidates as potential biomarkers of SZ. Specifically, we discriminated topological characteristics in the frequency domain and investigated them in the context of psychotic symptoms in patients with SZ. METHODS: We performed graph theory analysis of electrophysiological RSN data using magnetoencephalography to compare topological characteristics represented by microscale (degree centrality and clustering coefficient) and macroscale (global efficiency, local efficiency, and small-worldness) indices in 29 patients with SZ and 38 healthy controls. In addition, we investigated the aberrant topological characteristics of the RSN in patients with SZ and their relationship with SZ symptoms. RESULTS: SZ was associated with a decreased clustering coefficient, local efficiency, and small-worldness, especially in the high beta band. In addition, macroscale changes in the low beta band are closely associated with negative symptoms. CONCLUSIONS: The local networks of patients with SZ may disintegrate at both the microscale and macroscale levels, mainly in the beta band. Adopting an electrophysiological perspective of SZ as a failure to form local networks in the beta band will provide deeper insights into the pathophysiology of SZ as a 'dysconnection' syndrome.

Glutamine + glutamate level predicts the magnitude of microstructural organization in the gray matter in the healthy elderly.

BACKGROUND: Diffusion tensor imaging (DTI), which is a technique for measuring the degree and direction of movement of water molecules in tissue, has been widely used to noninvasively assess white matter (WM) or gray matter (GM) microstructures in vivo. Mean diffusivity (MD), which is the average diffusion across all directions, has been considered as a marker of WM tract degeneration or extracellular space enlargement in GM. Recent lines of evidence suggest that cortical MD can better identify early-stage Alzheimer's disease than structural morphometric parameters in magnetic resonance imaging. However, knowledge of the relationships between cortical MD and other biological factors in the same cortical region, e.g. metabolites, is still limited. METHODS: Thirty-three healthy elderly individuals [aged 50-77 years (mean, 63.8±7.4 years); 11 males and 22 females] were enrolled. We estimated the associations between cortical MD and neurotransmitter levels. Specifically, we measured levels of γ-aminobutyric acid (GABA) and glutamate + glutamine (Glx), which are inhibitory and excitatory neurotransmitters, respectively, in medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) using MEGA-PRESS magnetic resonance spectroscopy, and we measured regional cortical MD using DTI. RESULTS: Cortical MD was significantly negatively associated with Glx levels in both mPFC and PCC. No significant association was observed between cortical MD and GABA levels in either GM region. CONCLUSION: Our findings suggest that degeneration of microstructural organization in GM, as determined on the basis of cortical MD measured by DTI, is accompanied by the decline of Glx metabolism within the same GM region.

Frequency-Specific Resting Connectome in Bipolar Disorder: An MEG Study.

BACKGROUND: Bipolar disorder (BD) is a serious psychiatric disorder that is associated with a high suicide rate, and for which no clinical biomarker has yet been identified. To address this issue, we investigated the use of magnetoencephalography (MEG) as a new prospective tool. MEG has been used to evaluate frequency-specific connectivity between brain regions; however, no previous study has investigated the frequency-specific resting-state connectome in patients with BD. This resting-state MEG study explored the oscillatory representations of clinical symptoms of BD via graph analysis. METHODS: In this prospective case-control study, 17 patients with BD and 22 healthy controls (HCs) underwent resting-state MEG and evaluations for depressive and manic symptoms. After estimating the source current distribution, orthogonalized envelope correlations between multiple brain regions were evaluated for each frequency band. We separated regions-of-interest into seven left and right network modules, including the frontoparietal network (FPN), limbic network (LM), salience network (SAL), and default mode network (DMN), to compare the intra- and inter-community edges between the two groups. RESULTS: In the BD group, we found significantly increased inter-community edges of the right LM-right DMN at the gamma band, and decreased inter-community edges of the right SAL-right FPN at the delta band and the left SAL-right SAL at the theta band. Intra-community edges in the left LM at the high beta band were significantly higher in the BD group than in the HC group. The number of connections in the left LM at the high beta band showed positive correlations with the subjective and objective depressive symptoms in the BD group. CONCLUSION: We introduced graph theory into resting-state MEG studies to investigate the functional connectivity in patients with BD. To the best of our knowledge, this is a novel approach that may be beneficial in the diagnosis of BD. This study describes the spontaneous oscillatory brain networks that compensate for the time-domain issues associated with functional magnetic resonance imaging. These findings suggest that the connectivity of the LM at the beta band may be a good objective biological biomarker of the depressive symptoms associated with BD.

γ-Aminobutyric acid type A receptor binding affinity in the right inferior frontal gyrus at resting state predicts the performance of healthy elderly people in the visual sustained attention test.

ABSTRACTBackground:Although recent studies have suggested that the γ-aminobutyric acid type A (GABAA) receptor binding affinity can be a more sensitive marker of age-related neuronal loss than regional gray matter (GM) volume, knowledge about the relationship between decreased GABAA receptor binding affinity and cognitive decline during normal aging is still limited. METHODS: Thirty-seven healthy elderly individuals (aged 50-77 years (mean, 64.5 ± 7.3 years); 15 males and 22 females) were enrolled in this study. We investigated the association of the performance of the healthy elderly in the attentional function test with regional GM volume, regional cerebral bold flow (rCBF), and GABAA receptor binding affinity in the resting state by structural magnetic resonance imaging (MRI), arterial spin labeling (ASL), and 123I-iomazenil (IMZ) SPECT, with the analysis focusing on the bilateral inferior frontal gyri. RESULTS: The score of the rapid visual information processing (RVP) test, which is used to assess visual sustained attention, showed a positive correlation with GABAA receptor binding affinity in the right inferior frontal gyrus. No significant correlation was found between RVP test score and regional GM volume or rCBF. CONCLUSION: The findings of 123I-IMZ SPECT, but not those of structural MRI or ASL, suggest that a decreased GABAA receptor binding affinity can be a sensitive marker of cognitive impairment.

The inhibition/excitation ratio related to task-induced oscillatory modulations during a working memory task: A multtimodal-imaging study using MEG and MRS.

Detailed studies on the association between neural oscillations and the neurotransmitters gamma-aminobutyric acid (GABA) and glutamate have been performed in vitro. In addition, recent functional magnetic resonance imaging studies have characterized these neurotransmitters in task-induced deactivation processes during a working memory (WM) task. However, few studies have investigated the relationship between these neurotransmitters and task-induced oscillatory changes in the human brain. Here, using combined magnetoencephalography (MEG) and magnetic resonance spectroscopy (MRS), we investigated the modulation of GABA and glutamate + glutamine (Glx) concentrations related to task-induced oscillations in neural activity during a WM task. We first acquired resting-state MRS and MEG data from 20 healthy male volunteers using the n-back task. Time-frequency analysis was employed to determine the power induced during the encoding and retention phases in perigenual anterior cingulate cortex (pg-ACC), mid-ACC, and occipital cortex (OC). Statistical analysis showed that increased WM load was associated with task-induced oscillatory modulations (TIOMs) of the theta-gamma band relative to the zero-back condition (TIOM0B) in each volume of interest during the encoding phase of the n-back task. The task-induced oscillatory modulations in the two-back condition relative to the zero-back condition (TIOM2B-0B) were negatively correlated with the percent rate change of the correct hit rate for 2B-0B, but positively correlated with GABA/Glx. The positive correlation between TIOM2B-0B and GABA/Glx during the WM task indicates the importance of the inhibition/excitation ratio. In particular, a low inhibition/excitation ratio is essential for the efficient inhibition of irrelevant neural activity, thus producing precise task performance.

Relationship of γ-aminobutyric acid and glutamate+glutamine concentrations in the perigenual anterior cingulate cortex with performance of Cambridge Gambling Task.

The anterior cingulate cortex (ACC), consisting of the perigenual ACC (pgACC) and mid-ACC (i.e., affective and cognitive areas, respectively), plays a significant role in the performance of gambling tasks, which are used to measure decision-making behavior under conditions of risk. Although recent neuroimaging studies have suggested that the γ-aminobutyric acid (GABA) concentration in the pgACC is associated with decision-making behavior, knowledge regarding the relationship of GABA concentrations in subdivisions of the ACC with gambling task performance is still limited. The aim of our magnetic resonance spectroscopy study is to investigate in 20 healthy males the relationship of concentrations of GABA and glutamate+glutamine (Glx) in the pgACC, mid-ACC, and occipital cortex (OC) with multiple indexes of decision-making behavior under conditions of risk, using the Cambridge Gambling Task (CGT). The GABA/creatine (Cr) ratio in the pgACC negatively correlated with delay aversion score, which corresponds to the impulsivity index. The Glx/Cr ratio in the pgACC negatively correlated with risk adjustment score, which is reported to reflect the ability to change the amount of the bet depending on the probability of winning or losing. The scores of CGT did not significantly correlate with the GABA/Cr or Glx/Cr ratio in the mid-ACC or OC. Results of this study suggest that in the pgACC, but not in the mid-ACC or OC, GABA and Glx concentrations play a distinct role in regulating impulsiveness and risk probability during decision-making behavior under conditions of risk, respectively.

Near-infrared spectroscopic study of frontopolar activation during face-to-face conversation in major depressive disorder and bipolar disorder.

Major depressive disorder (MDD) and bipolar disorder (BD) patients show speech characteristics that vary greatly according to mood state. In a previous study, we found impaired temporal and right inferior frontal gyrus (IFG) activation in schizophrenia during face-to-face conversation; no study had, however, previously investigated mood disorders during face-to-face conversation. Here, we investigated frontal and temporal lobe activation during conversation in patients with MDD and BD. Frontal and temporal lobe activation was measured using near-infrared spectroscopy (NIRS) in 29 patients with MDD, 31 patients with BD, and 31 normal controls (NC). We compared continuous activation and rapid change of activation with talk/listen phase changes during the conversation and analyzed the correlation between these indices and clinical variables. Both the MDD and BD groups showed decreased continuous activation in the left dorsolateral prefrontal (DLPFC) and left frontopolar cortices (FPCs); they also showed decreased rapid change in bilateral FPC activation. In the MDD group, the rapid change of activation was positively correlated with Global Assessment of Functioning (GAF) scores. In the BD group, continuous activation was negatively correlated with age of onset. These results indicate that frontal activation during conversation decreases in both MDD and BD. However, both continuous activation and rapid change may reflect the pathophysiological character of MDD and BD; in particular, the reduced amount of rapid change in the right FPC may be related to impaired adaptive ability in MDD.