Noriko Sakurai

Autistic Traits and Brain Activation during Face-to-Face Conversations in Typically Developed Adults

Background Autism spectrum disorders (ASD) are characterized by impaired social interaction and communication, restricted interests, and repetitive behaviours. The severity of these characteristics is posited to lie on a continuum that extends into the general population. Brain substrates underlying ASD have been investigated through functional neuroimaging studies using functional magnetic resonance imaging (fMRI). However, fMRI has methodological constraints for studying brain mechanisms during social interactions (for example, noise, lying on a gantry during the procedure, etc.). In this study, we investigated whether variations in autism spectrum traits are associated with changes in patterns of brain activation in typically developed adults. We used near-infrared spectroscopy (NIRS), a recently developed functional neuroimaging technique that uses near-infrared light, to monitor brain activation in a natural setting that is suitable for studying brain functions during social interactions. Methodology We monitored regional cerebral blood volume changes using a 52-channel NIRS apparatus over the prefrontal cortex (PFC) and superior temporal sulcus (STS), 2 areas implicated in social cognition and the pathology of ASD, in 28 typically developed participants (14 male and 14 female) during face-to-face conversations. This task was designed to resemble a realistic social situation. We examined the correlations of these changes with autistic traits assessed using the Autism-Spectrum Quotient (AQ). Principal Findings Both the PFC and STS were significantly activated during face-to-face conversations. AQ scores were negatively correlated with regional cerebral blood volume increases in the left STS during face-to-face conversations, especially in males. Conclusions Our results demonstrate successful monitoring of brain function during realistic social interactions by NIRS as well as lesser brain activation in the left STS during face-to-face conversations in typically developed participants with higher levels of autistic traits.

Large‐scale analysis of glucocorticoid target genes in rat hypothalamus

Insufficient glucocorticoid (GC) signaling is frequently observed in major depressive disorder (MDD). Since emotional and behavioral symptoms are often accompanied by disturbances in hypothalamic systems, GC insufficiency in this region is regarded as important in the pathogenesis of MDD. In this study, 22 early GC‐responsive genes comprising 15 up‐regulated and 7 down‐regulated genes in rat hypothalamus were identified as being regulated at least two‐fold by dexamethasone using microarray with 22 599 unique transcripts. Among these 22 genes, five of which are novel GC‐responsive genes, the expression patterns of sgk, bcl6, pdk4, and plekhf1 were examined in vitro in detail, and GC‐responsive regions were identified only within the promoter of sgk. This suggests that glucocorticoid response element‐independent pathways also play a critical role in early GC‐response in hypothalamus. Considering that a number of these GC‐responsive genes are candidate neuronal regulators, this gene list should be useful in clarifying the relationship between GC insufficiency and the pathogenesis of MDD.

Effects of SKF-38393, a dopamine D1 receptor agonist on expression of amphetamine-induced behavioral sensitization and expression of immediate early gene arc in prefrontal cortex of rats

Repeated administrations of psychostimulants into rodents produce behavioral sensitization. We examined whether a dopamine D1 agonist can reverse behavioral sensitization once established by repeated amphetamine (AMP) administrations and determined the mRNA expression levels of the D1 and D2 receptors, metabotropic glutamate receptor 1 (mGluR1), and activity-regulated cytoskeleton-associated protein (arc) in rats. Rats were pretreated with six intermittent AMP injections. Following a 14-day withdrawal period, the rats were divided into six groups and treated with either SKF-38393 (SKF; dopamine D1 agonist), SCH-23390 (SCH; selective D1 antagonist), YM-09151-2 (YM; selective D2 antagonist), SKF+SCH, SKF+YM or physiological saline once daily for 5 days. Three days or 4 weeks after the reversal treatments, all the rats were rechallenged with AMP. D1 and D2 antagonist treatments produced no significant decreases in locomotor activity or stereotyped behavior rate, respectively. In the SKF treatment group, stereotyped behavior rate decreased markedly after the three-day and four-week withdrawal periods. SKF+SCH treatment inhibited the effect of SKF treatment. The rats in the other groups that received AMP with or without SKF were decapitated 1 h after treatment, and the mRNA levels of the D1 and D2 receptors, mGluR1, and arc were measured by TaqMan real-time reverse transcriptase-polymerase chain reaction (RT-PCR). AMP administration significantly increased arc level. SKF also increased arc level significantly after the first single injection and after repeated injections of AMP during the pretreatment. There was no significant difference in arc expression level between the saline and SKF treatment groups after the AMP challenge, suggesting that arc expression level is not involved in the reversal effects of SKF in AMP sensitization.

Temporal lobe and inferior frontal gyrus dysfunction in patients with schizophrenia during face-to-face conversation: A near-infrared spectroscopy study

Schizophrenia (SC) is marked by poor social-role performance and social-skill deficits that are well reflected in daily conversation. Although the mechanism underlying these impairments has been investigated by functional neuroimaging, technical limitations have prevented the investigation of brain activation during conversation in typical clinical situations. To fill this research gap, this study investigated and compared frontal and temporal lobe activation in patients with SC during face-to-face conversation. Frontal and temporal lobe activation in 29 patients and 31 normal controls (NC) (n = 60) were measured during 180-s conversation periods by using near-infrared spectroscopy (NIRS). The grand average values of oxyhemoglobin concentration ([oxy-Hb]) changes during task performance were analyzed to determine their correlation with clinical variables and Positive and Negative Syndrome Scale (PANSS) subscores. Compared to NCs, patients with SC exhibited decreased performance in the conversation task and decreased activation in both the temporal lobes and the right inferior frontal gyrus (IFG) during task performance, as indicated by the grand average of [oxy-Hb] changes. The decreased activation in the left temporal lobe was negatively correlated with the PANSS disorganization and negative symptoms subscores and that in the right IFG was negatively correlated with illness duration, PANSS disorganization, and negative symptom subscores. These findings indicate that brain dysfunction in SC during conversation is related to functional deficits in both the temporal lobes and the right IFG and manifests primarily in the form of disorganized thinking and negative symptomatology.

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.

Blood Transcriptomic Markers in Patients with Late-Onset Major Depressive Disorder

We investigated transcriptomic markers of late-onset major depressive disorder (LOD; onset age of first depressive episode ≥ 50 years) from the genes expressed in blood cells and identified state-dependent transcriptomic markers in these patients. We assessed the genes expressed in blood cells by microarray and found that the expression levels of 3,066 probes were state-dependently changed in the blood cells of patients with LOD. To select potential candidates from those probes, we assessed the genes expressed in the blood of an animal model of depression, ovariectomized female mice exposed to chronic ultra-mild stress, by microarray and cross-matched the differentially expressed genes between the patients and the model mice. We identified 14 differentially expressed genes that were similarly changed in both patients and the model mice. By assessing statistical significance using real-time quantitative PCR (RT-qPCR), the following 4 genes were selected as candidates: cell death-inducing DFFA-like effector c (CIDEC), ribonuclease 1 (RNASE1), solute carrier family 36 member-1 (SLC36A1), and serine/threonine/tyrosine interacting-like 1 (STYXL1). The discriminating ability of these 4 candidate genes was evaluated in an independent cohort that was validated. Among them, CIDEC showed the greatest discriminant validity (sensitivity 91.3% and specificity 87.5%). Thus, these 4 biomarkers should be helpful for properly diagnosing LOD.

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.

Gene expression alterations in the medial prefrontal cortex and blood cells in a mouse model of depression during menopause

Aims The prevalence of major depressive disorder (MDD) is higher in women than in men, and this may be due to the decline in estrogen levels that occurs during the menopausal transition. We studied the biological alterations in the medial prefrontal cortex (mPFC), which is a region that is highly implicated in the neurobiology of MDD, and the blood cells (BCs) of ovariectomized (OVX) mice subjected to chronic mild stress (CMS), which represents a mouse model of depression during menopause. Main methods The mPFC and the BCs were obtained from the same individuals. Gene expression levels were analyzed by microarray. The data were used for the Ingenuity Pathway Analysis and the Gene Ontology analysis. Key findings The gene expression alterations (GEAs) induced by OVX were mainly associated with ribosomal and mitochondrial functions in both the mPFC and the BCs. Rapamycin-insensitive companion of mTOR (RICTOR) was identified as a possible upstream regulator of the OVX-induced GEAs in both tissues. The CMS-induced GEAs were associated with retinoic acid receptor signaling, inflammatory cytokines and post-synaptic density in the mPFC, but not in the BCs. Significance OVX and CMS independently affect biological pathways in the mPFC, which is involved in the development of the depression-like phenotype. Because a subset of the OVX-induced GEAs in the mPFC also occurred in the BCs, the GEAs in the BCs might be a useful probe to predict biological pathways in the corresponding brain tissue under specific conditions such as OVX in females.

57. Comparison of prefrontal activation by low-frequency rTMS using two types of coil: A near-infrared spectroscopy study

lished. Our study aimed to investigate the relationships between pain and the stimulus duration when stimulus intensity is just sufficient to obtain the supramaximal stimulation. Fourteen normal subjects were enrolled for this evaluation. Tibial nerve was stimulated at the ankle with two out of three durations of 0.05, 0.2, and 1.0 ms. Six such combinations were tested in a random order, and subjects were asked to report which duration was more painful at each trial. Following two stimulus patterns were examined: pattern 1 was single supramaximal stimulation, and pattern 2 was a train of five maximal stimulations with 1 Hz, respectively. The stimulus duration with 0.2 ms caused minimum pain for both patterns, followed by 0.05 and 1.0 ms. This result indicate shorter duration is not always less painful. Furthermore, if we use 0.05 ms duration, the intensity necessary for supramaximal stimulation may easily exceed 100 mA for a pathological nerve with increased threshold. It is concluded that 0.2 ms duration, widely employed in Japan, is well appropriate.

S24-4 Near-infrared spectroscopy in psychiatry

good agreement between NIRS and WADA test suggesting the clinical application of NIRS in place of WADA test. Monitoring aphasia recovery: We followed 52 cases with aphasia during recovery phase using language task. In 38%, NIRS showed activations in right frontal areas in the initial phase of recovery, which is followed by switching toward the left side activations. 32% showed activations in the cortical areas surrounding left language area throughout the whole course of recovery. Focus diagnosis in epilepsy: 72 cases were monitored by NIRS during epileptic seizures. In 87%, NIRS showed blood volume increase in the focus area. These findings indicated the clinical feasibility of NIRS in the identification of epilepsy focus. Monitoring the hypnotherapy: In 35 cases, NIRS were monitored during hypnotherapy. In every case, when introduction into good hypnotic trance were achieved, NIRS showed blood flow decease in the frontopolar area. On the contrary, when the introduction into trance was failed, no decrease of blood flow was observed in the frontal lobe. These findings suggest that the NIRS can be utilized to detect whether the patient goes into trance or not which has not been able to be attained by EEG.