Toshikazu Shinba

Decrease in heart rate variability response to task is related to anxiety and depressiveness in normal subjects

Aims:  Previous studies have shown that heart rate variability (HRV) measurement is useful in investigating the pathophysiology of various psychiatric disorders. The present study further examined its usefulness in evaluating the mental health of normal subjects with respect to anxiety and depressiveness.

Near-Infrared Spectroscopy Analysis of Frontal Lobe Dysfunction in Schizophrenia

BACKGROUND Previous studies have shown that near-infrared spectroscopy (NIRS) has high temporal resolution, requires little restraint, and is suitable for examining the effect of psychological tasks on brain circulation. In the present study, frontal function in schizophrenic patients was analyzed by NIRS during random number generation (RNG), ruler-catching (RC), and sequential finger-to-thumb (SFT) tasks. METHODS Two sets of NIRS probes were attached to the foreheads of 13 schizophrenic patients and 10 control subjects approximately at Fp1-F7 and Fp2-F8. Near-infrared spectroscopy was conducted at a sampling rate of 1 Hz, with the pathlength being determined by time-resolved spectroscopy with differential pathlength factor measurements. The absolute changes in oxygenated (oxy-Hb) and deoxygenated (deoxy-Hb) hemoglobin concentrations in response to each task were measured, and total hemoglobin (total-Hb) concentration was calculated as the sum of the two. RESULTS During RNG task, total- and oxy-Hb concentrations increased, and deoxy-Hb decreased, but the responses were significantly smaller in schizophrenic patients. During RC task, oxy-Hb in schizophrenic patients tended to decrease, in contrast to the mostly increasing response in control subjects. No group difference was observed during SFT task. CONCLUSIONS Task-dependent profile of functional abnormalities was observed in schizophrenic frontal brain metabolism. These results support the usefulness of NIRS data in investigating frontal lobe dysfunction and evaluating psychopathologic condition in schizophrenic patients.

Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice

ARX (the aristaless-related homeobox gene) is a transcription factor that participates in the development of GABAergic and cholinergic neurons in the forebrain. Many ARX mutations have been identified in X-linked lissencephaly and mental retardation with epilepsy, and thus ARX is considered to be a causal gene for the two syndromes although the neurobiological functions of each mutation remain unclear. We attempted to elucidate the causal relationships between individual ARX mutations and disease phenotypes by generating a series of mutant mice. We generated three types of mice with knocked-in ARX mutations associated with X-linked lissencephaly (P353R) and mental retardation [P353L and 333ins(GCG)7]. Mice with the P355R mutation (equivalent to the human 353 position) that died after birth were significantly different in Arx transcript/protein amounts, GABAergic and cholinergic neuronal development, brain morphology and lifespan from mice with P355L and 330ins(GCG)7 but considerably similar to Arx-deficient mice with truncated ARX mutation in lissencephaly. Mice with the 330ins(GCG)7 mutation showed severe seizures and impaired learning performance, whereas mice with the P355L mutation exhibited mild seizures and only slightly impaired learning performance. Both types of mutant mice exhibited the mutation-specific lesser presence of GABAergic and cholinergic neurons in the striatum, medial septum and ventral forebrain nuclei when compared with wild-type mice. Present findings that reveal a causal relationship between ARX mutations and the pleiotropic phenotype in mice, suggest that the ARX-related syndrome, including lissencephaly or mental retardation, is caused by only the concerned ARX mutations without the involvement of other genetic factors.

Event-related potentials in the dorsal hippocampus of rats during an auditory discrimination paradigm

The relation of the hippocampal neuronal activity to the rat event-related potential (ERP) generation was examined during an auditory discrimination oddball paradigm. ERPs were recorded using a linearly-arranged series of electrodes chronically implanted at the skull, in the frontoparietal cortex, in the CA1 and CA3 regions of the dorsal hippocampus and in the thalamus. The target tone elicited N40, P100, N200, and P450 at the skull electrode. The non-target tone, on the other hand, prominently evoked only the P100 component. At the intracranial electrodes, the ERP amplitude at the latency of the skull P450 was significantly greater in the CA3 region than that at other recording sites, although a phase reversal was not observed. The results indicate that the P450 of the rat may correspond to the human P3, and that the neuronal activity in the hippocampus is involved in its generation.

Altered autonomic activity and reactivity in depression revealed by heart-rate variability measurement during rest and task conditions

The aim of the present study was to assess autonomic activity and reactivity reflecting arousal functions in depression using heart‐rate variability (HRV) and heart rate (HR) measurements.

POSSIBLE NORADRENERGIC DYSFUNCTION IN SCHIZOPHRENIA

In spite of extensive studies over the last 2 decades to find direct evidence in support of the dopamine hypothesis of schizophrenia, no undisputed experimental data has been obtained. In contrast, estimation of noradrenalin (another major catecholamine) and its metabolites in postmortem brain and in the cerebrospinal fluid appears to be producing consistent results. To understand the meaning of this change for the pathogenesis of the illness, we have carried out animal experiments in which reproducibility of schizophrenic signs and symptoms by noradrenergic dysfunction, and treatability of the disorder by modulation of noradrenergic activity were studied. First, psychophysiological signs in skin conductance responsiveness (nonhabituating or nonresponding change) and smooth pursuit eye movement (spiky or stepwise pursuit) could be reproduced by enhancing or suppressing central noradrenergic activity. Behavioral abnormalities resembling schizophrenic symptoms are known to be reproducible by over- or underactivity of the system (overarousal or underarousal syndrome). Secondly, the action of various drugs capable of modulating schizophrenic symptoms was analyzed in relation to noradrenergic activity. Haloperidol, in particular, had a potent suppressing effect on skin conductance activity (spontaneous fluctuation rate and habituation rate) when administered chronically, suggesting its inhibitory action on noradrenergic activity.

Psychiatric symptoms of noradrenergic dysfunction: a pathophysiological view.

What psychiatric symptoms are caused by central noradrenergic dysfunction? The hypothesis considered in this review is that noradrenergic dysfunction causes the abnormalities in arousal level observed in functional psychoses. In this review, the psychiatric symptoms of noradrenergic dysfunction were inferred pathophysiologically from the neuroscience literature. This inference was examined based on the literature on the biology of psychiatric disorders and psychotropics. Additionally, hypotheses were generated as to the cause of the noradrenergic dysfunction. The central noradrenaline system, like the peripheral system, mediates the alarm reaction during stress. Overactivity of the system increases the arousal level and amplifies the emotional reaction to stress, which could manifest as a cluster of symptoms, such as insomnia, anxiety, irritability, emotional instability and exaggerated fear or aggressiveness (hyperarousal symptoms). Underactivity of the system lowers the arousal level and attenuates the alarm reaction, which could result in hypersomnia and insensitivity to stress (hypoarousal symptoms). Clinical data support the hypothesis that, in functional psychoses, the noradrenergic dysfunction is in fact associated with the arousal symptoms described above. The anti‐noradrenergic action of anxiolytics and antipsychotics can explain their sedative effects on the hyperarousal symptoms of these disorders. The results of animal experiments suggest that excessive stress can be a cause of long‐term noradrenergic dysfunction.

Increased neuronal firing in the rat auditory cortex associated with preparatory set

Extracellular single neuronal firings were recorded in the auditory cortex of rats (n = 4) performing a visual reaction-time task with a warning tone (10 kHz, 10 ms duration), which preceded the imperative light stimulus by an interstimulus interval (ISI) of 1.4 s. Thirty-six neuronal firings were evoked by the warning tone, with the peak latency being between 15 and 55 ms. Among them, nine neurons (25%) showed an increased firing frequency following the evoked response during the ISI, which was, in average, 2.5 times as high as the firing frequency during the baseline period. When the tones were presented independent of the imperative stimulus, such sustained increase in neuronal firing was not observed. Activation of the sensory cortex during the ISI may constitute one of the neuronal modulations related to preparatory set.

Functional influence of the central noradrenergic system on the skin conductance activity in rats

Pharmacological studies on neuroleptics and amphetamine strongly suggest that some dysfunction of the central catecholamine system may play a key role in the pathogenesis of schizophrenia. Our previous studies have demonstrated that intraventricular administration of 6-hydroxydopamine, a selective neurotoxin of the catecholamine neuron, can reproduce schizophrenia-like abnormalities in the skin conductance activity. In the present experiments, effects of pharmacological modulation of the central noradrenergic activity were studied in rats. Stimulation of the central noradrenergic activity by yohimbine (0.6 mg/kg, i.m.) slowed down the habituation of the skin conductance response (SCR) and increase the spontaneous fluctuation of the skin conductance (SF), while inhibition of the activity by clonidine (0.06 mg/kg, i.m.) accelerated or obliterated the SCR and decreased the SF frequency. If the functional significance of the central noradrenergic system lies in vigilance control, the present results are consistent with classical theory in psychophysiology: the habituation rate of SCR and the frequency of SF are correlated well with each other and both indices reflect arousal level. The disorder of the system should produce not only these psychophysiological abnormalities but also psychological disturbances; i.e., overarousal and underarousal syndromes. Therefore, the dysfunction of the noradrenergic system might constitute an essential aspect of schizophrenic disorder.

Event-related potentials during an auditory discrimination task in rats

Event-related potentials (ERPs) during an auditory discrimination task were recorded both on the surface and at a depth of the auditory cortex in rats. Ten-kilohertz rare and 5-kHz frequent tones were used with the probabilities of 0.2 and 0.8. Lever pressing within 2 s, following the onset of the rare tone, was rewarded with food paste. In the performing condition, the surface ERPs for the rare tones consisted of P30, N50, P80, N130, and P290 components. Only the surface P30 and N50 showed a polarity reversal at the intracortical electrode, suggesting that these components are generated in the auditory cortex. The P290 was elicited in the performing condition but not in the resting condition, showing its task-relevancy. These results suggest that auditory ERPs similar to those in humans can be recorded in rats during an active discrimination task.