Nobuyuki Ozawa

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.

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.

Increased firing of locus coeruleus neurons associated with preparatory set in rats

The activity of locus coeruleus (LC) neurons was studied during the performance of a reaction-time task with warning. Seventeen cells were tentatively identified as LC neurons using two criteria: (1) Relative location from the mesencephalic trigeminal (Me5) neurons, which have large-amplitude bursting discharges synchronized with masticatory movements. (2) The presence of an antidromic response to the stimulation of the dorsal pathway. Of these 17 cells, 16 neurons showed intense and consistent firing during the period between the warning stimulus and the response. Neither the stimuli nor the lever pressing movements alone were accompanied by such a change, suggesting that increased firing occurs in association with preparatory set. The one remaining neuron of the 17 cells showed no change with the task performance. It is supposed that only the 16 homogeneous neurons belong to the LC.

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.

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.

CNV-like potentials on the cortical surface associated with conditioning in head-restrained rats ☆

Head-restrained rats were conditioned to perform a CNV task: to press a lever in response to an imperative auditory stimulus (S2) given 1.5 sec after a warning stimulus (S1) for a drop of jelly food. With an electrode on the surface of the forelimb cortex, (1) sharp wave complexes immediately after S1 and S2, and (2) a negative slow potential (SP) between S1 and S2, on which early and late components were discernible, were recorded in association with performance of this task. With the electrode at a depth of 2 mm in the same cortical area, the corresponding field potential showed a long-lasting positive shift in addition to the components of the surface potential. These monopolar recordings were obtained with respect to a common reference at the frontal sinus. The surface-minus-depth potential (the transcortical potential), consequently, showed a surface-negative tonic wave, confirming Pirchs report (1980). During extinction of this conditioning, the SP between S1 and S2 disappeared, while the sharp waves following S1 and S2 remained with little modification, suggesting that the sharp waves are a kind of evoked potential (EP) elicited by the stimuli. Recording from 5 surface electrodes set in an array over the left hemisphere contralateral to the used forelimb during development of the conditioning revealed not only a spatial distribution of the SP but also a transition of the potentials. As the conditioning progressed, the negativity of the early SP component tended to increase, while that of the late component tended to decrease and was confined to the sensorimotor cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Auditory-evoked response of the cortex after yohimbine administration: phase advance effect of central noradrenergic activation.

The effects of central noradrenergic activation on an auditory-evoked cortical response were studied using systemic administration of yohimbine (2 mg/kg intravenously, IV), a noradrenergic stimulant, in 13 anesthetized rats. To analyze changes of the response, surface and intracortical evoked potentials (EP) as well as extracellular single-unit recordings with tungsten microelectrodes were employed. It was noted that the initial-positive wave of the surface EP corresponded to unit firing responses in a restricted area of the auditory cortex, where the surface EP was largest and a polarity inversion of the intracortical EP was observed. The following effects were produced by yohimbine: 1) The initial-positive surface potential (n = 10) and corresponding intracortical potential with inverted polarity (n = 6) both showed an increase in amplitude and a decrease in peak latency; 2) the unit firing response (n = 10) tended to show an increase in peak frequency and a decrease in peak firing latency; and 3) yohimbine produced an earlier ending of the firing period, and in paired stimulation experiments (n = 7) it prolonged the period during which the second response was suppressed, indicating an augmentation of postexcitation inhibition. Later histological examination suggested that most of the units recorded were pyramidal cells. These findings indicate that chemical stimulation of the central noradrenergic system by yohimbine enhances both the initial excitatory and following inhibitory processes in the auditory-evoked response of the cortical units (probably pyramidal cells), resulting not only in amplification of the response but also in advancement of the response phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Skin conductance activity after intraventricular administration of 6-hydroxydopa in rats

Absence of skin conductance response (SCR) and failure of its habituation are psychophysiological signs observed in most schizophrenics. In the present experiments, skin conductance activity was studied in rats before and after intraventricular administration of 6-hydroxydopa (6-OHdopa), a neurotoxin that selectively destroys noradrenaline nerve terminals and induces denervation supersensitivity at the synapse. All intact rats studied (n = 32) showed SCR and its habituation to repeated auditory stimuli (500 Hz, 90 dB, 1 sec, 20 times). They also showed some spontaneous fluctuation (SF) of the skin conductance. In the early stage following the 6-OHdopa (100 micrograms) administration (n = 16), it was noted that the SCR disappeared and the SF were markedly reduced in frequency (p less than 0.001). From the third day to the fourth week after this treatment, there was some recovery of the SF rate, and the SCR tended to reappear with a marked slowing down of its habituation. Eight weeks after the treatment, the majority (11/16) of the 6-OHdopa rats showed habituation failure of the SCR (p less than 0.005); vehicle-treated rats (n = 16) did not show these alterations. Estimation of catecholamine concentration after the experiment confirmed the selective depletion of brain noradrenaline. These results suggest that destruction of the noradrenergic fibers after the 6-OHdopa treatment and denervation supersensitivity which developed later are the cause of the nonresponding and nonhabituating changes of SCR, respectively.