Auditory change-related cerebral responses and personality traits.

The rapid detection of changes in sensory information is an essential process for survival. Individual humans are thought to have their own intrinsic preattentive responsiveness to sensory changes. Here we sought to determine the relationship between auditory change-related responses and personality traits, using event-related potentials. A change-related response peaking at approximately 120 ms (Change-N1) was elicited by an abrupt decrease in sound pressure (10 dB) from the baseline (60 dB) of a continuous sound. Sixty-three healthy volunteers (14 females and 49 males) were recruited and were assessed by the Temperament and Character Inventory (TCI) for personality traits. We investigated the relationship between Change-N1 values (amplitude and latency) and each TCI dimension. The Change-N1 amplitude was positively correlated with harm avoidance scores and negatively correlated with the self-directedness scores, but not with other TCI dimensions. Since these two TCI dimensions are associated with anxiety disorders and depression, it is possible that the change-related response is affected by personality traits, particularly anxiety- or depression-related traits.

Source localization of posterior slow waves of youth using dipole modeling.

AIM: Posterior slow waves of youth have a well-known electroencephalographic pattern that peaks in adolescence and usually disappears in adulthood. In general, posterior slow waves of youth are regarded as normal, but some reports have suggested that their presence is related to immature personalities or inappropriate social behavior. The physiological significance of this electroencephalographic pattern, however, remains unclear. The purpose of this study was to investigate the neural origins of posterior slow waves of youth using dipole source modeling. METHODS: Electroencephalographic epochs, including clear posterior slow waves of youth, were visually selected from electroencephalograms obtained from six normal adolescents using 25 scalp electrodes. The selected epochs were then averaged by arranging the negative peak of the slow waves at the occipital area of each epoch on the time axis. The averaged waveforms consisting of six right and one left posterior slow waves of youth were used for dipole source analysis. A single equivalent current dipole was estimated for the averaged waveforms. RESULTS: The best equivalent current dipoles were estimated to be located in or around the fusiform and middle occipital gyrus ipsilateral to the posterior slow waves of youth. CONCLUSIONS: The location of the estimated dipoles of posterior slow waves of youth was on the so-called ventral visual pathway. Further research is required to clarify the physiological significance of posterior slow waves of youth with respect to their origin.

Memory-based pre-attentive auditory N1 elicited by sound movement.

Quickly detecting changes in the surrounding environment is one of the most important functions of sensory processing. Comparison of a new event with preceding sensory conditions is necessary for the change-detection process. A sudden change in a continuous sound elicits auditory evoked potentials that peak approximately 100 ms after the onset of the change (Change-N1). In the present study, we recorded Change-N1 under an oddball paradigm in 19 healthy subjects using an abruptly moving sound (SM-stimulus) as a deviant stimulus and investigated effects of the probability of the SM-stimulus to reveal whether Change-N1 is a memory-based response. We compared the amplitude and latency of Change-N1 elicited by the SM-stimulus among three probability conditions (33, 50 and 100%). As the probability of the SM-stimulus decreased, the amplitude of Change-N1 increased and its latency decreased. The present results indicate that the preceding sensory history affects Change-N1 elicited by the SM-stimulus.

Electroencephalographic dipole source modeling of frontal intermittent rhythmic delta activity.

BACKGROUND: Frontal intermittent rhythmic delta activity (FIRDA) on electroencephalography (EEG) consists of a run of rhythmic delta waves with frontal predominance. Although FIRDA is a relatively common abnormal EEG finding, the underlying mechanisms that produce FIRDA remain unclear. The aim of this study was to investigate the cortical source of FIRDA using dipole source modeling. METHODS: We selected EEG epochs, including typical FIRDAs, from EEG recordings obtained using 25 scalp electrodes on 5 subjects. We averaged these epochs by arranging the negative peaks of the delta waves at the Fp electrodes and estimated dipoles for nine averaged waveforms. RESULTS: Averaged waveforms were explained by a single-dipole model in seven FIRDAs and by a two-dipole model in the remaining two FIRDAs with high reliability. Estimated dipoles had a radial orientation with respect to the frontal pole and were located in the medial frontal region. The anterior cingulate cortex was the most common dipole location. CONCLUSIONS: This is the first study to approach the fundamental FIRDA mechanism by dipole source modeling and to clarify that FIRDA may be generated from the medial frontal region, particularly from the anterior cingulate cortex.

Effect of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex.

To clarify the mechanisms of action of blonanserin, an atypical antipsychotic drug, we studied the effects of systemic administration of blonanserin and risperidone on extracellular levels of norepinephrine, dopamine, serotonin, GABA and glutamate in the medial prefrontal cortex using microdialysis, and neuronal firing in the ventral tegmental area, locus coeruleus, dorsal raphe nucleus and mediodorsal thalamic nucleus using radiotelemetry. The binding affinities of blonanserin to D(2) and 5-HT(2A) receptors in the rat brain were confirmed and found to be similar. Blonanserin transiently increased neuronal firing in locus coeruleus and ventral tegmental area but not in dorsal raphe nucleus or mediodorsal thalamic nucleus, whereas risperidone increased the firing in locus coeruleus, ventral tegmental area and dorsal raphe nucleus but not in mediodorsal thalamic nucleus. Blonanserin persistently increased frontal extracellular levels of norepinephrine and dopamine but not serotonin, GABA or glutamate, whereas risperidone persistently increased those of norepinephrine, dopamine and serotonin but not GABA or glutamate. These results suggest a pharmacological correlation between the stimulatory effects of these antipsychotics on frontal monoamine release and neuronal activity in monoaminergic nuclei. Inhibition of the α(2) adrenoceptor increased extracellular monoamine levels and enhanced blonanserin-induced increase in extracellular serotonin level. These results indicated that the combination of antagonism of D(2) and 5-HT(2A) receptors contribute to the rise in extracellular levels of norepinephrine and dopamine, and that α(2) adrenoceptors play important roles in frontal serotonin release. They also suggest that blonanserin-induced activation of monoaminergic transmission could be, at least partially, involved in atypical antipsychotic properties of blonanserin.

Effects of valproate on neurotransmission associated with ryanodine receptors.

To clarify the antiepileptic mechanisms of valproate (VPA), we determined the effects of acute and sub-acute administrations of VPA on ryanodine receptor (RyR)-associated hippocampal releases of GABA and glutamate using microdialysis, as well expression of mRNA and protein of RyR subtypes in the rat hippocampus. Acute administration of therapeutic-relevant VPA did not affect the hippocampal extracellular levels of GABA or glutamate, whereas sub-acute administration increased GABA level without affecting that of glutamate. Perfusion with ryanodine increased the hippocampal extracellular level of glutamate (ryanodine concentration range: 1-1000µM) concentration-dependently; however, that of GABA was increased by 1-100µM ryanodine concentration-dependently but the stimulatory effects of 1000µM ryanodine on GABA release was not observed. Both acute and sub-acute administrations of therapeutic-relevant VPA inhibited ryanodine-induced responses of hippocampal extracellular glutamate level without affecting that of GABA. Especially, both acute and sub-acute administrations of VPA prevented the breakdown of GABA release induced by 1000µM ryanodine. Sub-acute administration of therapeutically-relevant dose VPA weakly increased RyR mRNA expression but we could not detect the changes of RyR protein expression in rat hippocampus. These results suggest that VPA inhibited the neurotransmitter release associated with RyR without affecting the expression of RyR protein. Therefore, the antiepileptic action of VPA seems to be mediated, at least in part, by an increase in basal GABA release and inhibition of RyR-associated glutamate release.

Effects of quetiapine on monoamine, GABA, and glutamate release in rat prefrontal cortex.

INTRODUCTION: The atypical antipsychotic drug, quetiapine (QTP), is effective in schizophrenia and mood disorders, but induces seizures compared to typical antipsychotics. METHODS: To explore the mechanisms of action of QTP, we determined its effects on extracellular levels of norepinephrine, dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate in the medial prefrontal cortex (mPFC) using microdialysis, and neuronal firing in the ventral tegmental area (VTA), locus coeruleus (LC), dorsal raphe nucleus (DRN), and mediodorsal thalamic nucleus (MTN) by telemetry in freely moving rats. RESULTS: QTP (10 and 30 mg/kg, i.p.) activated neuronal firing in the VTA, LC, and MTN without affecting that in the DRN. QTP increased extracellular levels of norepinephrine, dopamine, and glutamate without affecting serotonin or GABA levels in the mPFC. The stimulatory effects of QTP on norepinephrine and dopamine were mediated by positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/glutamatergic and negative GABA-mediated NMDA/glutamatergic regulation. DISCUSSION: The dopaminergic terminal projecting from the VTA received inhibitory GABA-mediated NMDA/glutamatergic regulation, but not stimulatory AMPA/glutamatergic regulation. However, both dopaminergic and noradrenergic terminals from the LC received stimulatory AMPA/glutamatergic regulation from the MTN, but not inhibitory GABA-mediated NMDA/glutamatergic regulation. These findings correlating neuronal activities in nuclei with neurotransmitter release suggested that the effects of QTP on neurotransmission in the mPFC depend on activated neuronal projections located outside the mPFC. Furthermore, positive interaction between LC and MTN afferents are potentially important in the pharmacological mechanisms of neurotransmitter regulation by QTP and hint at mechanisms underlying the atypical profile of this drug for treatment of schizophrenia and as a mood stabilizer and proconvulsive agent.

Effects of zonisamide on neurotransmitter release associated with inositol triphosphate receptors.

To clarify the antiepileptic mechanisms of zonisamide (ZNS), we determined the interaction between ZNS and inositol-1,4,5-triphosphate receptor (IP3R) on exocytosis of GABA and glutamate in rat frontal cortex using microdialysis. ZNS increased basal GABA release, but not glutamate, concentration-dependently, and reduced concentration-dependently K(+)-evoked GABA and glutamate releases. Inhibition and activation of IP3R reduced and enhanced basal and K(+)-evoked GABA releases, respectively. The K(+)-evoked glutamate release was reduced and enhanced by IP3R antagonist and agonist, respectively, whereas basal glutamate release was increased by IP3R agonist but not affected by IP3R antagonist. Under extracellular Ca(2+) depletion, IP3R agonist increased basal GABA and glutamate releases. The latter effects of IP3R agonist were weakly enhanced by ZNS, but such stimulatory action of ZNS was abolished by extracellular Ca(2+) depletion. In contrast, ZNS inhibited the stimulatory effect of IP3R agonist on K(+)-evoked release. The stimulatory effect of IP3R agonist on basal release was regulated by N-type voltage-sensitive Ca(2+) channel (VSCC) rather than P- and L-type VSCCs, whereas the stimulatory effect of IP3R agonist on K(+)-evoked release was regulated by P- and L-type VSCCs rather than N-type VSCC. These results suggest that ZNS-activated N-type VSCC enhances IP3R-associated neurotransmitter release during resting stage, whereas ZNS-induced suppression of P- and L-type VSCCs possibly attenuates IP3R-associated neurotransmitter release during neuronal hyperexcitability. Therefore, the combination of both of these two actions of ZNS on IP3R-associated neurotransmitter release mechanism seems to be involved, at least in part, in the mechanisms of antiepileptic and neuroprotective actions of ZNS.

Topiramate and zonisamide prevent paradoxical intoxication induced by carbamazepine and phenytoin.

The mechanisms of paradoxical aggravation of epileptic seizures induced by selected antiepileptic drugs (AEDs) remain unclear. The present study addressed this issue by determining the seizure-threshold doses of carbamazepine (CBZ) and phenytoin (PHT), as well the dose-dependent effects of CBZ, PHT, and carbonic anhydrase-inhibiting AEDs, acetazolamide (AZM), topiramate (TPM), and zonisamide (ZNS), on neurotransmitter release in rat hippocampus. The dose-dependent effects of AEDs on hippocampal extracellular levels of glutamate (Glu), GABA, norepinephrine (NE), dopamine (DA), and serotonin (5-HT) were determined by microdialysis with high-speed and high-sensitive extreme liquid chromatography. Proconvulsive effects of AEDs were determined by telemetric-electrocorticography. Therapeutically relevant doses of AZM, CBZ, TPM, and ZNS increased hippocampal extracellular levels of GABA, NE, DA, and 5-HT, while PHT had no effect. Supratherapeutic doses of AZM, CBZ, PHT, TPM, and ZNS decreased extracellular levels of GABA, NE, DA, and 5-HT, without affecting Glu levels. Toxic doses of CBZ and PHT produced seizures (paradoxical intoxication), markedly increasing all transmitter levels, but TPM and ZNS even at toxic doses did not produce seizure. Co-administration experiments showed that therapeutically relevant doses of CBZ or PHT reduced the seizure-threshold doses of PHT or CBZ, respectively. In contrast, therapeutically relevant doses of AZM, TPM, and ZNS elevated the seizure-threshold doses of CBZ and PHT. These results suggested that blockade of high percentage of the population of voltage-dependent sodium channels by CBZ and PHT might be important in inducing paradoxical intoxication/reaction, and that inhibition of carbonic anhydrase inhibits this effect. TPM and ZNS are candidate first-choice agents in treatment of epilepsy when first-line AEDs are ineffective.