Spectral Modification by Operant Conditioning of Cortical Theta Suppression in Rats

OBJECTIVE: Brain activity is known to be voluntarily controllable by neurofeedback, a kind of electroencephalographic (EEG) operant conditioning. Although its efficacy in clinical effects has been reported, it is yet to be uncovered whether or how a specific band activity is controllable. Here, we examined EEG spectral profiles along with conditioning training of a specific brain activity, theta band (4–8 Hz) amplitude, in rats. METHODS: During training, the experimental group received electrical stimulation to the medial forebrain bundle contingent to suppression of theta activity, while the control group received stimulation non-contingent to its own band activity. RESULTS: In the experimental group, theta activity gradually decreased within the training session, while there was an increase of theta activity in the control group. There was a significant difference in theta activity during the sessions between the two groups. The spectral theta peak, originally located at 7 Hz, shifted further towards higher frequencies in the experimental group. CONCLUSION: Our results showed that an operant conditioning technique could train rats to control their specific EEG activity indirectly, and it may be used as an animal model for studying how neuronal systems work in human neurofeedback.

Effect of carbamazepine on tetrodotoxin-resistant Na⁺ channels in trigeminal ganglion neurons innervating to the dura

Migraine is a neurological disorder characterized by recurrent and disabling severe headaches. Although several anticonvulsant drugs that block voltage-dependent Na⁺ channels are widely used for migraine, far less is known about the therapeutic actions of carbamazepine on migraine. In the present study, therefore, we characterized the effects of carbamazepine on tetrodotoxin-resistant (TTX-R) Na⁺ channels in acutely isolated rat dural afferent neurons, which were identified by the fluorescent dye DiI. The TTX-R Na⁺ currents were measured in medium-sized DiIpositive neurons using the whole-cell patch clamp technique in the voltage-clamp mode. While carbamazepine had little effect on the peak amplitude of transient Na⁺ currents, it strongly inhibited steady-state currents of transient as well as persistent Na⁺ currents in a concentration-dependent manner. Carbamazepine had only minor effects on the voltage-activation relationship, the voltage-inactivation relationship, and the use-dependent inhibition of TTX-R Na⁺ channels. However, carbamazepine changed the inactivation kinetics of TTX-R Na⁺ channels, significantly accelerating the development of inactivation and delaying the recovery from inactivation. In the current-clamp mode, carbamazepine decreased the number of action potentials without changing the action potential threshold. Given that the sensitization of dural afferent neurons by inflammatory mediators triggers acute migraine headaches and that inflammatory mediators potentiate TTX-R Na⁺ currents, the present results suggest that carbamazepine may be useful for the treatment of migraine headaches.

Push-in Head Restraining Apparatus for Intracranial Self Stimulation Tasks in Rats

Head restraining is an experimental technique that firmly secures the animal's head to a fixation apparatus for the precise control and sensing of behaviors. However, procedural and surgical difficulties and limitations have been obstructing the use of the technique in neurophysiological and behavioral experiments. Here, we propose a novel design of the head-restraining apparatus which is easy to develop and convenient for practical use. Head restraining procedure can be completed by sliding the head mounter, which is molded by dental cement during implantation surgery, into the port, which serves as matching guide rails for the mounter, of the fixation bar. So neither skull-attached plates nor screws for fixation are needed. We performed intracranial self stimulation experiment in rats using the newly designed device. Rats were habituated to acclimatize the head-restraint environment and trained to discriminate two spatially distinguished cues using a customized push-pull lever as an operandum. Direct electrical stimulation into the medial forebrain bundle served as reward. We confirmed that head restraining was stable throughout experiments and rats were able to learn to manipulate the lever after successful habituation. Our experimental framework might help precise control or sensing of behavior under head fixed rats using direct electrical brain stimulation as a reward.

Effects of Single Treatment of Anti-Dementia Drugs on Sleep-Wake Patterns in Rats

We studied the effects of acetylcholinesterase inhibitors, donepezil and galantamine, and an N-methyl-D-aspartate (NMDA) receptor blocker, memantine, on sleep-wake architecture in rats. Screw electrodes were chronically implanted into the frontal and parietal cortex for the electroencephalography (EEG). EEG was recorded with a bio-potential amplifier for 8 h from 09:30 to 17:30. Vibration was recorded to monitor animal activity with a vibration measuring device. Sleep-wake states such as wake (W), slow-wave sleep (S) and paradoxical or rapid eye movement sleep (P), were scored every 10 sec by an experimenter. We measured mean episode duration and number of episode to determine which factor sleep disturbance was attributed to. Donepezil and memantine showed a significant increase in total W duration and decreases in total S and P duration and delta activity. Memantine showed increases in sleep latency and motor activity. Changes of S and P duration in memantine were attributed from changes of mean episode duration. Galantamine had little effect on sleep architecture. From these results, it is showed that galantamine may be an anti-dementia drug that does not cause sleep disturbances and memantine may be a drug that causes severe sleep disturbance.

Differences between Physostigmine- and Yohimbine-induced States Are Visualized in Canonical Space Constructed from EEG during Natural Sleep-wake Cycle in Rats

Although quantitative EEG parameters, such as spectral band powers, are sensitive to centrally acting drugs in dose- and time-related manners, changes of the EEG parameters are redundant. It is desirable to reduce multiple EEG parameters to a few components that can be manageable in a real space as well as be considered as parameters representing drug effects. We calculated factor loadings from normalized values of eight relative band powers (powers of 0.5, 1.0~2.0, 2.5~4.0, 4.5~5.5, 6.0~8.0, 8.5~12.0, 12.5~24.5, and 25~49.5 Hz bands expressed as ratios of the power of 0.5-49.5 Hz band) of EEG during pre-drug periods (11:00~12:00) by factor analysis and constructed a two-dimensional canonical space (reference canonical space) by canonical correlation analysis. Eight relative band powers of EEG produced by either physostigmine or yohimbine were reduced to two canonical scores in the reference canonical space. While changes of the band powers produced by physostigmine and yohimbine were too redundant to describe the difference between two drugs, locations of two drugs in the reference canonical space represented the difference between two drug's effects on EEG. Because the distance between two locations in the canonical space (Mahalanobis distance) indicates the magnitude of difference between two different sets of EEG parameters statistically, the canonical scores and the distance may be used to quantitatively and qualitatively describe the dose-dependent and time-dependent effects and also tell similarity and dissimilarity among effects. Then, the combination of power spectral analysis and statistical analysis may help to classify actions of centrally acting drugs.

The Effects of Tramadol on Electroencephalographic Spectral Parameters and Analgesia in Rats

The effects of different doses of tramadol on analgesia and electroencephalographic (EEG) spectral parameters were compared in rats. Saline or tramadol 5, 10, 20 or 40 mg/kg was administered. The degree of analgesia was evaluated by tail-flick latency, and the degree of seizure was measured using numerical seizure score (NSS). Additionally, band powers, median power frequency and spectral edge frequency 95 were measured to quantify the EEG response. All doses of tramadol produced spike-wave discharge. Tramadol significantly and dose-dependently increased the analgesia, but these effects did not correspond with the changes in the EEG spectral parameters. NSS significantly increased in the Tramadol 20 and 40 mg/kg treatment groups compared to the Control and TRA5 groups, and two rats given 40 mg/kg had convulsions. In conclusion, tramadol dose-dependently increased the analgesic effect, and the 10 mg/kg dose appears to be a reliable clinical dose for analgesia in rats, but dose-dependent increases in analgesia and seizure severity did not correlate with EEG spectral parameters.

Effects of Isoflurane Anesthesia on Post-Anesthetic Sleep-Wake Architectures in Rats

The sleep homeostatic response significantly affects the state of anesthesia. In addition, sleep recovery may occur during anesthesia, either via a natural sleep-like process to occur or via a direct restorative effect. Little is known about the effects of isoflurane anesthesia on sleep homeostasis. We investigated whether 1) isoflurane anesthesia could provide a sleep-like process, and 2) the depth of anesthesia could differently affect the post-anesthesia sleep response. Nine rats were treated for 2 hours with ad libitum sleep (Control), sleep deprivation (SD), and isoflurane anesthesia with delta-wave-predominant state (ISO-1) or burst suppression pattern-predominant state (ISO-2) with at least a 1-week interval. Electroencephalogram and electromyogram were recorded and sleep-wake architecture was evaluated for 4 hours after each treatment. In the post-treatment period, the duration of transition to slow-wave-sleep decreased but slow wave sleep (SWS) increased in the SD group, but no sleep stages were significantly changed in ISO-1 and ISO-2 groups compared to Control. Different levels of anesthesia did not significantly affect the post-anesthesia sleep responses, but the deep level of anesthesia significantly delayed the latency to sleep compared to Control. The present results indicate that a natural sleep-like process likely occurs during isoflurane anesthesia and that the post-anesthesia sleep response occurs irrespective to the level of anesthesia.

Role of Dopamine Receptors on Electroencephalographic Changes Produced by Repetitive Apomorphine Treatments in Rats

Repeated psychostimulants induce electroencephalographic (EEG) changes, which reflect adaptation of the neural substrate related to dopaminergic pathways. To study the role of dopamine receptors in EEG changes, we examined the effect of apomorphine, the dopamine D1 receptor antagonist, SCH-23390, and the D2 receptor antagonist, haloperidol, on EEG in rats. For single and repeated apomorphine treatment groups, the rats received saline or apomorphine for 4 days followed by a 3-day withdrawal period and then apomorphine (2.5 mg/kg, i.p.) challenge after pretreatment with saline, SCH-23390, or haloperidol on the day of the experiment. EEGs from the frontal and parietal cortices were recorded. On the frontal cortex, apomorphine decreased the power of all the frequency bands in the single treatment group, and increased the theta (4.5~8 Hz) and alpha (8~13 Hz) powers in the repeated treatment group. Changes in both groups were reversed to the control values by SCH-23390. On the parietal cortex, single apomorphine treatment decreased the power of some frequency bands, which were reversed by haloperidol but not by SCH-23390. Repeated apomorphine treatment did not produce significant changes in the power profile. These results show that adaptation of dopamine pathways by repeated apomorphine treatment could be identified with EEG changes such as increases in theta and alpha power of the frontal cortex, and this adaptation may occur through changes in the D1 receptor and/or the D2 receptor.

Effect of Modafinil and Methylphenidate on Sleep-Wake Architecture and EEG Power Spectra in Rats / 대한정신약물학회지

OBJECTIVE : Modafinil, methylphenidate, and caffeine are wakefulness-promoting substances. Previously, it was reported that caffeine-induced wakefulness differs from natural wakefulness in terms of the EEG spectral profiles. In order to evaluate whether wakefulness induced by other psychostimulants differs from both caffeine-induced and natural wakefulness, we examined the effects of the psychostimulants on sleep-wake architecture and EEG spectral profiles. METHODS : Eighteen Sprague-Dawley male rats underwent an EEG/EMG recording session from 10 : 30 to 17 : 30. They received caffeine (7.5, 15, 30 mg/kg i.p.), methylphenidate (1, 2, 5, 10 mg/kg i.p.) or modafinil (5, 10, 25, 50, 100 mg/kg i.p.) at 13 : 30. The number, total duration, and average duration of sleepwake states were obtained. EEG band powers were calculated by spectral analysis. Frequency bands were divided into the following ranges : D1, 1-2.5 Hz ; D2, 2.5-4.5 Hz ; T1, 4.5-7 Hz ; T2, 7-10 Hz ; SI, 10-14 Hz ; B1, 14-22 Hz ; B2, 22-34 Hz ; GA, 34-50 Hz. RESULTS : All three psychostimulants significantly and dose-dependently increased active wake duration and decreased slow-wave sleep. Equipotent doses of caffeine, methylphenidate, and modafinil for increasing active wake and decreasing slow-wave sleep were 7.5 mg/kg, 10 mg/kg, and 100 mg/kg, respectively. In equipotent doses, an increase of active wake duration by caffeine and methylphenidate was attributed to increases of both frequency and average duration of active wake state, whereas increase of active wake duration by modafinil was attributed to increase of average duration of active wake state only. In equipotent doses, caffeine and methylphenidate decreased the power of lower frequency bands (1-22 Hz), whereas modafinil did not. During slow-wave sleep, modafinil and methylphenidate increased the power of lower frequency bands, but caffeine did not. All the psychostimulants increased the power of the GA band, which was more prominent in the frontal cortex than the parietal cortex. CONCLUSION : These results suggest that moda-nil-induced wakefulness differs from caffeine- or methylphenidate-induced wakefulness in terms of EEG spectral profiles and sleep-wake architecture.

Changes of CA1 Excitability in Rats after Prenatal Methylazoxymethanol Treatment

Experimentally induced cortical disorganization exhibits many anatomical features which are characteristic of cortical malformations in children with early-onset epilepsy. We used an immunocytochemical technique and extracellular field potential recordings from the dorsal hippocampus to determine whether the excitability of the CA1 pyramidal cells was enhanced in rats with experimentally induced hippocampal dysplasia. Compared with control rats, the MAM-treated rats displayed a decrease of paired pulse inhibition. When GABAA receptor antagonists were blocked with 10microM bicuculline, the amplitude of the second population spike of the MAM-treated of rats was similar to that of the first population spike, as was in the control rats. The MAM-treated rats had fewer somatostatin and parvalbumin-immunoreactive neurons than the control rats. These results suggest that the enhanced neuronal responsiveness of the in vivo recording of the CA1 in this animal model may involve a reduction of CA1 inhibition.

Effects of Ethosuximide on the Pilocarpine Induced Seizure in Rat Model of Neuronal Migration Disorder

Cortical malformation-associated epileptic seizures are resistant to conventional anticonvulsant drugs. Relatively little research has been conducted on the effects of antiepileptic drugs (AEDs) on seizure activity in a rat model of dysplasia. We have used rats exposed to methylazoxymethanol acetate (MAM) in utero, an animal model featuring nodular heterotopia, to investigate the effects of ethosuximide (ETX) in the dysplastic brain. Pilocarpine was used to induce acute seizure in MAM-exposed and age-matched vehicle-injected control animals. Field potential recordings were used to monitor the amplitude and number of population spikes, and paired pulse inhibition in response to stimulation of the commissural pathway. Pharmaco-resistance was tested by measuring seizure latencies after pilocarpine administration (320 mg/kg, i.p.) with and without pre-treatment with ETX. Pre-treatment with 300 mg of ETX significantly prolonged the latency to the status epilepticus (SE) in both control and MAM-treated groups. Pre-treatment with ETX 100mg and ETX 200 mg had little effect in MAM-exposed rats. However, ETX 200 mg prolonged the latency to the SE in control groups. Spontaneous field potential and secondary after-discharges were higher for MAM-treated rat in comparison with control rats injects with ETX. The main findings of this study are that acute seizures initiated in MAM-exposed rats are relatively resistant to standard ETX assessed in vivo. These data suggest that ETX do not prolong seizure latencies in MAM-rats exposed to pilocarpine.

Differential Effects of Typical and Atypical Antipsychotics on MK- 801-induced EEG Changes in Rats

We examined whether the abnormal EEG state by NMDA receptor blocker MK-801 can be reversed by typical and atypical antipsychotics differentially by comparing their spectral profiles after drug treatment in rats. The spectral profiles produced by typical antipsychotics chlorpromazine (5 mg/kg, i.p.) and haloperidol (0.5 mg/kg, i.p.) were differ from that by atypical antipsychotic clozapine (5 mg/kg, i.p.) in the rats treated with or without MK-801 treatment (0.2 mg/kg, i.p.) which produce behavioral abnormalities like hyperlocomotion and stereotypy. The dissimilarity between the states produced by antipsychotics and the control state was examined with the distance of the location of the canonical variables calculated by stepwise discriminant analysis with the relative band powers as input variables. Although clozapine produced more different state from normal state than typical antipsychotics, clozapine could reverse the abnormal schizophrenic state induced by MK-801 to the state closer to the normal state than the typical antipsychotics. The results suggest that atypical anesthetic can reverse the abnormal schizophrenic state with negative symptom to the normal state better than typical antipsychotic. The results indicate that the multivariate discriminant analysis using the spectral parameters can help differentiate the antipsychotics with different actions.

Interhemispheric Modulation on Afferent Sensory Transmission to the Ventral Posterior Medial Thalamus by Contralateral Primary Somatosensory Cortex

Single unit responses of the ventral posterior medial (VPM) thalamic neurons to stimulation were monitored in anesthetized rats during activation of contralateral primary somatosensory (SI) cortex by GABA antagonist. The temporal changes of afferent sensory transmission were quantitatively analyzed by poststimulus time histogram (PSTH). Mainly, afferent sensory transmission to VPM thalamus was facilitated (15 neurons of total 23) by GABA antagonist (bicuculline) applied to contralateral cortex, while 7 neurons were suppressed. However, when ipsilateral cortex was inactivated by GABA agonist, musimol, there was significant suppression of afferent sensory transmission of VPM thalamus. This suppressed responsiveness by ipsilateral musimol was not affected by bicuculline applied to contralateral cortex. These results suggest that afferent transmission to VPM thalamus may be subjected to the interhemispheric modulation via ipsilateral cortex during inactivation of GABAergic neurons in contralateral SI cortex.

Electroencephalographic effects of chlorpromazine in rats

The effects of an antipsychotic, chlorpromazine, on the electroencephalogram (EEG) were observed while rats were awake but immobile. The time course and the dose-dependency of the EEG changes were examined. The method of the power spectrum analysis was used to examine the EEG changes by the drug. The bands were divided into delta (1 ~ 3.5 Hz), theta (3.5 ~ 8 Hz), alpha (8 ~ 13 Hz), beta1 (13 ~ 21 Hz), beta2 (21 ~ 30 Hz) and gamma (30 ~ 50 Hz). In rats, the low dose of chlropromazine (1 mg/kg, i.p.) produced a significant increase in the power of the beta1 band. The higher doses (5, 10 mg/kg, i.p.) produced a significant increase in the power of the delta, theta, alpha and beta1 bands, and the decrease in the power of the gamma band. The powers of the bands changed dose-dependently. Then, the authors discussed whether the EEG effects produced by a drug are associated with the accompanying behavioral changes specifically.

Electroencephalographic correlation dimension changes with depth of halothane

This study was designed to evaluate the efficacy of dynamic parameters, such as correlation dimension D2, by comparing spectral electroencephalographic (EEG) parameters. These parameters are used to estimate the depth of halothane anesthesia as defined by the presence of body movement in response to a tail clamp. Six rats were used and each of them was exposed to halothane sequentially at the concentrations of 0%, 0.5%, 1.0% and 1.5% for 30 min. A tail clamp was applied every five min and the movements were recorded at each concentration level. The spectral parameters and the dynamic parameters were derived from 20-sec and 10-sec segments, respectively, from the last 5-mins of EEG recording at each concentration level. Correlation coefficients between the parameters and the movements were calculated. Standardized values of three parameters, betaL power, median power frequency (MPF), and D2 were derived by calculation based on the number of animals showing the movement in response to a tail clamp. The betaL power had the largest correlation coefficient to spontaneous movement and to the response to a tail clamp than any other band parameter. MPF had a better correlation with the movement than 90% spectral edge frequency. Among the dynamic parameters, D2 on the parietal cortex had a better correlation with the movement. The level of deviation and variation of standardized D2, MPF, and betaL were significant (p MPF > D2. The correlation dimension serves as a better index for the depth of halothane anesthesia defined in forms of a response to external stimulation.

Changes of Functional Connectivity of the Hippocampus in Ketamine-induced Schizophrenic Rat Model / 대한정신약물학회지

It has been proposed that the schizophrenic symptoms may be emerged from the dysfunctional connection and abnormal glutamate neurotransmission between prefrontal and temporolimbic cortex. Thus, we examined the functional connectivity between entorhinal cortex-hippocampus in the schizophrenic animal model induced by the NMDA receptor channel blocker, ketamine. Under ketamine+xylazine anesthesia, the electrodes for recording and stimulating were implanted into the hippocampus of the male rat. Recording of EEG and EP was started 3 or more days after operation in 3 different behavioral states (normal mobile and immobile, and ketamine-injected). Each hippocampal area had a characteristic EP. While it did not produce changes on the normal EPs, ketamine produced greater changes on the normal EEG : prominant theta in normal mobile state ; fast and irregular wave accompanying with 1-2 Hz spikes in normal immobile states and ; fAst and irregular rhythm with spindles of 2.5 Hz and 30 Hz which were prominant on DG and CA3 in ketamine-injected state. Log scale of spectrum showed that ketamine increased the power of 6-8 Hz band on CA1 radiatum and of the band over 25 Hz on DG. Also ketamine disrupted the correlated electrical activity among several hippocampal areas. These results may suggest that the symptom of schizophrenics is emerged from reduction of correlated activity but increase of irregular activity over the cortical area and uncontrolled input which is mediated by NMDA receptor.

Changes of renal peripheral benzodiazepine receptor in the stress/anxiety response

Peripheral benzodiazepine receptor(PBR) has been identified in various peripheral tissues including kidney. The physiological and pharmacological functions of PBR are still uncertain, although it has been suggested that these are associated with the regulation of stress/anxiety response. Diazepam progeny, which were exposed to diazepam perinatally, was reported to be an animal model of chronic anxiety. However, PBR in the diazepam progenies are not known yet. In the present study, therefore, we examined the changes of PBR in the stress/anxiety response. Dams of rats were given injection of diazepam or vehicle during puerperium. Diazepam progenies showed increased level of anxiety on the performance of elevated plus maze, and increased Bmax of PBR. Saturation experiments followed by scatchard analysis of the results showed that the increase in the density of PBR and the affinity of the PBR remained unchanged. Forced swim stress increased anxiety on the plus maze in both groups of rats. In contrast to control, diazepam progenies did not show further upregulation of renal PBR immediately after swimming stress, but still higher than control. From the above results, it may be concluded that upregulation of renal PBR is associated with chronic anxiety as well as stress-induced response.

Spectral Analysis of EEG during Inhalation of Halothane, Enflurane, and Isoflurane in the Rat / 대한마취과학회지

The dose-related effects of halothane, enflurane, and isoflurane on the rat EEG were evaluated qusntitstively by spectral analysis of the EEG recorded from the rat skull. The anesthetics were inhaled by animal ventilator into 10L glass bottle, in which the preparated rats were placed, at various concentrations, and then bipolar EEG was recorded from the rat skull and its spectrum was calculated by power speetral analysis. The density of each spectral bands (delta 1-3.25, theta 3.5-7.75, alpha 8-12.25, and beta 13-31.75Hz), total density, delta ratio, spectral edge frequency, and medisn power frequency were derived from the spectra. With inspection of conventional EEG, 1.5 MAC of hslothane revealed spindles, but higher dose decreased the amplitude. 1.5 MAC of enflurane revealed a lot of spike waves but 2.0 MAC revealed several spike waves and decreased the amplitude, and 1.5 MAC isoflurane revealed isolated spike waves but 2.0 MAC revealed cerebro- electrical silence. In quantitative spectral analysis of EEG, significant EEG changes were identified during inhalation of all anestheties. In halothane dominent frequencies in EEG were delta waves at 1.5 MAC and 2.0 MAC. In enflurane dominent waves in EEG were theta waves at 1.5 MAC and 2.0 MAC and in isoflurane those were theta waves. Taken together, these findings suggest that analysis for EEG parameters derived from power spectral analysis could be applied to determine the depth of halothane, enflurane, and isoflurane anesthesia.