Lorraine Mackenzie

Cognitive tasks augment gamma EEG power

OBJECTIVE Gamma EEG oscillations are low amplitude rhythms in the 30-100 Hz range that correlate with cognitive task execution. They are usually reported using time-locked averaging of EEG during repetitive tasks. We tested the hypothesis that continuous gamma EEG would be measurable during mental tasks. METHODS We investigated sustained human gamma EEG oscillations induced by 8 cognitive tasks (Visual Checkerboard, Expectancy, Reading, Subtraction, Music, Expectancy, Word learning, Word recall, and a Video Segment) in 20 subjects using standard digital EEG recording and power spectral analysis. RESULTS All of the cognitive tasks augmented gamma power relative to a control condition (eyes open watching a blank computer screen). This enhancement was statistically significant at more than one scalp site for all tasks except checkerboard. The Expectancy, Learning, Reading and Subtraction tasks expressed the most impressive gamma response, up to 5 fold above the control condition and there was some task-related specificity of the distribution of increased gamma power, especially in posterior cortex with visual tasks. CONCLUSIONS Widespread gamma activation of cortical EEG can easily be demonstrated during mental activity. SIGNIFICANCE These results establish the feasibility of measuring high frequency EEG rhythms with trans-cranial recordings, demonstrate that sustained gamma EEG activity correlates with mentation, and provides evidence consistent with the temporal binding model.

Kainic acid induces distinct types of epileptiform discharge with differential involvement of hippocampus and neocortex.

Systemic administration of kainic acid (KA), an excitatory amino acid agonist, provides a model of epilepsy due to increased neural excitation. We examined discharges using multi-channel EEG recording and spectral analysis in rats implanted with neocortical and hippocampal electrodes after intravenous infusion of KA (10 mg/kg), until and including the first convulsive seizure. Gamma activity (30-80 Hz) increased in hippocampus from 3-9 min after KA administration. Two types of preconvulsive bilateral rhythmic discharges were observed, both consisting of generalised high voltage sharp waves at low frequencies (<10 Hz) mixed with fast oscillations (<20 Hz): (1) generalised non-convulsive discharges (GNCD) occurred in all animals and (2) spike-wave discharges (SW), predominantly localised in neocortex, occurred in 45% of animals. Convulsive seizure evolved out of a GNCD. Spectral profiles of epileptiform discharges were characterised by an increase in power of low (<10 Hz) and high (beta and gamma range, 20-80 Hz) frequencies which were differently expressed in neocortex and hippocampus. Thus, in this model of convulsive epilepsy caused by increased excitation, there is an early increase in gamma activity, a process that might contribute to synchronisation, and two distinct types of bilateral discharges, hippocampal-neocortical (GNCD) and preferentially neocortical (SW). Neocortical, not hippocampal, changes in EEG power correlated with development of convulsive behaviours.

Fos Induction Following Systemic Kainic Acid: Early Expression in Hippocampus and Later Widespread Expression Correlated With Seizure

We determined the distribution of Fos protein expression in a model of generalised epilepsy caused by excessive neuronal excitation. Fos immunoreactivity was mapped in forebrain in unrestrained rats, previously prepared with an indwelling venous catheter, after the intravenous administration of kainic acid (10 mg/kg). We determined cerebral activation following various periods of exposure to kainic acid by using intravenous administration of pentobarbitone to prevent further activation. Within a few minutes, kainic acid caused episodes of staring, sniffing, wet dog shakes, nodding and chewing. Fos induction occurred initially and simultaneously in hippocampus, subiculum, septum and entorhinal cortex as early as 9.5 min after kainate injection. After up to 40 min of staring, sniffing, wet dog shakes, nodding and chewing, Fos induction was not further increased above levels present within the first 9.5 min. After 56 +/- 6 min a motor convulsion occurred, initially affecting the jaw, head and tail and variably extending to the forelimbs, trunk or hindlimbs. Following the convulsive event, additional Fos was expressed in hippocampus, thalamus, caudate-putamen and other subcortical structures and in the cerebral cortex. Fos induction was sometimes asymmetric in entorhinal, visual, piriform, cingulum, parietal and frontal cortices and in amygdala and dorsal endopiriform area. Electroencephalographic recordings after a few minutes exposure to kainic acid revealed an increased amplitude of fast frequencies in hippocampus which appeared to correlate with Fos induction in this structure. The findings are generally consistent with the reported distribution and slow development of kainic acid-induced seizure activity using electrophysiological and deoxyglucose methods. However, the Fos distribution suggests that (i) hippocampal, possibly dentate, activation precedes significant activation elsewhere, (ii) extensive involvement of other cerebral structures and cerebral cortex occurs simultaneously and correlates with motor seizures and (iii) brain structures can be recruited asymmetrically.

Persistent abnormality detected in the non-ictal electroencephalogram in primary generalised epilepsy.

Objectives: Gamma oscillations (30–100 Hz gamma electroencephalographic (EEG) activity) correlate with high frequency synchronous rhythmic bursting in assemblies of cerebral neurons participating in aspects of consciousness. Previous studies in a kainic acid animal model of epilepsy revealed increased intensity of gamma rhythms in background EEG preceding epileptiform discharges, leading the authors to test for intensified gamma EEG in humans with epilepsy. Methods: 64 channel cortical EEG were recorded from 10 people with primary generalised epilepsy, 11 with partial epilepsy, and 20 controls during a quiescent mental state. Using standard methods of EEG analysis the strength of EEG rhythms (fast Fourier transformation) was quantified and the strengths of rhythms in the patient groups compared with with controls by unpaired t test at 1 Hz intervals from 1 Hz to 100 Hz. Results: In patients with generalised epilepsy, there was a threefold to sevenfold increase in power of gamma EEG between 30 Hz and 100 Hz (p<0.01). Analysis of three unmedicated patients with primary generalised epilepsies revealed an additional 10-fold narrow band increase of power around 35 Hz–40 Hz (p<0.0001). There were no corresponding changes in patients with partial epilepsy. Conclusions: Increased gamma EEG is probably a marker of the underlying ion channel or neurotransmitter receptor dysfunction in primary generalised epilepsies and may also be a pathophysiological prerequisite for the development of seizures. The finding provides a new diagnostic approach and also links the pathophysiology of generalised epilepsies to emerging concepts of neuronal correlates of consciousness.

Distribution of Fos-positive neurons in cortical and subcortical structures after picrotoxin-induced convulsions varies with seizure type

The distribution of Fos protein was mapped in rat brain following a single non-focal convulsive seizure. Single seizures were induced with intravenous picrotoxin in unhandled animals housed in isolation. Different convulsive behaviours occurred unpredictably. The least severe seizures were predominantly localised to the face, head and forelimbs, without loss of posture control (restricted seizures). The most extensive seizures affected all limbs and trunk, sometimes with falling (generalised seizures). There was a correlation between seizure behaviour and distribution of Fos induction. After restricted seizures, Fos was induced at highest levels in neocortex and piriform cortex and was prominent in entorhinal cortex, caudal-ventral caudate-putamen and amygdala. Regions of thalamus were consistently and lightly labelled, but Fos induction did not occur in hippocampus. After generalised seizures, there was Fos induction in cortex but less than after restricted seizures and, in three of four animals, also in dentate gyrus, hippocampus and subiculum. There was occasional or variable labelling of thalamus, basolateral amygdala and caudate-putamen. One animal with generalised seizures showed no hippocampal Fos induction. The findings indicate that picrotoxin induces seizures with at least two different patterns of neuronal involvement. The cortex, part of the caudate-putamen, amygdala and thalamus are involved in restricted seizures while the hippocampus, cortex and thalamus are involved in generalised seizures. The results do not support the view that generalised seizures are a progression from restricted forms. Cortical Fos involvement is entirely consistent with the participation of cortex in non-focal epilepsy. In these non-focal seizures, the dentate-hippocampus may be a source of excitation to cortex in the generalised group while the cortex appears to be the predominant site of excitation in the restricted group.

Fluorocitrate‐mediated astroglial dysfunction causes seizures

A role for astroglia in epileptogenesis has been hypothesised but is not established. Low doses of fluorocitrate specifically and reversibly disrupt astroglial metabolism by blocking aconitase, an enzyme integral to the tricarboxylic acid cycle. We used cerebral cortex injections of fluorocitrate, at a dose that we demonstrated to inhibit astroglial metabolism selectively, to determine whether astroglial disturbances lead to seizures. Rats were halothane‐anesthetized, and 0.8 nmol of sodium fluorocitrate was injected into the cerebral cortex. Extradural electroencephalogram (EEG) electrodes were implanted, after which the anesthesia was ceased and the animals were observed. In all experiments, 14 of 15 fluorocitrate‐treated animals exhibited epileptiform EEG discharges, with some animals exhibiting convulsive seizures. Discharges commenced as early as 30 min postfluorocitrate injection. Intraperitoneal octanol, but not halothane by inhalation, given to test the possible participation of gap junctions in EEG discharge generation, blocked or delayed the occurrence of discharges after fluorocitrate. These results indicate that focal cerebrocortical astroglial dysfunction leads to focal epileptiform discharges and sometimes to convulsive seizures and that the process possibly depends on effects mediated by gap junctions.

Cell swelling, seizures and spreading depression: An impedance study

The cellular processes that take place during the transition from pre-seizure state to seizure remain to be defined. In this study in awake, paralyzed rats, we used an electrical impedance measure of changes in extra-cellular intracranial volume to estimate changes in cell size in acute models of epilepsy. Animals were prepared with extradural electroencephalographic (EEG)/impedance electrodes and a venous catheter. On a subsequent day, animals were paralyzed, ventilated and treated with picrotoxin, kainic acid or fluorocitrate in doses that usually induce epileptiform discharges. We now report that increases in baseline impedance were induced by kainic acid and smaller increases by picrotoxin. We also demonstrated that epileptiform discharges were preceded by small, accelerated increases in impedance. Increases in baseline impedance were highly correlated with increases in power of non-ictal high frequency EEG activity. Seizures were accompanied by increases in impedance and all treatments induced transient, relatively large, increases in impedance often associated with unilateral reductions in low frequency EEG, likely periods of spreading depression. We conclude: cerebral cells swell in convulsant models of epilepsy, that there are pre-ictal accelerations in cell swelling, and that spreading depression-like events are frequently associated with seizures.

Picrotoxin-induced generalised convulsive seizure in rat: changes in regional distribution and frequency of the power of electroencephalogram rhythms.

OBJECTIVES It is unknown how generalised discharges in primary generalised epilepsy (PGE) develop from background brain electrical activity or how widespread these discharged are throughout the brain. Here we address this by determining which neural structures and rhythms lead to and participate in generalised discharges in the picrotoxin rat model of PGE. METHODS Rats with chronically implanted electrodes were infused with picrotoxin until a seizure occurred. This process we refer to as acute epileptogenesis. The electroencephalogram (EEG) was recorded and spectral analysis applied off-line to determine changes in the spectral power of contributing frequencies in 13 brain regions. RESULTS Two types of generalised discharge occurred, spindles and seizure, which were present in all brain regions studied. None of the frequencies (1-100 Hz) were significantly increased in background EEG before either spindles or seizure. Within the generalised discharges, power changes revealed significant increases in 6-8 Hz, most powerful in ventrolateral thalamus and neocortex. Gamma frequencies were increased significantly in neocortical structures during spindles with further increases in most structures at seizure onset. 1 Hz was significantly increased in parietal cortex during spindles with differential increases at seizure onset. CONCLUSIONS We conclude that gamma, 1 and 6-8 Hz frequencies do not appear to contribute to picrotoxin epileptogenesis but do play a role in generalised seizures. The distribution of these frequencies during discharges suggests that the spindles are thalamocortical events and that the seizure is a cortical event with downstream effects on other brain regions.

Physiological and pathological spindling phenomena have similar regional EEG power distributions

Sleep spindles in human and in rat are known to have a thalamocortical substrate. It has also been suggested that absence epilepsy spike and wave discharges may be generated by a similar mechanism. In addition, we have previously reported a possible thalamocortical origin of the EEG spindling rhythmic discharges associated with myoclonic jerks in the picrotoxin rat model of primary generalised epilepsy. To investigate whether pathological and physiological brain rhythms have common mechanisms of generation, we analysed four electroencephalographic (EEG) spindling activities in the rat. These were the non-convulsive spindle discharges induced by picrotoxin (picrotoxin spindles), naturally occurring absence epilepsy spike and wave discharges (absence spindles), spindle discharges during natural sleep (sleep spindles) and spindling activity that occurs under barbiturate anaesthesia (barbiturate spindles). We used power spectral analysis to define and compare the strength and brain distribution of EEG power during the spindling activities in 12 forebrain and 7 brainstem regions. There were brain-wide differences in power for each of the different spindle types with the pathological rhythms of the epilepsies containing more power than the physiological rhythms. There were also similar differences in the expression of spindles related to the region examined and no thalamic emphasis. These results provide evidence for a similar regional EEG power distribution for all four types of spindling activity and thus for the different spindles being expressions of a single phenomenon.

Fos induction in subtypes of cerebrocortical neurons following single picrotoxin-induced seizures.

In adult rats single seizures of varying behavioural severities were caused by slow, systemic infusion of picrotoxin, an antagonist of the C1- channel at the GABAA receptor. We used a double labelling immunohistochemical method to define the subclasses of neurons that contained Fos protein following seizures. In four cortical regions (piriform, entorhinal, motor and sensory) neuronal subclasses were defined with antibodies against the calcium-binding proteins D-28K, parvalbumin and calretinin (aspiny neurons), and neurofilament protein (spiny neurons). The remaining spiny neuron population was estimated by subtraction of defined subclasses from total neuronal numbers determined from Nissl stain. After seizures, most of the calbindin D-28K immunoreactive interneurons (> 80%) and many of the unlabelled spiny neurons (60-80%) were FOs positive. Co-localisation of Fos was found in about 30% of parvalbumin, calretinin and neurofilament protein immunoreactive neurons. Paradoxically, mild seizures were associated with induction of Fos in up to 80% of cortical cells and more severe seizures with 60%, the difference being due to different levels of Fos induction in spiny neurons. These results also demonstrate that seizures induce Fos predominantly in excitatory cortical neurons.