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Changes in cortical excitability differentiate generalized and focal epilepsy.

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Changes in Cortical Excitability Differentiate
Generalized and Focal Epilepsy
Radwa A. B. Badawy, MBBCh, MSc,1,2 Josie M. Curatolo, MApplSci,1 Mark Newton, MD, FRACP,1,2
Samuel F. Berkovic, MD, FRACP,1,2 and Richard A. L. Macdonell, MD, FRACP1,2
Objective: Different pathophysiological mechanisms related to the balance of cortical excitatory and inhibitory influences may
underlie focal and generalized epilepsies. We used transcranial magnetic stimulation to search for interictal excitability differences
between patients with idiopathic generalized epilepsy (IGE) and focal epilepsy.
Methods: Sixty-two drug-naive patients with newly diagnosed epilepsy (35 IGE, 27 focal epilepsy) were studied. In the latter
group, the seizure focus was not located in the motor cortex. Motor threshold at rest, cortical silent period threshold, recovery
curve analysis using paired-pulse stimulation at a number of interstimulus intervals), and cortical silent period were determined.
Results were compared with those of 29 control subjects.
Results: Hyperexcitability was noted in the recovery curves at a number of interstimulus intervals in both hemispheres in
patients with IGE and in the hemisphere ipsilateral to the seizure focus in those with focal epilepsy compared with control
subjects and the contralateral hemisphere in focal epilepsy. Motor threshold and cortical silent period threshold were higher in
the ipsilateral hemisphere in focal epilepsy compared with the contralateral hemisphere. No other intragroup or intergroup
differences were found in the other measures.
Interpretation: The disturbance of cortical excitatory/inhibitory function was found to be bilateral in IGE, whereas in focal
epilepsy it spread beyond the epileptic focus but remained lateralized. This finding confirms that there are differences in cortical
pathophysiology comparing the two major types of epilepsy.
Ann Neurol 2007;61:324 –331
The epilepsies are a complex group of conditions characterized by episodic brain dysfunction with multifactorial causes reflecting acquired and genetic factors.
The epilepsy syndromes can be subdivided into focal
and generalized types depending on whether seizures
arise from a localized brain area or show widespread
involvement of both hemispheres from the outset. The
most common type of generalized epilepsy, idiopathic
generalized epilepsy (IGE) is, for the most part, considered to have a genetic basis. Focal epilepsies, in contrast, more often arise from an abnormal focal anatomic substrate such as hippocampal sclerosis or an
area of cortical dysgenesis.1 The causative factors and
the pathophysiological mechanisms underlying these
two major subdivisions may be quite different, yet they
are both characterized by recurrent unpredictable spontaneous seizures, which may be generated through
common cellular mechanisms and networks. Animal
studies using experimental models and postoperative
hippocampal slice preparations demonstrate that there
are disturbances in both excitatory and inhibitory in-
fluences. Two sets of changes determine the epileptogenic properties of neuronal tissues. The first is hyperexcitability of multiple neurons within a population
and the second is hypersynchrony.2 Studies have
shown that the excitation/inhibition disturbance not
only affects the seizure focus, but may also involve
more distant areas. These may include the motor cortex.3,4
Transcranial magnetic stimulation (TMS) is a safe
and painless tool by which the underlying pathophysiology of seizure disorders can be explored in vivo in
humans. TMS offers the opportunity to examine both
excitatory and inhibitory functions of central motor
pathways in both hemispheres separately, providing
noninvasive clinical measurements of neuronal excitability.5 Furthermore, because it is sensitive to relatively subtle alterations in the physiological state of the
brain, it may serve as a marker for the excitatory/inhibitory imbalance in cortical neurons of patients with
The results obtained from TMS studies in patients
From the 1Department of Neurology, Austin Health, Heidelberg;
and 2Epilepsy Research Centre, Department of Medicine, University of Melbourne, Heidelberg West, Victoria, Australia.
Address correspondence to Dr Macdonell, Deputy Director of Neurology, Department of Neurology, Austin Health, Studley Road,
Heidelberg, Victoria 3084, Australia.
Received Jul 13, 2007, and in revised form Dec 29. Accepted for
publication Jan 2, 2007.
Published online Mar 14, 2007, in Wiley InterScience
( DOI: 10.1002/ana.21087
© 2007 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
with epilepsy to date have been somewhat conflicting.
They have often been conducted in patients with
chronic epilepsy taking at least one antiepileptic drug
(AED). AEDs have been shown to affect various TMS
parameters used to assess cortical excitability, and accordingly, it is difficult to separate these from the exclusive effects of epilepsy.7 Only a limited number of
studies using small cohorts have been conducted in
AED-naive patients with varying results.8 –12 This
study was specifically designed to evaluate measures of
cortical excitability and inhibition in a large population
of AED-naive patients with new-onset epilepsy who
had either a definite diagnosis of IGE or a focal epilepsy that originated outside the motor cortex.
Subjects and Methods
Patients were recruited through the First Seizure Clinic at
Austin Health in Melbourne, Australia, an acute referral service for patients who present with new-onset seizures.
Thirty-five patients with IGE (18 female patients; mean age,
25 years; range, 14 –59 years) and 27 patients with focal epilepsy (16 female patients; mean age, 32 years; range, 14 –77
years) were included in this study. The diagnosis of epilepsy
and its subsyndrome was made by at least two experienced
epileptologists from the clinical history, imaging, and electroencephalographic (EEG) findings. Only patients with a
confirmed diagnosis of epileptic seizures and a normal neurological examination were included. None of the patients
had taken AEDs. A diagnosis of IGE required generalized
epileptiform abnormalities on EEG (n ⫽ 30) or, where EEG
studies were nondiagnostic (n ⫽ 5), a clear history of either
absence or myoclonic seizures in addition to generalized
tonic-clonic seizures. All IGE patients had suffered at least
one generalized tonic-clonic seizure. Eleven were diagnosed
with juvenile myoclonic epilepsy and two with juvenile absence epilepsy. In 22 patients, no IGE subsyndrome could be
For a diagnosis of focal epilepsy, it was required that the
seizure symptomatology or the EEG showed either a left- or
right-sided lateralization. Patients with bilateral foci or electroclinical features of localization to the motor strip were not
included. Twenty-four focal epilepsy patients had at least one
secondarily generalized seizure, whereas the remaining three
had complex partial seizures only. Based on the seizure semiology and EEG findings, 21 patients were diagnosed with
temporal lobe epilepsy, 3 with frontal lobe epilepsy, 1 with
parietal lobe epilepsy, and 2 with occipital lobe epilepsy. All
focal epilepsy patients underwent brain magnetic resonance
imaging, and hippocampal asymmetry was detected in two of
them. No abnormalities were found in the remaining patients. All patients had experienced a seizure between 2 and 4
weeks before the TMS examination.
The TMS results were compared with those of 29 healthy
control subjects (12 female subjects; mean age, 33 years;
range, 13–73 years) without a history of seizures or other
neurological conditions. The study protocol was approved by
the Austin Health Human Research Ethics Committee and
written informed consent was obtained from all subjects, in-
cluding parental consent from those subjects younger than
18 years.
Transcranial Magnetic Stimulation
TMS was delivered to both hemispheres in 32 of the 35 IGE
patients and in all 27 focal epilepsy patients. Only the dominant hemisphere was stimulated in the remaining three IGE
patients either because of patient fatigue because of the
length of time it took to complete the procedure (two patients) or because motor threshold in the untested hemisphere exceeded the maximum stimulus capacity of the machine (one patient). In control subjects, TMS was delivered
to both hemispheres in 12 of the 29 subjects, and to the
dominant motor cortex only in the remaining 17. Previous
studies and the findings obtained in our first 12 subjects
demonstrated no difference in excitability measures between
hemispheres in healthy subjects.13 During TMS, subjects sat
in a comfortable, reclining chair. Surface electromyographic
(EMG) recording was made from the abductor pollicis brevis
muscle. The stimulus was delivered to the contralateral cerebral hemisphere using the appropriate direction of coil current flow (anticlockwise for left cortical stimulation and
clockwise for right cortical stimulation), using a flat circular
9cm diameter magnetic coil (14cm external diameter) with
the center of the coil positioned over the vertex using a pair
of Magstim 200 magnetic stimulators (Magstim, Whitland,
Dyfed, United Kingdom). The coil was held in place by a
support stand, and its position was checked regularly
through each experiment. Intracortical excitability was studied by paired stimulation at various interstimulus intervals
(ISIs) using a Bistim module to connect two stimulators to
the coil. The experimental session lasted for 60 to 90 minutes and was conducted according to established protocols in
the literature.5
Several parameters were recorded. First, motor threshold
(MT) was recorded. MT was determined in all tested hemispheres while the subject was at rest, verified by continuous
visual and auditory EMG feedback. Stimulation commenced
at 30% of maximum output and increased in 5% increments
until the motor-evoked potential (MEP) was established.
One percent changes in intensity were then used to calculate
the threshold value. Motor threshold was defined as the lowest level of stimulus intensity that produced a MEP in the
target muscle of peak-to-peak amplitude greater than 100mV
on 50% or more of 10 trials.14 Second, cortical silent period
threshold (CSPT) was determined in 12 of the patients with
focal epilepsy, 20 of the patients with IGE, and 12 of the
control subjects while the subject was asked to perform a
maximal voluntary contraction of the abductor pollicis brevis
muscle against resistance. The subjects were instructed to
maintain a maximal contraction for 5 seconds (verified by
continuous visual and auditory EMG feedback) on each trial
while the stimulus was applied to the contralateral hemisphere. The CSPT was defined within 1% stimulus output
intensity as the minimum stimulus required to produce an
interruption of EMG response lasting 10 milliseconds or
longer in 50% of 10 trials. Third, for cortical recovery time
using paired-pulse stimulation, subjects were stimulated at rest
at an intensity 20% greater than MT using paired stimuli at
ISIs of 200, 250, 300, and 400 milliseconds. At ISIs of 1, 2,
Badawy et al: Cortical Excitability and Epilepsy
5, 10, and 15 milliseconds, the first stimulus was given at
80% of MT and the second stimulus 20% greater than MT.
Ten stimuli at 20% greater than MT without a preconditioning stimulus were also given. A minimum interval of 15
seconds was kept between the delivery of each pair of stimuli. Stimuli were given at randomly selected ISIs until a total
of 10 at each ISI was achieved. The recovery curve at longer
ISIs (200, 250, 300 milliseconds) was constructed for each
hemisphere using data from 32 patients with IGE, all patients with focal epilepsy, and 12 of the control subjects.
Only the dominant hemisphere was stimulated in the remaining 3 patients with IGE and 17 control subjects. The
400-millisecond ISI data were drawn from 20 patients with
IGE, 12 with focal epilepsy, and 12 control subjects. This
curve was derived using the ratio of the mean peak-to-peak
amplitudes of the response to the second stimulus termed the
test response (TR) and the first stimulus termed the conditioning response at each ISI measured as a percentage (TR/
conditioning response %).
In the case of the recovery curve at short ISIs (1, 2, 5, 10,
15 milliseconds), the ratio of the mean peak-to-peak amplitude of the response at each ISI after the conditioning stimulus given less than MT (TR) was expressed as the percentage of the mean MEP when the test stimulus was given alone
without a preconditioning stimulus (MEP) to generate recovery curves for each subject (TR/MEP%). This testing paradigm was conducted on both hemispheres of 13 patients
with IGE and 15 patients with focal epilepsy, and on the
dominant hemisphere of 2 patients with IGE and 17 control
subjects. Fourth, the duration of cortical silent period (CSP)
after TMS was measured in both hemispheres of 12 patients
with focal epilepsy, 19 patients with IGE, and 12 control
subjects, and on the dominant hemisphere of 1 patient with
IGE. Single stimuli were given at output stimulus intensities;
MT, 5 and 15% greater than MT. The stimuli were given at
randomly selected output intensities while the subject maintained a maximum voluntary contraction. The responses to
10 trials were recorded at each output level. The CSP was
measured from stimulus onset until the return of continuous
EMG activity after a period of EMG silence. The mean CSP
duration at each stimulus intensity was calculated in each
subject. Fifth, the duration of the peripheral silent period
(PSP) was measured on both sides in 20 patients with IGE,
12 patients with focal epilepsy, and 12 control subjects. The
median nerve at the wrist was stimulated using a bipolar
electrical bar stimulator. The stimulus intensity was increased
until maximal compound motor action potential amplitude
was obtained, when recording from the resting abductor pollicis brevis muscle via the existing metal disc electrodes. Ten
stimuli were given at this intensity while the patient maintained a maximum voluntary contraction on each occasion.
The mean period of EMG silence (in milliseconds) after
stimulation was evaluated using 10 stimuli on both sides.
Statistical Analysis
The results were always subdivided according to hemisphere
dominance, assessed by handedness according to the Edinburgh Handedness Inventory.15 The results in focal epilepsy
were also analyzed according to the ipsilateral (hemisphere
ipsilateral to the presumed seizure focus) and contralateral
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hemispheres. This was based on EEG findings, seizure semiology, or both.
We used repeated-measures analysis of variance to compare motor threshold and paired-pulse recovery curves within
and among the groups. Each analysis of variance had a
between-subjects factor “group” (control vs IGE or control
vs partial epilepsy) and a within-subject factor “hemisphere”
(interhemispheric comparison). Post hoc analysis with pairwise paired t test and Bonferroni correction was used to
compare all significant interactions (group*hemisphere). The
software used for statistical analysis was Analyse it (for Microsoft Excel) version 1.73 (Analyse it software, United
The effect size (d) between patients with epilepsy and control subjects was calculated for the significant results using
the following formula:
d ⫽ (mean of epilepsy group ⫺ mean of control group)⫼
Standard deviation of control group
Correction for bias was calculated using the following formula:
Unbiased estimate of d ⫽
calculated value of d ⫻ (1 ⫺ 3/{4(NE ⫹ NC)⫺9}
where NE ⫽ number of patients in the epilepsy group and
NC ⫽ number of control subjects.
The same formulas were used to calculate the effect size
between the two hemispheres in focal epilepsy where the
contralateral hemisphere was considered as the control variable. Effect size of 0.2 was considered small, 0.5 was considered medium, and ⱖ0.8 was considered large.16
Interside comparisons were first assessed according to
hemisphere dominance. There were no significant sideside differences in any of the groups (control subjects,
IGE patients, focal epilepsy patients) related to dominance. Interside differences in the focal epilepsy group
were found when the side of the seizure focus was
taken into account.
Motor and Cortical Silent Period Thresholds
MT and CSPT tended to be lowest in the contralateral
hemisphere of patients with focal epilepsy, but this did
not reach statistical significance compared with the results in control subjects or patients with IGE (Table
1). There was a significant interhemispheric difference
in these measures ( p ⬍ 0.05) only in the focal epilepsy
group. The ipsilateral hemisphere MT (effect size, 0.2)
and CSPT (effect size, 0.5) were increased compared
with the contralateral hemisphere.
Table 1. Motor and Cortical Silent Period Thresholds for Each Hemisphere in Each Group (Mean ⴞ Standard
(stimulus intensity %)
(stimulus intensity %)
Control (dominant hemisphere)
57.1 ⫾ 8.4
46.8 ⫾ 6.8
p ⫾ 0.23
Control (nondominant hemisphere)
56.4 ⫾ 11.6
45.3 ⫾ 9.4
IGE (dominant hemisphere)
55.7 ⫾ 10.0
45.8 ⫾ 8.8
IGE (nondominant hemisphere)
56.2 ⫾ 11.1
46.0 ⫾ 9.8
Focal epilepsy (ipsilateral hemisphere)
57.8 ⫾ 10.3
46.8 ⫾ 6.0
Focal epilepsy (contralateral hemisphere)
53.7 ⫾ 10.9
42.6 ⫾ 6.6
p ⫾ 0.12
p ⫾ 0.03
MT ⫽ motor threshold; CSPT ⫽ cortical silent period threshold; IGE ⫽ idiopathic generalized epilepsy.
Cortical Recovery Curves
The control group showed the expected results in both
the short and long ISI recovery curves, with inhibition
of the TR at ISIs of 1, 2, and 5 milliseconds, facilitation at of ISIs 10 and 15 milliseconds, and TRs approaching unity at the longer ISIs (Fig 1).
Comparison of the IGE group with the control subjects demonstrated an increase in cortical excitability at
an ISI of 2 milliseconds ( p ⬍ 0.01; effect size, 1.7) and
particularly at long ISIs (250 milliseconds; p ⬍ 0.01;
effect size, 2.6) (Fig 2). There was no interhemispheric
difference between the dominant and nondominant
hemispheres (see Fig 1).
In the focal epilepsy group, the ipsilateral hemisphere demonstrated an increase in cortical excitability
at both short (2 and 5 milliseconds; p ⬍ 0.01; effect
size, 0.5) and long ISIs (250 milliseconds; p ⬍ 0.01;
effect size, 0.8) compared with the contralateral hemisphere (see Fig 1). Compared with the control group
there were increases in excitability at ISIs of 250 milliseconds ( p ⬍ 0.01; effect size, 1.2) and 2 milliseconds ( p ⬍ 0.05, effect size, 0.8) in the ipsilateral hemisphere. There were no differences in the contralateral
hemisphere compared with control subjects (see Fig 2).
Comparison of the findings in the IGE group with
the ipsilateral hemisphere in the focal epilepsy group
showed a trend toward higher cortical excitability in
the IGE group; however, this failed to reach significance at any ISI (see Fig 2).
Cortical Silent Period
The mean CSP duration increased as expected with increasing stimulus intensity in both hemispheres in all
groups. There was no interhemispheric difference in
the mean CSP duration at any stimulus intensity in
any group. Although the IGE group tended to have the
longest CSP at each intensity, no significant differences
were seen (Table 2).
Peripheral Silent Period
There were no differences in PSP duration, either in
side-side comparisons or between groups.
We found that increased motor cortex excitability is a
feature of untreated epilepsy and its pattern is syndrome specific. The main finding, based on effect size,
was a net increase in cortical excitability using recovery
curve analysis in both hemispheres in patients with
IGE during focal epilepsy; this change was observed
only in the ipsilateral hemisphere containing the seizure focus. Because none of the focal epilepsy patients
included in our study had bilateral foci or an epileptic
focus in the primary motor area, this suggests that in
focal epilepsy there is a disturbance in extensive intracortical neural networks that extends beyond the focus
yet remains lateralized. Our data show no evidence of
involvement of contralateral motor cortex, but an effect
in contralateral cortex homologous to the seizure focus
is not directly testable by TMS.
No differences in MT or CSPT were found in subjects with IGE when compared with the other groups,
although both hemispheres in the IGE group trended
toward a lower MT. This finding is similar to previous
studies in patients with IGE,5 although there are reports of lower8 or higher9,17 MT compared with control subjects in other studies. This may be a methodological issue related to the timing of TMS studies
after seizures.
In the focal epilepsy group, MT and CSPT results
were more difficult to interpret. There was an interside
difference showing increased MT and CSPT in the ipsilateral compared with the contralateral hemisphere
(see Table 1). There were, however, no differences
compared with control subjects, probably because of
the large standard deviation of these measures. Thus,
the interside differences in the focal epilepsy group
could represent somewhat abnormally high values in
the ipsilateral hemisphere, or abnormally low values on
the contralateral side. The latter explanation is counterintuitive and difficult to support in the light of our
other TMS findings, but it cannot be discarded. We
favor the first explanation and, in the case of MT, one
previous study has also demonstrated an increase in the
Badawy et al: Cortical Excitability and Epilepsy
Fig 1. Short and long interstimulus interval (ISI) recovery curves for the dominant and nondominant hemisphere of the idiopathic
generalized epilepsy (IGE) patients (filled and open triangles, respectively) and control groups (filled and open circles, respectively)
and ipsilateral (filled squares) and contralateral (open squares) hemispheres of the focal epilepsy groups. Ratios less than 100%
indicate inhibition, and ratios greater than 100% indicate facilitation. TR/CR ⫽ test response/conditioning response; TR/MEP ⫽
test response/motor-evoked potential.
ipsilateral hemisphere18 whereas others have not shown
such a side-side difference.11,19 There are no previous
studies of CSPT in this patient population.
The paired-pulse recovery curve in IGE showing a
decrease in intracortical inhibition (ICI; ISIs 1–5 milliseconds) in both hemispheres of the IGE group is
similar to most previous results.20,21 Contradictory
findings have been reported in two studies. In one
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study, there was increased ICI in two patients with
IGE, but these patients were taking medication22; in a
group of unmedicated patients studied shortly after a
tonic-clonic seizure, no difference in ICI was shown
compared with control subjects.9 This was proposed to
be a protective mechanism against spread or recurrence
of seizures.
There was also increased cortical excitability at
Fig 2. Short and long interstimulus interval (ISI) recovery curves for the ipsilateral (squares) and contralateral (diamonds) hemispheres of the focal epilepsy group and the dominant hemisphere of the idiopathic generalized epilepsy (IGE; triangles) and control
groups (circles). Ratios less than 100% indicate inhibition, and ratios greater than 100% indicate facilitation. TR/CR ⫽ test response/conditioning response; TR/MEP ⫽ test response/motor-evoked potential.
longer ISIs, peaking at 250 milliseconds in both
hemispheres of the IGE group. This finding is identical to those of our previous study using a separate
group of untreated patients with IGE.12 It is of interest that the mean interspike interval of spike-wave
discharges on EEG in these patients occurs with a
similar timing.
There was a reduction of ICI at both short- and
long-latency ISIs in the patients with focal epilepsy in
the ipsilateral hemisphere, but not the contralateral
hemisphere. Similar results at short ISIs were reported
in one study performed on patients with untreated focal epilepsy,11 but conflicting results showing no
change in ICI have been reported10,19; this could be
due to the effects of AEDs or the heterogeneity of
those studies, most of which did not examine hemispheres with and without the seizure focus separately
and did not specify whether patients with foci in the
motor area were included in their cohort. These studies
may have also been confounded by using small numbers or limiting studies to special subgroups of patients,
factors that have been avoided in this study.
An interesting and previously unreported finding is
the facilitation of the TR at longer ISI, indicating increased cortical excitability at the 250-millisecond ISI
in the ipsilateral hemisphere. Although less marked
than that observed at this ISI in IGE, it was not observed in the contralateral hemisphere. Changes in excitability at both short- and long-latency ISIs in the
ipsilateral hemisphere indicate there is a lateralized
change in the balance of cortical excitatory and inhibitory influences confined to the ipsilateral hemisphere.
We did not find any significant interhemispheric or
intragroup difference in the mean duration of the CSP.
In IGE, this is consistent with some reports,9,21 though
CSP duration has been shown to be longer in untreated patients with IGE in some studies.23,24 The
findings from previous studies in focal epilepsy are
Table 2. Cortical Silent Period Duration (Mean ⴞ Standard Deviation) for Each Hemisphere in Each Group
MT ⴙ 5%
MT ⴙ 15%
Control (dominant hemisphere)
96.3 ⫾ 24.4
118.1 ⫾ 25.0
167.3 ⫾ 22.1
Control (nondominant hemisphere)
95.8 ⫾ 28.0
122.1 ⫾ 33.0
162.6 ⫾ 31.6
IGE (dominant hemisphere)
97.0 ⫾ 38.1
123.8 ⫾ 38.9
167.2 ⫾ 40.3
IGE (nondominant hemisphere)
99.1 ⫾ 23.6
125.3 ⫾ 24.3
171.9 ⫾ 27.5
Focal epilepsy (ipsilateral hemisphere)
87.3 ⫾ 23.5
107.1 ⫾ 30.9
151.7 ⫾ 31.4
Focal epilepsy (contralateral hemisphere)
84.9 ⫾ 26.1
103.9 ⫾ 24.1
150.4 ⫾ 28.9
Cortical silent period (CSP) was measured at three stimulus intensities: at resting motor threshold (MT), then at 5 and 15% greater
than MT. IGE ⫽ idiopathic generalized epilepsy.
Badawy et al: Cortical Excitability and Epilepsy
contradictory and conflicting. The PSP studies did not
suggest any segmental changes in excitability.
Pathophysiological Implications
Motor thresholds to TMS mainly reflect neuronal
membrane excitability, which largely depends on sodium channel conductivity.25 The cellular mechanisms
underlying the CSPT have not been defined,26 but in
this study, interhemispheric CSPT differences mirrored
changes in MT and they may share a similar basis.
Paired-pulse recovery curves used to measure ICI at
short ISI (1–5 milliseconds) reflect the activity of
GABAergic interneurons, probably GABAA receptor
mediated, located within the motor cortex.27 In contrast, inhibition at longer ISI (200 –300 milliseconds)
does not reflect GABAA receptor inhibition, but is
more likely to be mediated by changes in GABAB circuits.7,28,29
Idiopathic Generalized Epilepsy
Unfortunately, apart from absence epilepsy, there are
no good animal models of IGE. In absence epilepsy,
most studies performed on thalamic slices maintained
in vitro and in vivo have demonstrated that both the
thalamus and cortex are involved in the typical 3Hz
spike-wave discharges observed on EEG. Based on cellular studies and computer modeling, it has been hypothesized that this discharge is triggered by the inhibition of GABAA-mediated circuits and depends
critically on the activation of thalamic GABAB receptor–mediated inhibitory postsynaptic potentials for its
generation.2 It is not clear whether these findings are
generalizable to other forms of IGE. Our human data
now directly address disturbances in cortical excitability. Our results imply that in patients with IGE, within
the motor cortex there is bilateral reduction in both
GABAA- and GABAB-mediated inhibition; our experiments do not test the question of increased GABABmediated inhibition in thalamus, as suggested by animal data. It is noteworthy that the timing of maximum
TR facilitation at 200 to 300 milliseconds correlates
with the interspike interval at a frequency of 3 to 5Hz,
which is one of the main interictal EEG patterns seen
in patients with IGE.30 Further research into a possible
dysfunction of GABAB-mediated network activity in
particular in different subtypes of IGE is clearly warranted.
Focal Epilepsy
In focal epilepsy, we found, using the recovery curve
technique, evidence in the ipsilateral motor cortex of
increased cortical excitability and reduced GABAergic
function. This supports the contention that GABAmediated mechanisms are altered in a hemisphere affected by an epileptic process and can be expressed
even when the motor cortex is remote from the seizure
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focus.31 One consequence of the massive interconnectivity of excitatory cells in hippocampal and cortical
circuits is the generation of “runaway” excitation if the
recurrent excitation inherent in these networks is left
unchecked. Focal interictal spikes appear to be generated through a brief period of runaway excitation that
spreads rapidly through a large local network of neurons that is terminated largely by the activation of inhibitory synaptic conductances mediated by both
GABAA and GABAB circuits.2 Studies have shown that
functionally aberrant GABAA subunits are expressed
during the early phases of epilepsy development,32 and
interestingly, reduction of GABAB receptor function
has been demonstrated in tissue from both rodents33
and humans34 with temporal lobe epilepsy.
If the interhemispheric differences in MT in patients
with focal epilepsy are taken to indicate an ipsilateral
effect, it could imply that there is a reduction in sodium channel conductivity decreasing membrane excitability on this side. This may be secondary to the
change in GABAergic functions and could play a protective role limiting the spread of seizures. Alternatively, and less likely in our opinion, if the MT results
are taken to indicate a contralateral effect, it could be
interpreted that in the contralateral hemisphere there is
relative membrane hyperexcitability or increased sodium channel conductivity, which could also play an
inhibitory role by reducing the threshold for activation
of interhemispheric corticocortical inhibition.35
TMS has proved to be a useful means of investigating the mechanisms of epilepsies. We were able to
demonstrate noninvasively that the major disturbance,
altered GABAergic function in the motor cortex, is
widespread and bilateral in patients with IGE, yet remains localized to the affected hemisphere in patients
with focal epilepsy whereas spreading beyond the epileptogenic focus. This lends further support to the contention that pathophysiological differences exist between focal and generalized epilepsies.
We thank the neurologists in the First Seizure Clinic for their help
in recruiting the patients and providing input for the study, Dr R.
Briellmann for her continual support throughout this work, Dr M.
Fedi for his help with the statistical analysis of the results, Dr I.
Helbig for his help, the EEG technicians at Austin Health, and the
participants who gave up so much of their time to make this study
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Badawy et al: Cortical Excitability and Epilepsy
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generalized, change, cortical, focal, differential, excitability, epilepsy
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