Clinical Neurophysiology 119 (2008) 212–223
www.elsevier.com/locate/clinph
Functional interactions in brain networks underlying epileptic
seizures in bilateral diffuse periventricular heterotopia
Luc Valton a,b,c,*, Maxime Guye
Fabrice Wendling d,e, Jean Régis
a,b,c,g
b,c,f
, Aileen McGonigal a,b,c, Patrick Marquis b,
, Patrick Chauvel a,b,c, Fabrice Bartolomei a,b,c
a
g
CHU Timone, Service de Neurophysiologie Clinique, 264 Rue St Pierre, 13005 Marseille, France
b
INSERM, U751, Laboratoire de Neurophysiologie et Neuropsychologie, Marseille, France
c
Université de la Méditerranée, Faculté de Médecine, Marseille, France
d
Laboratoire Traitement du Signal et de L’Image, INSERM U642, Rennes, F-35000, France
e
Université de Rennes 1, LTSI, Rennes, F-35000, France
f
CHU Timone, Service de Neurochirurgie fonctionnelle, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale (CRMBM), UMR CNRS 6612, Faculté de Médecine,
Université de la Méditerranée, 27 Bvd Jean Moulin, 13385 Marseille cedex 05, France
Accepted 23 September 2007
Available online 26 November 2007
Abstract
Objective: Our aim was to investigate relationships between heterotopic and remote cortical structures at seizure initiation, in a patient
with bilateral periventricular nodular heterotopias (BPNH) explored by intracerebral electrodes.
Methods: Stereoelectroencephalography (SEEG) was performed in a man with BPNH and refractory epilepsy to investigate the hypothesis of right temporal lobe epilepsy and the possible involvement of heterotopic structures during seizures. SEEG signals were analyzed
with quantification of functional coupling between different brain structures during seizures, using nonlinear regression. We have used Zscore transformation of correlation values to reflect the change from the preictal period. Relationships between BPNH and cortical structures were investigated using analysis of stimulation-induced potentials.
Results: Three spontaneous seizures were recorded and analyzed. Signal analysis of interdependencies in two seizures demonstrated a
large initial network involving both heterotopia and cortical structures. Stimulations of heterotopia induced responses in remote cortical
structures.
Conclusions: Distinct epileptogenic networks were identified, in which leader structures were either the heterotopic or the mesial temporal structures, with functional connections between heterotopic and cortical areas.
Significance: These results confirm that a vast epileptogenic network, including heterotopic and cortical neurons, may be responsible for
seizure generation in BPNH. This may explain certain surgical failures in this group.
Ó 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Periventricular nodular heterotopias; SEEG; Signal processing; Synchrony; Epilepsy
1. Introduction
Heterotopic grey matter aggregates were first identified
more than a century ago at post-mortem examination
(Tüngel, 1857). High-resolution cerebral magnetic reso*
Corresponding author. Tel.: +33 491385833; fax: +33 491385826.
E-mail address: [email protected] (L. Valton).
nance imaging (MRI) now allows their in-vivo recognition
and characterization, depending on their shape and brain
distribution (Barkovich and Kjos, 1992). Periventricular
nodular heterotopia (PNH) appears as smooth ovoid nodules that are not calcified; they are isointense with normal
cortical grey matter on all imaging sequences and do not
enhance after administration of contrast medium. PNH
has been classified into different groups, depending on the
1388-2457/$32.00 Ó 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2007.09.118
L. Valton et al. / Clinical Neurophysiology 119 (2008) 212–223
periventricular distribution of the heterotopias (Barkovich
et al., 1996): bilateral diffuse symmetrical or asymmetrical
PNH (Dobyns et al., 1996); and bilateral focal and unilateral focal PNH with or without extension to neocortex
(Barkovich et al., 1996; Battaglia et al., 2006), the former
being the more frequent (Andermann et al., 1994; Battaglia
et al., 1997; Dubeau et al., 1995; Huttenlocher et al., 1994;
Li et al., 1997; Lu and Sheen, 2005). In bilateral diffuse
PNH (BPNH), MRI shows multiple periventricular nodules of grey matter symmetrically lining the lateral walls
of the lateral ventricles.
PNH is one of the malformations of cortical development often associated with epilepsy (Aghakhani et al.,
2005). The severity is variable: some individuals have no
seizures, some suffer rare seizures, and others medically
refractory seizures (Dubeau et al., 1995). The associated
epileptic syndrome is also variable (Raymond et al., 1995,
1994b); this may resemble generalized epilepsy, but more
frequently patients present with localization-related epilepsy, even in patients with BPNH (Battaglia et al., 2006,
1997; Dubeau et al., 1995; Raymond et al., 1995). In
patients with clear localization-related epilepsy, electroclinical features often suggest a temporal or parieto-occipital
onset, leading to the option of surgery being considered
in some patients. However, surgical treatment in patients
with PNH and refractory partial epilepsy is often unsuccessful (Li et al., 1997), calling into question the precision
of localization of the epileptogenic zone, and its relation
to the cortical resection.
A few previous studies using depth electrodes have suggested that the heterotopia and the temporal lobe could be
each or both the site of origin of seizures (Francione et al.,
1994; Kothare et al., 1998; Tassi et al., 2005). However the
functional relationships between heterotopic nodules and
cortical structures remain uncertain. A large epileptogenic
network consisting of the heterotopia and cortical structures could be responsible for seizure generation.
The objective of this work was to study the functional
relationships between periventricular heterotopic tissue
and cortical structures in a patient with BPNH and presumed right temporal epilepsy, who was investigated using
intracerebral electrodes (stereoelectroencephalography,
SEEG). We studied: (1) the functional coupling during
the first part of the seizures between heterotopic tissue
and temporal lobe structures using signal analysis (measure
of signal interdependencies); and (2) the responses evoked
in cortical structures after stimulation of heterotopic tissue.
This mode of stimulation can give insight into the connectivity between the stimulated tissue and remote brain areas
(Buser and Bancaud, 1983; Rutecki et al., 1989).
2. Methods
2.1. Patient
A right-handed 41-year-old man was investigated for
medically refractory partial epilepsy, suggestive of right
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temporal lobe epilepsy. He had experienced frequent
brief complex partial seizures since the age of 23, with
or without auras, characterized by anxiety associated
with a sensation of chest oppression and often a feeling
of ‘‘déjà vu’’. Seizures frequently occurred in clusters.
Secondary tonic clonic generalized seizures were rare.
Cerebral computed tomography (CT) scan showed large
ventricles, enlargement of the cisterna magna, and bilateral periventricular hyperdensity. Brain MRI confirmed
the diagnosis of BPNH (Fig. 1), and did not demonstrate
any hippocampal abnormalities. Brain fluoro-18 desoxyglucose PET found a severe hypometabolism of the right
antero-mesial temporal region, extending to the ipsilateral opercular cortex while heterotopic structures disclosed normal metabolic activity.
Video-EEG monitoring allowed recording of habitual
seizures, leading to the hypothesis of a right temporal epileptogenic zone. Recorded seizures were characterized by
staring followed by automatisms of the right hand and
both legs, mydriasis and chewing. Ictal scalp EEG onset
consisted of right fronto-temporal sharp waves (F8, T4,
FT10), followed by a fast discharge in the right anterior
temporal region before secondary propagation to the
whole of the right hemisphere.
2.2. Stereoelectroencephalography (SEEG)
SEEG was performed to investigate the hypothesis of
right temporal lobe epilepsy, and to determine the role of
periventricular heterotopic structures during seizures (see
details in Fig. 2).
This required the implantation of 11 multiple contact
intracerebral electrodes (diameter 0.8 mm; contacts 5–15;
length 2 mm; interval 1.5 mm). Placement was achieved
by using a standard double-grid system fastened to Talairach stereotaxic frame (Talairach et al., 1974).
Implantation accuracy was pre-operatively controlled
by telemetric X-ray imaging. A post-operative computerized tomography scan without contrast was then used to
verify both the absence of haemorrhage and the precise
3D location of each lead. Intracerebral electrodes were then
removed and an MRI performed, permitting visualization
of the trajectory of each electrode. Finally, CT-scan/MRI
data fusion was performed to anatomically locate each
contact along the electrode trajectory.
Signals were recorded on a 128 channel Deltamedä
system sampled at 256 Hz and recorded on a hard-disk
(16 bits/sample) without digital filter. Two hardware filters are present in the acquisition procedure. The first
is a high-pass filter (cut-off frequency equal to 0.16 Hz
at 3 dB) used to remove very slow variations that
sometimes contaminate the baseline. The second is a
1st order low-pass filter (cut-off frequency equal to
97 Hz at 3 dB) to avoid aliasing. Visual analysis
allowed description of the interictal spike distribution
and the structures involved by the epileptic ictal
discharge.
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L. Valton et al. / Clinical Neurophysiology 119 (2008) 212–223
Fig. 1. Symmetrical bilateral periventricular band heterotopia (arrowheads). (A) Axial T2-weighted images, (B) coronal T1-weighted images, (C) coronal
FLAIR images.
c
Fig. 2. (a) Intra-cerebral implantation scheme defined for SEEG exploration (left lateral view). Intra-cerebral electrodes are implanted under stereotactic
conditions in Talairach’s reference frame. In our group electrodes are identified by letter (A, etc.) and the recordings’ leads are numbered from 1 to 15, low
numbers corresponding to the deepest structures (for example, leads A 1–2 recorded the electrical activity of the amygdala). Bipolar signals are obtained by
subtracting the signals recorded from two adjacent leads. All 11 electrodes were implanted on the right side (nine lateral electrodes, one oblique electrode
‘‘FO’’, one longitudinal electrode ‘‘X’’). A, amygdala (medial contacts), and anterior part of middle temporal gyrus (MTG, lateral contacts); B, C,
anterior, posterior hippocampus (medial contacts), medial, posterior part of MTG (lateral contacts); T, thalamus (medial contacts), Insula, Heschl’s gyrus
(intermediar contacts), and superior temporal gyrus (STG, lateral contacts); TB, entorhinal cortex (medial contacts), anterior part of inferior temporal
gyrus (lateral contacts); TP, temporal pole; FO, posterior part of orbito-frontal region (medial contacts), dorso-lateral frontal cortex (lateral contacts);
GC, cingulum (medial contacts), inferior parietal gyrus (lateral contacts); HT, posterior heterotopic structures (medial contacts), posterior temporal cortex
(lateral contacts); F, cingulum anterior (medial contacts), lateral frontal cortex (lateral contacts); X, right heterotopic structures, from posterior (contacts
1, 2) to anterior (contacts 10, 11) part. (b) Reconstruction of the electrode X route in the MRI and its relation with the heterotopia. Positions between the
contacts X 6–7 and X 1–2 are indicated.
Fig. 3. (a) Time–frequency (spectrogram computed from short-term fast Fourier transform) representation of a seizure recorded in the heterotopic tissue.
Time–frequency is used to reveal the high-frequency activity at the seizure onset (arrow). (b) Signal processing procedure used to characterize coupling
between structures (here Hip, hippocampus and Het, heterotopic tissue) from signals they generate. On each pair of signals, nonlinear regression analysis is
used to compute the nonlinear correlation coefficient h2 and the time delay s from upper signal to lower and asymmetry information (difference between h2
coefficients) and time delays are jointly used to compute the direction index D that characterizes the direction of coupling (c). When greater than 0
(respectively, lower than 0), D indicates a coupling from upper to lower signal (respectively, lower to upper signal). h2 values are averaged over considered
periods and information is represented as a graph in which the arrow indicates coupling direction, when significant. Standard deviation of coefficient h2 is
also provided. In this case, the third seizure is analyzed. An increase in correlation is observed in the first period (seizure onset) and the direction index D
indicates that the heterotopic structure is leader. The second period (Mid Sz) is characterized by the maintenance of a significant correlation and the D
index also indicates that the hippocampus is leader.
L. Valton et al. / Clinical Neurophysiology 119 (2008) 212–223
2.3. Analysis of SEEG signal interdependencies during
seizures
Signal analysis was performed in order to study signal
interdependencies that is a mean to study the ‘‘functional’’
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interactions between brain structures (Bartolomei et al.,
2005, 2001; Guye et al., 2006). To this aim, three periods
of interest were identified for each seizure, based upon clear
seizure onset recognition: two ictal epochs and a background ‘‘reference’’ epoch.
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– The ‘‘Seizure onset’’ (Sz onset) epoch corresponds to 5 s
before and 5 s after the onset of the rapid discharge in
any of the explored structures, characterizing the seizure
onset and preceding the clinical symptoms. A time-frequency representation of signals (spectrogram computed
from short-term fast Fourier transform) was used to
accurately determine the beginning and the end of the
rapid activity.
– The ‘‘middle part of the seizure period’’ (mid Sz) epoch
corresponds to a 10 s period beginning after the end of
the rapid discharge. This part generally corresponds to
a slowing of the ictal discharge.
– The ‘‘background’’ (BKG) epoch corresponds to background SEEG activity. Twenty sec BKG periods were
selected in order to be temporally distant (at least
1 min) from analyzed ictal epochs and were used as reference periods for the analysis of correlations between
signals averaged over periods of interest.
Correlation between signals recorded from the different
cortical regions explored was estimated as a function of
time using nonlinear regression analysis. Nonlinear regression analysis is aimed at estimating the degree of association between two signals X and Y independently from
the linear or nonlinear nature of this association (Bartolomei et al., 2001; Pijn and Lopes Da Silva, 1993; Wendling
et al., 2001, 2000). In practice, analysis provides the coefficient h2 that takes its values in [0, 1]. Low values of h2
denote that signals X and Y are independent, and high values of h2 mean that signals X and Y are dependent. The
calculation of h2 between two signals X and Y gives two
values ðh2XY and h2YX Þ because of the asymmetrical nature
of the nonlinear estimation. In this work, we used the average value of these two quantities. This will be simply
referred to as h2 from now on.
In addition, the direction index D takes into account
both the estimated latency between signals X and Y and
the asymmetrical nature of the h2. Values of D range from
1.0 (X is driven by Y) to 1.0 (Y is driven by X) (Wendling
et al., 2001). In order to follow the temporal evolution of
the correlation between signals X and Y, estimation of h2
and D is performed over a temporal sliding window of
fixed duration (4 s by steps of 0.25 s). According to previous studies (Bartolomei et al., 2001, 2004b; Wendling
et al., 2001), reliable estimation of parameters h2 and D is
obtained for scatterplots (Y versus X) that include at least
one thousand points (Fig. 3).
Finally, h2 values were averaged over each period of
interest (BKG, Sz onset, and mid Sz epochs, as defined
above), for each pair of signals and for each seizure. Average h2 values were compared before and during a given period of interest to study variations in the functional coupling
of different cerebral structures. To identify the neural structures involved at Sz onset, and during the seizure, h2 values
from the three different periods were compared. For each
of the three periods, interactions between the various cortical regions explored were studied.
To limit the number of interactions (N sites allow
(N2 N)/2 different correlations values), we studied the
correlations between bipolar signals from the following
regions: amygdala (A), anterior part of middle temporal
gyrus (MTG), anterior hippocampus (Hip), temporal posterior cortex (TP), anterior part of superior temporal gyrus
(STG), entorhinal cortex (EC), posterior part of orbitofrontal region (OFC), dorso-lateral posterior frontal cortex
(DLPFC), inferior parietal gyrus (Par), and periventricular
heterotopic structures (intermediary contacts from electrode X) (Heter).
For each analyzed epoch (background and ictal periods)
the h2 values were first normalized according to the following equation w = log (h2/(1 h2))/2. w takes values in
[inf, +inf] with a distribution that can be assumed to be
Gaussian. We then have used a Z-score transformation
of correlation values in order to reflect the change of each
ictal period from the preictal (background) period. The Zscore transformation was carried out for w values obtained
in the ‘‘Sz onset’’ and the ‘‘mid Sz’’ epochs relative to the
mean and SD of w values averaged in the background
epoch. A Z-score of +2.0 on w values indicates a raw value
that is 2 SD above the mean of background on that measure and was considered significant for simple comparison.
We used a Bonferroni correction to take account of multiple comparisons and Z-scores of +3.06 on average w values
were considered significant (p < 0.05).
Results are represented in a graph for each epoch of
each seizure. In this representation, an arrow is used to
indicate unidirectional coupling direction, when significant,
i.e., when two conditions are satisfied: (i) Z-score of w
value is P2 or 3.06 (after Bonferroni correction) and (ii)
D P 0.5.
2.4. Stimulation study
During the recording session, the patient reclined comfortably in a chair in a sound attenuated room. Intra-cerebral electrical stimulations were performed as part of the
usual SEEG protocol using low frequency stimulation
(61 Hz) (Munari et al., 1993). These stimulations were produced by a constant current-regulated neurostimulator
designed for a safe diagnostic stimulation of the human
brain (Bartolomei et al., 2004a). Square pulses of current
were applied between two adjacent contacts localized in
the periventricular heterotopic structures (bipolar stimulation of contacts of electrodes ‘‘X’’). The stimulation
parameters were chosen to avoid tissue damage (Gordon
et al., 1990).
They consisted of series of 10 pulses of 1 ms duration,
0.5 Hz frequency and 2 mA intensity. Data were recorded
using an amplifier filter settings of 0.05–1000 Hz, and a
sampling rate of 5000 Hz. The recordings of intracerebral
EPs were bipolar, with each lead of each depth electrode
referenced to a scalp electrode distant from the central
regions. Data acquisition for post-stimulation evoked
responses started 21 ms before stimulation and lasted for
L. Valton et al. / Clinical Neurophysiology 119 (2008) 212–223
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Fig. 4. Interictal SEEG recordings. Spikes and sharp waves were recorded in right medial temporal lobe structures (amygdala, anterior and posterior
hippocampus, entorhinal cortex). Frequent independent multifocal paroxysms (sharp waves, spikes, polyspikes) are observed in all the contacts of
electrode X exploring the periventricular heterotopia. Abbreviations of electrodes contacts (bipolar recordings) and related brain structures (see the
electrodes’ position in Fig. 2) A 1–2, amygdala; A 9–10, anterior middle temporal gyrus (MTG); B 1–2, anterior hippocampus; B 10–11, MTG; C 2–3,
posterior hippocampus; C 12–13, posterior MTG; TB 1–2, entorhinal cortex; TB 9–10, inferior temporal gyrus; TP, temporal pole; T 1–2, thalamus; T 8–9,
Heschl’s gyrus; T 12–13, superior temporal gyrus; HT 1–2, posterior part of right heterotopia; HT 6–7, temporal posterior neocortex; GC 1–2, posterior
cingulum; GC 7–8, inferior parietal cortex; X 1–11, posterior to anterior part of the right periventricular heterotopia; FO 1–2, orbito-frontal cortex; FO
12–13, dorso-lateral prefrontal cortex; F 1–2, anterior cingulate gyrus; F 9–10, dorso-lateral prefrontal cortex.
206 ms. Evoked responses data were averaged from a
sequence of 10 stimuli and stored on a hard-disk (SynAmpsÒ amplifiers and NeuroscanÒ software) for further
analysis. All curves were corrected to obtain the same baseline. For each short-latency component, the contacts
between which an inversion of polarity was observed
and/or those which showed high amplitude, rapidly
decreasing over short distances, were identified. These conditions indicate which electrodes traverse regions generating a component which can be considered as the source
of that potential (Godey et al., 2001; Liégeois-Chauvel
et al., 2001). In order to demonstrate the different distribution of evoked responses after stimulation over different
parts of the right heterotopia, and in addition to the visual
analysis, we statistically compared the changes observed
after stimulation of X 1–2 leads (posterior heterotopia)
and stimulation of the more anterior part of the heterotopia (leads X 8–9) from which the maximal responses were
obtained (see result section). Evoked responses were then
considered significantly different when the curves clearly
separated from each other (paired t test, p < 0.05, df = 9)
during more than 10 ms (Molholm et al., 2006).
3. Results
3.1. SEEG recordings
Interictal spikes and sharp waves were recorded in right
mesial temporal lobe structures (amygdala, anterior and
posterior hippocampus, entorhinal cortex). Frequent independent paroxysms (sharp waves, spikes and polyspikes)
were recorded from all contacts of electrode X, exploring
the periventricular heterotopia (Fig. 4). Brief fast discharges were recorded from the intermediate contacts of
electrode X. Three spontaneous seizures were recorded,
each of which revealed a different pattern (Fig. 5).
Seizure 1 lasted 43 s: the patient experienced a brief disturbing sensation while reading aloud, without any other
manifestation. This seizure started with a low voltage fast
discharge (LVFD, around 40 Hz) in right heterotopic
structures, which propagated as a brief discharge in the
posterior perisylvian (Heschl’s gyrus, lateral posterior temporal, lateral inferior parietal) cortices, and in the frontal
lobe (dorso-lateral prefrontal cortex, DLPFC).
Seizure 2 lasted 122 s. The patient suddenly stopped
reading, seemed to feel something, looked from right to
left with a frightened facial expression, and then presented successive gaze deviation to the right, eyelid fluttering, slow head version to the right and then
secondary generalization. Ictal EEG discharge began 8 s
before clinical onset, with a LVFD seen in heterotopic
structures, and secondarily in Heschl’s gyrus, and temporal posterior cortex.
Seizure 3 lasted 96 s and was similar to those previously
recorded on the scalp video-EEG: this began with right
hand automatisms over the sternal region, over-breathing
and swallowing; the patient complained of an unpleasant
feeling and then lost consciousness with arrest of activity,
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L. Valton et al. / Clinical Neurophysiology 119 (2008) 212–223
219
heterotopic structures, and with a short delay, in right
mesial anterior temporal structures (amygdala, anterior
hippocampus, and entorhinal cortex). Delayed propagation to the DLPFC, to the parietal region, and the lateral
temporal structures was observed.
3.2. Analysis of nonlinear correlations between brain regions
Fig. 6. Graphs of signal intercorrelations between studied regions. For
each seizure (Sz1, Sz2, Sz3), the interactions between the different studied
regions are indicated at seizure onset (SO) and during the seizure (mid Sz).
The Z-scores values of mean w values during SO and mid Sz periods,
relative to the values obtained in the BKG periods, are indicated when a
significant change (value that is 2 SD (3.06 SD after Bonferroni correction)
above or below the mean of background w values) is observed. Studied
regions include the entorhinal cortex (EC), the hippocampus (Hip), the
amygdala (A), the middle temporal gyrus (MTG), the orbito-frontal
cortex (OFC), the dorso-lateral prefrontal cortex (DLPFC), the heterotopia (Heter), the temporal posterior cortex (TP), the superior temporal
gyrus (STG), the parietal cortex (Par).
staring, and then secondary generalization with a left clonic
head version. The ictal SEEG discharge started 6 s before
the clinical onset, with a high-voltage slow polyspike complex over the anterior-mesial temporal region and the posterior orbito-frontal region. A LVFD then emerged first in
The results are shown in two graphs for each of the three
spontaneous seizures (Fig. 6). These graphs show significant variations of average w values (Z-score in each interaction P2 or 3.06 (after Bonferroni correction)) during ‘‘Sz
onset’’ and ‘‘mid Sz’’ epochs.
For Seizure 1, analysis did not reveal significant changes
in signal correlations at seizure onset. Since the visual
inspection showed that the seizure had a very local onset
in one part of the heterotopia, we view this as reflecting this
very focal onset, without clear interaction between the heterotopic structures and the temporal lobe cortex. The mid
part of the seizure was characterized by significant interactions between heterotopic structures and lateral frontal and
posterior temporal cortices, reflecting a secondary synchronization in network involved in the ictal propagation.
During Seizure 2, a restricted network was engaged at
seizure onset, since interactions were found mainly between
heterotopic and posterior temporal structures (Heschl’s
gyrus and temporal posterior cortex). The second part of
Seizure 2 (mid Sz epoch) was characterized by an extension
of this network to the mesial and lateral part of the temporal lobe.
In Seizure 3, analysis showed a very large neural network both during ‘‘Sz onset’’ and ‘‘mid Sz’’ epochs. The
interactions included both heterotopic and cortical structures. At seizure onset, heterotopic structures were found
to be leader in most of the interactions with the temporal
lobe structures.
3.3. Evoked potentials
Stimulation over the posterior contacts of the right heterotopia produced evoked potentials in the lateral parietal
cortex. Stimulation over more anterior contacts of the heterotopia resulted in evoked potentials in Heschl’s gyrus, in
the superior temporal cortex and in the posterior part of
the hippocampus (Fig. 7).
b
Fig. 5. SEEG recordings of three spontaneous seizures. (a) The first seizure started with a low voltage fast discharge (LVFD) in the contacts exploring the
right periventricular heterotopia (*, contacts 5 & 6 of electrode X) and secondarily propagated to the more anterior part of the heterotopia (contacts 8, 9, &
10 of electrode X), to the superior temporal gyrus (Heschl’s gyrus, contacts 7 & 8 of electrode T), to the lateral posterior temporal cortex (contacts 6 & 7 of
electrode HT) and to the prefrontal cortex (contacts 12 & 13 of electrode FO). (b) The second seizure started with a LVFD in the right heterotopic
structures (*, X 4–6), propagated to Heschl’s gyrus (T 8–9), the posterior temporal cortex (HT 6–7), and then continued with a slower discharge affecting
the frontal lateral cortex and the hippocampus (C 2–3, B 1–2). (c) The third seizure began with a high-voltage slow polyspike complex over the anteriormesial temporal region (*, amygdala A 1–2, hippocampus B 1–2 and entorhinal cortex TB 1–2) and the posterior orbito-frontal cortex (OF 1–2). A LVFD
(70 Hz) developed in heterotopic structures (**, contacts 3 & 4, to contacts 6 & 7 of electrode X) and (***) secondarily in amygdala, anterior hippocampus,
and entorhinal cortex. Propagation of the discharges was also and later observed in several structures including the parietal cortex, the temporal posterior
cortex and the prefrontal region.
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L. Valton et al. / Clinical Neurophysiology 119 (2008) 212–223
Stimulations in these parts of the heterotopia did not
produce evoked potentials in the anterior medial temporal
region. However, very early responses within the 10 first ms
could not be specifically evaluated, due to the presence of a
stimulation-induced artefact.
4. Discussion
This study provides formal demonstration of a high
degree of inter-relation between heterotopia and cortical
structures in a patient with BPNH and epilepsy. The originality of our study was to combine two different functional
approaches: a study of interdependencies indicating a possible functional relationship between structures through the
signals they generate and an electrostimulation-evoked
response study that gives insight into the anatomical connectivity. We have shown that early interactions may occur
at seizure onset between heterotopic and cortical areas and
that stimulation of the heterotopic tissue induces evoked
responses in remote cortical structures.
BPNH was demonstrated in our patient, according to
MRI criteria (Barkovich and Kjos, 1992; Dobyns et al.,
1996): heterotopic grey matter nodular contiguous aggregates were globally symmetrically distributed within
bilateral periventricular regions. In this context, although
cerebral MRI shows widespread bilateral pathology, the
seizure semiology is frequently suggestive of partial epilepsy. In previously published cases, electroclinical semiology of monitored seizures was often in favour of a
epileptogenic zone located in the lateral temporal region
(Battaglia et al., 1997; Dubeau et al., 1999; Raymond
et al., 1995), or as in our case, in the temporal anterior-mesial region (Dubeau et al., 1995; Kothare et al.,
1998). The hypothesis of a prevalent temporal anteriormesial epileptogenic zone may be reinforced by the possible association of a hippocampal sclerosis (Dubeau
et al., 1999; Li et al., 1997; Raymond et al., 1994a).
However, although temporal structure involvement was
demonstrated in some of these previously reported
patients, temporal surgery has often proved unsuccessful.
For example, in a series of ten patients with PNH and
presurgical investigations for refractory temporal epilepsy, none of the nine patients with more than 12
months’ follow-up remained seizure free after temporal
lobe resection (Li et al., 1997).
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These findings could suggest the possible role of a large
epileptogenic network that includes heterotopic structures
and remote structures. Data from depth electrode recording are available for several patients. In two patients with
epilepsy and focal PNH investigated by intra-cerebral electrodes, no interictal or ictal paroxysmal activities were
found within the heterotopia (Dubeau et al., 1999). In contrast, other studies of patients with epilepsy and PNH
investigated by intra-cerebral electrodes with at least one
electrode in heterotopic structures have demonstrated an
involvement of heterotopic structures in seizure genesis
(Aghakhani et al., 2005; Battaglia et al., 2006, 2002;
Dubeau et al., 1995; Francione et al., 1994; Kothare
et al., 1998; Scherer et al., 2005; Tassi et al., 2005). Most
patients had focal PNH unilaterally or bilaterally distributed along the wall of lateral ventricles. Seizures were
reported to begin simultaneously from heterotopia and
cortex (Battaglia et al., 2006; Dubeau et al., 1995; Francione et al., 1994; Kothare et al., 1998; Tassi et al., 2005),
from the PNH (Dubeau et al., 1995; Kothare et al., 1998;
Scherer et al., 2005) or from one or multiple localized foci
involving temporal cortex and specifically mesial structures
(Dubeau et al., 1995; Tassi et al., 2005). In the series by
Tassi et al. (Tassi et al., 2005), seizure onset was either
simultaneous in both heterotopic nodules and overlying
cortex (five out of 8) or limited to cortical structures in
the remaining three patients. Very few published cases of
BPNH have been previously explored by SEEG; for example, only one case in each of the three published series
(Aghakhani et al., 2005; Li et al., 1997; Tassi et al., 2005)
underwent SEEG, only one of which was explored with
an electrode in the heterotopic structures (Aghakhani
et al., 2005). In this case, the seizures started in the temporo-mesial structures (right or bilaterally) without involvement of the explored part of the heterotopia. It is however
noteworthy that only a small part (one nodule) of the heterotopia was studied. The patient was improved but not
cured by a right selective amygdalo-hippocampectomy
(Engel class III) (Aghakhani et al., 2005).
Conversely, SEEG recordings of the three spontaneous
seizures in our patient demonstrated variable patterns but
a constant involvement of both heterotopic nodules and
cortical regions. Seizure onset was recorded in periventricular heterotopia (2 Szs) or concomitantly in heterotopic
and cortical structures (1 Sz). Functional coupling at sei-
b
Fig. 7. Evoked responses from four different bipolar stimulations in the heterotopic structures, respectively, from the posterior to the anterior part of
electrode X: from contacts 1 & 2 (green), from contacts 3 & 4 (red), from contacts 6 & 7 (blue), and from contacts 8 & 9 (yellow) are shown over all the
intracerebral recorded contacts: Stimulation of the posterior part of the right heterotopia (X 1–2 (green), to X 3–4 (red)) produced evoked potentials in the
lateral parietal cortex (maximum responses were observed on GC 7 contact and after stimulation of X 1–2 contacts) with a latency of 32.9 ms. This evoked
response after stimulation of X 1–2 is significantly different from the response after stimulation of X 8–9, during the [29.1–39.9 ms] period (t > 1.8;
p < 0.05), maximum at peak latency (t = 2.46; p < 0.05). Stimulation of anterior contacts (X 6–7 (blue), and X 8–9 (yellow)) evoked potentials (maximum
after stimulation of X 8–9) in Heschl’s gyrus (maximum on T9) with a latency of 18.2 ms, in superior temporal cortex (T12) with a latency of 21.5 ms, and
in the posterior part of the hippocampus (C3) with a latency of 30.6 ms, and none in parietal cortex (GC7). Comparison with evoked responses obtained
after stimulation of X 1–2 showed significant differences for T9 during the [12.2–37.9 ms] period, maximum at peak latency = 18.2 ms (t = 10.8; p < 0.001),
for T12 during the [14.1–38.1 ms] period, maximum at peak latency 21.5 ms (t = 3.2; p < 0.01), but not for C3.
222
L. Valton et al. / Clinical Neurophysiology 119 (2008) 212–223
zure onset between structures forming the epileptogenic
zone has been well documented in the past. We particularly
demonstrated that preferential interactions occur between
mesial temporal lobe structures when temporal lobe seizures are generated (Bartolomei et al., 2004b, 2005) or
for studying cortico-thalamic interactions (Guye et al.,
2006). This approach has been used here to determine if
‘‘functional coupling’’ could be observed during the generation of seizures in BPNH.
We demonstrated increase in correlation between signals
of both heterotopic and cortical structures at seizure onset
(for seizures 2 and 3) or/and during the course of the seizures. Analysis of coupling direction also suggested a leading role for heterotopic structures in the analyzed seizures.
In addition, it is interesting to note that the three recorded
seizures showed different patterns, suggesting a great variety
of mechanisms underlying seizure generation in this disease.
In addition to the study of signal interdependencies, we
used a single-shock stimulation paradigm, a classical way
to functionally determine the connections between brain
structures explored by depth electrodes (Buser and Bancaud, 1983; Rutecki et al., 1989). We particularly observed
that the stimulation of the heterotopic regions evoked
responses in remote cortices. These results suggest that
connections exist between periventricular heterotopic and
cortical neurons. These results may explain why a limited
surgical strategy (particularly limited to the temporal lobe)
may fail to cure patients in this context.
These results are in agreement with neuro-pathological
and animal studies (Chevassus-Au-Louis et al., 1998; Hannan et al., 1999; Tassi et al., 2005). Immuno-histochemistry
findings on brain tissue from four children with subcortical
or periventricular nodular heterotopia operated on for
refractory epilepsy demonstrated that intranodular neurons were connected to other regions of the brain, possibly
including the cortex itself; they also demonstrated cellular
composition and cytoarchitecture abnormalities that may
contribute to increased epileptogenicity both in nodules
and overlying cortex (Hannan et al., 1999). Moreover, in
animals with experimentally induced PNH, it has been
demonstrated that heterotopic neurons can form aberrant
connections with the hippocampus, thus giving rise to a
complex epileptogenic network (Chevassus-Au-Louis
et al., 1998). It is interesting to note that we recorded
evoked responses in the posterior hippocampus after stimulation of the heterotopic tissue.
Finally, these two approaches provide complementary
and congruent insight into the comprehension of the epileptogenic network in this patient with epilepsy and
BPNH.
Both are in favour of tight relationships between heterotopic tissue, and some cortical regions. Moreover, both
gave arguments in favour of a leading role for heterotopic
tissue in the epileptogenic network, as shown by analysis of
coupling direction in the analyzed seizures, and by electrostimulation experiments that show clear connection from
posterior heterotopia to the cortex near the temporal pos-
terior neocortex. Unfortunately given the fact that electro-stimulation study was performed during the clinical
assessment of the patient, the study of correlation performed later was not available in time to influence the
design of the electrostimulation-evoked response study.
Therefore all the possible sites were not systematically
explored by stimulations. Nevertheless, and although it
may be difficult to obtain a complete study in a patient
because of concurrent time constraints, we think that the
combination of these different approaches could be of high
interest to better understand the epileptogenic network and
functional connectivity between remote brain structures in
pre-surgical evaluation of patients with refractory epilepsy.
In conclusion, our study demonstrates a close relationship between heterotopic nodules and cortical regions in
BPNH, with an epileptogenic network including both
structures. These results may explain why a limited surgical
strategy (particularly limited to the temporal lobe) may fail
to cure patients in this context.
Acknowledgements
The authors thank the reviewers for constructive suggestions on the statistical analysis of the data presented in this
paper. We thank Dr. C. Liegeois-Chauvel for helpful review and comment of our work.
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