Thesis
Reference
Functional imaging of epileptic activity in humans
VULLIEMOZ, Serge
Abstract
Around 20% of patients suffering from epilepsy have medically refractory seizures and epilepsy surgery can offer a cure or at least a significant improvement of their seizures. in well selected patients. A comprehensive work-up combining different imaging techniques is necessary to localise brain regions involved in the epileptic network. Simultaneous ElectroEncephaloGraphy and functional Magnetic Resonance Imaging (EEG-fMRI) is a new technique that allows mapping epileptic networks at a whole-brain scale. In this work, I present several EEG-fMRI studies that investigate the clinical relevance of this technique and propose new analysis strategies to improve its sensitivity and specificity. I also report the first measurements of simultaneous intracranial EEG and fMRI in humans. These studies show that EEG-fMRI has become a non-invasive clinically useful and reliable technique. It is a precious tool in presurgical evaluation or in the investigation of the mechanisms underlying epileptic activity in humans. Résumé Environ 20% des patients souffrant d'épilepsie ont des crises pharmaco-résistantes. La chirurgie de [...]
VULLIEMOZ, Serge. Functional imaging of epileptic activity in humans. Thèse de privat-docent : Univ. Genève, 2012
DOI : 10.13097/archive-ouverte/unige:23178
Available at:
http://archive-ouverte.unige.ch/unige:23178
Disclaimer: layout of this document may differ from the published version.
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Clinical Medicine Section
Department of Clinical Neurosciences Service of Neurology
" FUNCTIONAL IMAGING OF EPILEPTIC ACTIVITY IN HUMANS
with simultaneous electroencephalography and functional magnetic resonance imaging:
from neurovascular coupling to clinical validation "
Thesis submitted to the Medical School of the University of Geneva
for the degree of Privat-Docent by
--- Serge VULLIEMOZ
Genève
2012
1
SUMMARY
Around 20% of patients suffering from epilepsy have medically refractory seizures and epilepsy surgery can offer a cure or at least a significant improvement of their seizures.
in well selected patients. A comprehensive work-up combining different imaging techniques is necessary to localise brain regions involved in the epileptic network.
Simultaneous ElectroEncephaloGraphy and functional Magnetic Resonance Imaging (EEG-fMRI) is a new technique that allows mapping epileptic networks at a whole-brain scale. The investigation of these patients, sometimes with intracranial EEG recordings, represents also a unique window to better understand the mechanisms of epileptic activity and investigate cognitive networks and their alterations in a chronic neurological condition.
In this work, I present several EEG-fMRI studies that investigate the clinical relevance of this technique and propose new analysis strategies to improve its sensitivity and specificity. I also report the first measurements of simultaneous intracranial EEG and fMRI in humans. These studies show that EEG-fMRI has reached the stage of a non- invasive clinically useful and reliable technique to map epileptic activity. It is a precious tool in presurgical evaluation or in the investigation of the mechanisms underlying epileptic activity in humans.
2
ACKNOWLEGMENTS
I would like to express my gratitude to the key persons who have guided and supported me during my training and career in all my scientific, clinical and teaching activities. I am very grateful to Professor Theodor Landis and to Professor Pierre Pollack for their enthusiastic support of my career path in a fine balance between clinical and research work. I am deeply indebted to Professor Margitta Seeck for being an incomparable and inspiring mentor over the past eight years. In addition to teaching me the art of EEG and epileptology, she has strongly encouraged me to pursue the field of neuroimaging and directed several of my research projects. I am also very thankful to Professor Christoph Michel, for his limitless and insightful scientific guidance. In London, Professor John Duncan and Professor Louis Lemieux offered wise supervision and support during and beyond my fulfilling scientific and clinical fellowship at the UCL Institute of Neurology.
Many other persons contributed to my research work with interesting discussions, useful suggestions, valuable advice or experimental assistance and all should be acknowledged here: more particularly, past and current collaborators in Geneva at the Neurology, Neurosurgery and Neuroradiology clinics, the Functional Brain Mapping Lab the Brain and Behaviour Lab, and the Centre d‟Imagerie Bio-Médicale (Geneva and Lausanne), as well as at the UCL Institute of Neurology, the National Hospital for Neurology and Neurosurgery and the Epilepsy Society in London, UK.
Finally, this thesis is dedicated to my parents for their loving support and to Lindsey Jules and Margot with whom I share the joys and challenges of life.
3
TABLE OF CONTENT
1 Epilepsy and Epilepsy Surgery ... 7
1.1 Epilepsy ... 7
1.1.1 Definitions ... 7
1.1.2 Epidemiology, morbidity and mortality ... 7
1.1.3 Pharmaco-resistance ... 8
1.2 Epilepsy surgery ... 9
1.2.1 Background ... 9
1.2.2 Non-invasive presurgical evaluation ... 9
1.2.3 Intracranial EEG recordings ... 10
1.2.4 Additional imaging tools ... 10
1.2.5 Post-operative seizure outcome ... 11
1.2.6 Risk of post-operative deficits ... 12
1.3 Conclusion ... 12
2 Electrical Source Imaging and simultaneous EEG-fMRI ... 13
2.1 Introduction ... 13
2.2 Neurophysiological background ... 14
2.2.1 Origin of the EEG signal ... 14
2.2.2 Origin of the fMRI signal ... 14
2.3 Electrical Source Imaging (ESI) ... 16
2.3.1 Methodological principles ... 16
2.3.2 Clinical ESI studies in focal epilepsy and validation studies ... 18
2.4 EEG-fMRI ... 18
2.4.1 Methodological principles ... 18
2.4.2 Clinical EEG-fMRI studies in focal epilepsy and validation ... 19
2.5 Combination of ESI and EEG-fMRI ... 22
3 Experimental studies ... 23
3.1 Synopsis ... 23
4 EEG correlated functional MRI and postoperative outcome in focal epilepsy ... 25
published paper
4 5 Epileptic networks in focal cortical dysplasia revealed using
electroencephalography-functional magnetic resonance imaging. ... 33
published paper 6 The spatio-temporal mapping of epileptic networks: combination of EEG-fMRI and EEG source imaging. ... 51
published paper 7 Continuous EEG source imaging enhances analysis of EEG-fMRI in focal epilepsy. ... 63
published paper 8 With or without spikes: localization of focal epileptic activity by simultaneous electroencephalography and functional magnetic resonance imaging. ... 77
published paper 9 Simultaneous intracranial EEG and fMRI of interictal epileptic discharges in humans. ... 99
published paper 10 Simultaneous intracranial EEG-fMRI in humans: safety and data quality ... 111
10.1 Abstract ... 113
10.2 Introduction ... 114
10.3 Methods ... 115
10.3.1 In-vitro RF heating safety testing ... 115
10.3.2 In-vivo studies of EEG and MR image data quality ... 117
10.3.3 Data acquisition ... 117
10.3.4 Data processing and analysis ... 120
10.4 Results ... 122
10.4.1 In vitro temperature measurements ... 122
10.4.2 icEEG data quality ... 122
10.4.3 MRI data quality ... 125
10.5 Discussion ... 128
10.5.1 Patient safety ... 128
10.5.2 EEG data quality ... 129
10.5.3 MRI data quality ... 129
10.5.4 fMRI protocol considerations for icEEG-fMRI ... 130
5
10.5.5 Limitations of the current study ... 131
10.6 Conclusions ... 132
10.7 References ... 133
11 General discussion ... 135
11.1 Summary of the findings ... 135
11.2 Neurophysiological relevance ... 136
11.3 Clinical relevance ... 137
11.4 Future research directions ... 138
11.4.1 EEG-informed fMRI analysis of brain networks ... 138
11.4.2 Neurovascular coupling ... 139
11.4.3 Functional and structural connectivity of epileptic networks ... 141
12 Conclusion ... 143
13 References ... 145
6
7
1 Epilepsy and Epilepsy Surgery
1.1
Epilepsy
1.1.1
Definitions
According to the definition of the International League Against Epilepsy (ILAE), an epileptic seizure is “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain” (Fisher et al. 2005). This can take a variety of forms, depending on the origin and the propagation of this pathological activity. Epilepsy is defined by the occurrence of at least two unprovoked seizures or the occurrence of an inaugural seizure in an individual presenting evidence of a functional or structural brain abnormality that predisposes to recurring seizures (Fisher et al. 2005).
1.1.2
Epidemiology, morbidity and mortality
Epilepsy is the most common chronic neurological condition affecting 40-70/100,000 persons per year in developed societies with a high incidence in infants and in the elderly population. The prevalence of epilepsy is 5-10 per 1000 persons (Hauser et al.
1993; MacDonald et al. 2000), corresponding roughly to 35’000-70’000 affected persons in Switzerland. Epilepsy is associated with neurological, cognitive, psychiatric and socio- professional co-morbidities and an increased mortality which is 2-3 times higher than the general population.
The majority of patients with epilepsy suffer from focal epilepsy that can be either symptomatic (caused by an acute of chronic congenital or acquired brain lesion) or cryptogenic (a focal origin is suspected but the cause is unknown). Focal epilepsies are classified according to the affected hemisphere and lobe (left/right, frontal, temporal, parietal, occipital, insular) and this can be further detailed with sublobar classification associated with specific clinical and electrophysiological features (i.e. medial and lateral temporal lobe epilepsy, orbito-frontal, fronto-polar) observed with ElectroEncephalography (EEG).
8 Thefollowing terminology is used to describe focal epileptic activity in the brain and has been developed in the context of epilepsy surgery (see section 1.2 below) (Rosenow&Luders 2001) :
- Symptomatogenic zone: The cortical area that produces the ictal symptoms of the individual patient when it is activated by the epileptic discharge. It is defined by history and video-EEG semiology.
- Irritative zone: the cortical area that generates interictal epileptiform activity. It is estimated by scalp EEG, magnetoencephalography (MEG), or intracranial EEG.
- Ictal onset zone: the zone capable to generate spontaneous seizures. It is a subset of the irritative zone. It can be estimated with the same tools as the irritative zone except that MEG rarely captures seizures due to recording sessions generally limited to less than one hour.
- Epileptogenic zone: area of brain tissue that is necessary to generate the seizures and which needs to be surgically removed to obtain seizure freedom. It is estimated by a combination of all the above zones estimated during presurgical evaluation.
- Epileptogenic lesion: structural brain abnormalities with the potential of generating interictal and ictal epileptic activity. It is identified by neuroimaging or by post-operative histological examination.
- Eloquent cortex: cortical region that is identified as crucial for neurological or cognitive functions (i.e. motor, sensory, visual, language cortex).
1.1.3
Pharmaco-resistance
Despite a well conducted therapy with antiepileptic drugs, around 30% of patients suffering from epilepsy will endure recurring seizures despite multiple anti-epileptic drug (AED) treatments (Kwan&Brodie 2000). The introduction of the first anti-epileptic drug will lead to seizure freedom in 47% with the first drug, 30% with the second drug, 10%
with the third and 5% with the fourth. Pharmaco-resistance is defined as the persistence of seizures despite a well conducted anti-epileptic drug treatment with at least two drugs during at least 2 years.
9 1.2
Epilepsy surgery
1.2.1
Background
In some carefully selected patients, epilepsy surgery, consisting in removing the cortical zone necessary for the initiation of epileptic seizures (the epileptogenic zone), can lead to seizure freedom or significant improvement of the seizure control. The determination of which brain structures should be targeted by surgery is tailored to the individual patients after a comprehensive presurgical evaluation, in order to remove the estimated epileptogenic zone, while sparing the eloquent cortex. Epilepsy surgery can consist in the resection of a radiological lesion (lesionectomy), removal of epileptogenic cortex (cortectomy), partial or total resection of a lobe (lobectomy) or multiple lobectomies.
Disconnective surgery can also be performed in specific cases to interrupt major white matter tracts responsible for the propagation of epileptic activity and the severity of the seizures. Callosotomy (section of the corpus callosum) or functional hemispherectomy (disconnection of a whole hemisphere) are the main examples of disconnective surgery.
1.2.2
Non-invasive presurgical evaluation
The recording of clinical and electrical manifestations of seizures with long-term video- EEG (telemetry) represents the core of the presurgical evaluation. Consistent electro- clinical patterns across several seizures are needed to ensure that the epilepsy is unifocal. However, scalp video-EEG per se is not sufficient to delineate which brain structures need to be surgically removed and additional structural/functional imaging is needed to find concordant areas of tissue damage or dysfunction.
Magnetic Resonance Imaging (MRI) is currently the gold standard for structural imaging in patients with epilepsy as it detects lesions in 75% of patients with pharmaco-resistant epilepsy. The most common lesions are hippocampal sclerosis, malformation of cerebral development such as focal cortical dysplasia or heterotopia, low grade tumors, cavernoma, traumatic or ischemic lesions, parasitic lesions such as cysticercosis (Duncan 2010).
In addition, neuropsychological and psychiatric assessments are needed to characterise the cognitive and affective disorders associated with epilepsy and stratify the risk of post-operative cognitive and psychiatric outcome.
10 1.2.3
Intracranial EEG recordings
In some patients, the non-invasive tests do not allow an unequivocal decision to be made on whether surgery is possible and intracranial EEG recordings are needed to clarifiy the localisation and extent of the epileptogenic tissue and their spatial relation with the eloquent cortex (Seeck&Spinelli 2004). This can be done with depth electrodes implanted into the brain via a stereotactic procedure (StereoEEG, SEEG) or with subdural electrodes laid on the cortex after craniotomy. Telemetry is then performed to record seizures and interictal activity with these invasive electrodes.
The number and position of electrodes and contacts is limited both by surgical considerations (vascular anatomy) and number of available channels of EEG recording systems (typically 64-128 channels). This highlights the limited spatial sampling of intracranial EEG recordings. Therefore, prior hypotheses about the possible localisation of the epileptic focus are critically needed in order to select the brain regions which need to be recorded with intracranial electrodes.
1.2.4
Additional imaging tools
A variety of imaging techniques can been applied to help detect structural lesions or abnormal brain function to better understand epileptic networks in individual patients, guide the placement of intracranial electrodes and tailor epilepsy surgery.
Isotopic imaging techniques such as 18F-Fluoro-Deoxy-Glucose Positron Emission Tomography (FDG-PET) and Single Photon Emission Computerised Tomography (SPECT) are based on the intravenous injection of radio-labeled tracers and can be used as functional imaging tools to help localise the epileptic focus via focal interictal hypometabolism on FDG-PET, interictal hypoperfusion or ictal hyperperfusion on SPECT. Magnetic Resonance Spectroscopy can detect focal disturbances of neuronal and glial metabolism and MRI volummetry can quantitatively identify structural abnormalities that had escaped visual detection (Duncan 2010).
Functional imaging of epileptic activity itself is mostly performed in the interictal state and therefore maps the irritative zone, Electric (Magnetic) Source Imaging, and EEG-fMRI can be used for that purpose and are presented in detail in chapter 2. Previous studies and experimental studies in this work suggest that the mapping of the clinically relevant
11 part of the irritative zone based on meaningful epileptic spikes is a good surrogate of the localisation of the epileptogenic zone to be removed.
In parallel, functional imaging of brain function allows localising the eloquent cortical and subcortical networks to tailor surgical resections and predict neurological and cognitive oucome. Currently, functional imaging is increasingly based on functional MRI to localise motor, sensory, language and memory functions and the techniques are progressively being translated from the research labs to the clinical setting. Finally, the mapping of white matter connections with Diffusion Tensor imaging is also a promising techniques with growing clinical applications, notably in the context of epilepsy surgery (Duncan 2010).
1.2.5
Post-operative seizure outcome
In temporal lobe epilepsy with hippocampal sclerosis, the most frequent pharmaco- resistant epileptic syndrome in adults, anterior temporal lobectomy can lead to seizure freedom in up to 85% of patients, at one-year follow-up (Spencer&Huh 2008). In a proportion of patients, seizures tend however to recur with time and seizure-freedom after a follow-up of 10 years is around 40% (McIntosh et al. 2004). Epilepsy surgery therefore is largely superior to the continuation of medical therapy in patients with pharmaco-resistant epilepsy, as confirmed by a randomised (Wiebe et al. 2001). Focal malformations of cortical development are the second most frequent cause of refractory epilepsy and can cause temporal and extra-temporal epilepsy. Up to 60% of these patients can be seizure-free after surgery (Fauser et al. 2004), with the outcome dependant on the complete resection of the abnormal cortex (Kim et al. 2009). In the absence of a detectable lesion (MRI-negative patients), surgical resection can also be associated with post-operative seizure. These cases are the best example of the need for additional functional and structural imaging tool to track subtle structural lesions and perform a functional mapping of the epileptogenic networks and the eloquent brain structures, particulary as the latter can be altered by the epileptic disease (Powell et al.
2007). Odds for a seizure-free outcome tend to be lower than in lesional cases but can be as high as 50-60% (Wetjen et al. 2008; Bell et al. 2009). These findings illustrate the importance of brain imaging for detecting focal structural brain abnormalities in the management of patients suffering from epilepsy.
12 1.2.6
Risk of post-operative deficits
Epilepsy surgery is associated with a 2% risk of permanent neurological impairment or mortality, caused by haemorragic, ischemic or infectious complications (Lüders 2008).
The site of surgical resection can be related to more specific deficits: e.g. memory decline (hippocampus) and visual field defect (optic radiation) in temporal lobe surgery, motor deficits in pericentral frontal regions, sensory deficits in parietal resections.
1.3
Conclusion
This chapter highlights the benefits of epilepsy surgery in well selected patients suffering from pharmacoresistant epilepsy. However, a significant proportion of patients is not improved by surgery and predictive factors are needed. Therefore, the development of new non-invasive tools and their combination is critically needed to improve patient selection, guide intracranial electrode placement and improve post-operative outcome while minimizing the risk of deficit. In this context, this work presents recent advances in the mapping of epileptic networks using simultaneous EEG and fMRI recordings and discusses their limitations and clinical relevance.
13
2 Electrical Source Imaging and simultaneous EEG-fMRI
Parts of this chapter have been published as
Vulliemoz S, Michel CM, Daunizeau J, Lemieux L, Duncan JS ; The combination of EEG souce imaging and EEG-correlated functional MRI to map epileptic networks; Epilepsia 2010 Apr 51(4): 491-505.
2.1
Introduction
First developed by Hans Berger in the late 1920’s, electroencephalographic (EEG) recording of human neuroelectrical activity has benefitted from tremendous development fuelled by advances in neurophysiology and digital technology. While routine clinical interpretation remains largely based on the visual interpretation of signal fluctuation of multichannel recordings, spatio-temporal analysis of EEG signals, including Electrical Source Imaging (ESI) have transformed this tool into a modern 3D imaging tool of brain activity. ESI consists in estimating the localisation of the intracerebral electrical generators of the signal recorded on the scalp with a temporal resolution of milliseconds.
This technique has moved on from the research laboratories and is now increasingly implemented in the clinical practice of epilepsy surgery centres to help localising focal epileptic activity and help clinical management of patients with medically refractory seizures.
Another application of EEG to map epileptic networks is the combination of EEG and functional Magnetic Resonance Imaging (EEG-fMRI) that allows whole brain mapping of haemodynamic changes related to specific electrophysiological features selected from the EEG, such as focal or generalised epileptic activity. Following the first proof-of- concept study (Ives et al. 1993), safety and data quality have now been thoroughly assessed and simultaneous EEG-fMRI can be safely performed and arises as a powerful method to explore epileptic networks, but also endogeneous brain rhythms and task-related brain activity.
Formal validation of new localising imaging techniques is a necessary but difficult task, which requires comparison with a gold standard, ideally in large homogeneous patient groups. One possibility is the spatial concordance with radiologically visible lesions that are considered to be the cause of symptomatic epilepsy. However, these can be
14 relatively large and often do not colocalise with the irritative or ictal onset zones. Patients undergoing invasive EEG recording with intracranial electrodes or resective surgery offer opportunities for validation that are unique in clinical and basic brain research. However, it needs to be reminded that validation with intracranial EEG is limited to rather small groups of patients with heterogeneous epileptic syndromes and limited intracranial spatial sampling. Post-operative seizure freedom in patients in whom the estimated epileptic focus was localised in the resection zone represents the most clinical relevant form of validation. In some cases, the resected areas are much larger than the epileptic zone making it difficult to assess the test’s specificity and long-term follow-up is required.
In the following we give an overview of the neurophysiological background, principles, limitations and main clinical validation studies of ESI and EEG-fMRI.
2.2
Neurophysiological background
2.2.1
Origin of the EEG signal
Scalp EEG electrodes record fluctuations in electrical potential caused by the summed excitatory and inhibitory post-synaptic potentials generated by populations of cortical pyramidal neurons with effective orientation perpendicular to the cortical surface (Niedermeyer&Lopes da Silva 2005). The solid angle theory applied to EEG generators explains why short lasting axonal action potentials of about 1 ms duration do not result in a combined macroscopic electric signal, despite frequent firing and high amplitude (Gloor 1985). Synchronous cortical activity over at least 6-10 cm2 of gyral surface is necessary for pathological events to be clearly detectable with scalp electrodes (Tao et al. 2005). The infolding and multi-laminar structure of the cortex can make the relationship between generators and electrodes complex (Megevand et al. 2008) and some neuronal activity gives rise to a “closed” electric field (e.g. stellate cells) invisible to scalp electrodes (Nunez&Silberstein 2000).
2.2.2
Origin of the fMRI signal
Functional MRI (fMRI) studies measure local changes in brain oxygenation by detecting differences in magnetic susceptibility between oxy- and deoxyhaemoglobin (Blood Level Oxygen Dependant, BOLD signal changes). The interpretation of fMRI studies relies on
15 the assumption that an increase of regional “neuronal activity” results in an increase in metabolic demand, an excessive increase in perfusion and a decreased concentration of deoxygenated haemoglobin in local venous blood (increase of BOLD signal) (Buzsaki et al. 2007; Logothetis 2008).
Animal studies have shown that BOLD signal changes do not correlate with the firing rate of action potentials (single- or multi-unit activity) in local neurons. It correlates much better with the local field potential, which represents the sum of perisynaptic electrical activity, as measured by extracellular intracranial electrodes. Neuronal activity and the BOLD signal vary over very different time scales (milliseconds vs seconds). The coupling between both variables can be modelled by Haemodynamic Response Function (HRF) (Glover 1999). Following a single short lasting stimulus (and consequently a short lasting evoked neuronal activity), there is an initial dip of the BOLD signal, then an increase to reach the peak about 5 seconds after the stimulus and finally an undershoot with a return to baseline after about 20 seconds. Spatially, fMRI studies typically use voxels with a volume of the order of 50 mm3 and are well suited to the anatomical scale of the haemodynamic changes (Logothetis 2008).
The interpretation of sustained negative BOLD changes observed in animal studies (Shmuel et al. 2006; Maier et al. 2008) as well as neurophysiological (Shmuel et al.
2002) and epilepsy studies in humans (Kobayashi et al. 2006a; Salek-Haddadi et al.
2006) is difficult and context dependent. A decrease in metabolic demand may be associated with a selective increase in neuronal activity (or synchrony), as in the case of the alpha rhythm (Laufs et al. 2006b) or generalised spike and wave epileptic discharges (Aghakhani et al. 2004; Hamandi et al. 2006), suggesting that reduced inhibition might have caused a reduction of metabolism despite an increased activity in selected neuronal populations. In localisation-related epilepsies, it is not clear whether the observed transient negative BOLD changes reflect surround inhibition, impaired neurovascular coupling, distant downstream/upstream metabolic decrease, propagated epileptic activity or, less probably, a vascular theft mechanism (Kobayashi et al. 2006a;
Salek-Haddadi et al. 2006).
16 2.3
Electrical Source Imaging (ESI)
2.3.1
Methodological principles
ESI can estimate the localisation of the electric source(s) within the brain volume which generate Interictal Epileptiform Discharges (IED, Spikes) recording with scalp electrodes. The relationship between a specific distribution of postulated electric sources in the brain and the resulting scalp voltage map is determined by the forward model:
the construction of a mathematical model of the head’s electromagnetic and geometrical properties to calculate the volume conduction; These head models can be categorised either as spherical or realistic models, the latter giving a more accurate description of individual head and brain morphology but are more computationally demanding. For a given scalp voltage field, there is an infinite number of possible source configurations, giving rise to the fundamental non-unicity of the inverse electromagnetic problem (Helmholtz 1853). As a consequence, solving the inverse problem requires assumptions about the sources and the volume conductor, in order to reduce the space of solutions (number and spatial configuration of possible solutions). Common assumptions for neural sources are equivalent dipoles and distributed solutions. Dipolar solution estimate the localisation and orientation of one or a few equivalent dipole(s) generating a given scalp voltage map as recorded by EEG electrodes. Distributed linear solutions estimate the activity of each point (source) in a solution space (usually the grey matter) and are better suited for extended sources but require further assumption to solve the inverse problem, among which is the restriction of the solutions to the grey matter and the smoothness of the solution. Dipolar and distributed linear solutions applied to spike localisation have been compared, with simulated EEG data (Grova et al. 2006) or clinical recordings (Ebersole 1999). The result of the comparison depends on the nature of the dataset and the spatial extent of neuronal generators.
Figure 1.1 summarizes the usual analysis steps required for ESI.
17 Figure 1.1: Principle of Electrical Source Imaging
A) EEG recording and analysis: (A1): Distribution of the electrodes on the scalp (in this case 256 electrodes). (A2): The exact position of the electrodes on the head can be determined with the use of a photogrammetry system (Electrical Geodesic Inc). (A3):
EEG recording and visual identification of interictal spikes. (A4): Averaging of similar epileptiform potentials leading to a potential map for each timepoint during the epileptiform discharge.
B) Head model: (B1): structural MRI. (B2): brain segmentation into different tissue classes. (B3): The grey matter is identified. (B4): The solution space is defined based on the gray matter definition. White matter, ventricles and large cavities within the brain are excluded from the solution space.
C) Inverse solution: For each timepoint within the spike wave complex, a mathematic algorithm (inverse solution calculation) is used to estimate the location of the epileptic source within the solution space (B4) based on the voltage map of that timepoint (A4).
From Lantz G, Grouiller F, Spinelli L, Seeck M, Vulliemoz S; Localisation of focal epileptic activity in children using high density EEG source imaging, Epileptologie, 2011 June, 84-90
18 2.3.2
Clinical ESI studies in focal epilepsy and validation studies
The comparison of ESI and invasive EEG recordings has been carried out with simultaneous scalp ESI and invasive recordings in patients with temporal lobe epilepsy.
ESI was able to differentiate between medial and lateral temporal spikes (Dinesh Nayak et al. 2004; Zumsteg et al. 2006) and to identify patterns of propagation within the temporal lobe. Concordance between intracranial EEG and dipolar sources has been found in over 90% of technically feasible cases in temporal and frontal lobe epilepsy (Gavaret et al. 2004; Gavaret et al. 2006). In another study of patients with both temporal and extra-temporal epilepsies recorded with dense-array EEG (128 electrodes), a distributed linear ESI model was concordant at a lobar level in 94% of 32 patients including 100% of patients with temporal lobe epilepsy (Michel et al. 2004).
Good concordance between ESI and the resection area was obtained in 79% of post- operative seizure-free cases. Finally ESI can be accurate despite large brain lesions (Brodbeck et al. 2009). The limitation of these studies is that they were un-blinded, retrospective and that the additional localisation information compared to other imaging modalities was not analysed. Finally, a large study investigated the sensitivity and specificity of ESI in a large group of 152 operated patients with temporal and extratemporal epilepsy. In the same group of patiehts, the results were compared with those of other conventional technique of localisation of the epileptic focus, namely MRI, PET and SPECT. ESI had a sensitivity of 84% and a specificity of 89% that were comparable to MRI when the analysis was based on high density EEG recordings and individual anatomy of the brain. For low density recordings or template head models, results were much less accurate.
2.4
EEG-fMRI
2.4.1
Methodological principles
Simultaneous EEG-fMRI recordings require that the artefacts caused by the interaction between both recording systems are kept to a minimum and are later corrected.
Moreover, it is necessary to follow a strict acquisition protocol in order to guarantee patient safety. Non ferro-magnetic MR compatible electrodes, cables and amplifiers are needed to record the EEG inside the MRI scanner. High amplitude and high frequency gradient artefacts on the EEG are caused by the switch of the scanner’s gradients and
19 pulse-related artefacts are caused by small amplitude head movement time-locked to the cardiac cycle. These two artefacts can be successively corrected by the substraction of average artefact templates, allowing the interpretation of EEG (Aarts et al. 1984; Allen et al. 1998; Allen et al. 2000). For fMRI data in epileptic patients, the conventional analysis strategy is to identify epileptic spikes on the corrected EEG and enter their timing into a statistical model (General Linear Model), together with centre-specific choices of confounds (e.g. motion, cardiac cycle) to model other sources of variance of the BOLD signal. The statistical estimation of this model identifies the voxels in which the BOLD signal time course is significantly correlated with the occurrence of the spikes.
2.4.2
Clinical EEG-fMRI studies in focal epilepsy and validation
So far, most EEG-fMRI studies in focal epilepsy have been exploratory whole-brain studies aiming at demonstrating BOLD changes throughout the brain linked to any pathological discharges on scalp EEG. The yield of BOLD responses is predominantly affected by EEG criteria (spike frequency). EEG-fMRI studies on patients with malformations of cortical development found changes extending beyond the radiological structural abnormalities consistent with histological and intracranial electrophysiological studies (Salek-Haddadi et al. 2002; Kobayashi et al. 2005; Kobayashi et al. 2006b;
Salek-Haddadi et al. 2006).
Comparison of EEG-fMRI results with other localising tools has shown promising results regarding the validation of EEG-fMRI as a localising tool of epileptic activity. EEG-fMRI results were concordant with interictal hypometabolism on Positron Emission Tomography (PET) and ictal hyperperfusion using Single Photon Emission Computer Tomography (SPECT) in 7 adults with various epileptic syndromes (Lazeyras et al.
2000). When they were performed, intracranial recordings confirmed the findings in 5/6 patients. Concordance with PET (2 patients) and SPECT (2 patients) was also reported in a paediatric study (De Tiege et al. 2007). Benar et al. found good agreement between clusters of BOLD response and intracranial spiking contacts in 5 patients but the authors did not analyse the correlation between the most significant BOLD cluster and the most active interictal contact or the ictal onset zone (Benar et al. 2006). In another study on an overlapping group of patients, congruence between interictal intracranial EEG and EEG- fMRI results was found in 3 of 8 patients in whom intracranial EEG was available (Grova
20 et al. 2008). BOLD response to focal slowing was shown to be consistent with intracranial EEG findings in one patient with frontal lobe epilepsy (Laufs et al. 2006a).
Figure 2.2 shows an example of EEG-fMRI study in focal non-lesional epilepsy and validation with subsequent intracranial EEG recording.
The co-localisation of the most significant BOLD changes within the resected volume has been related to a better outcome in small case-series (Lazeyras et al. 2000;
Thornton et al. 2009). Regarding the potential role of EEG-fMRI findings in clinical decision making, surgery or intracranial recording were reconsidered in 4/29 patients that had previously been rejected of poorly localised epileptic focus with other diagnostic modalities (Zijlmans et al. 2007).
Despite these promises, 40-70% of patients show no epileptic spikes in the EEG recording during fMRI or no BOLD signal changes correlated to IED so that advanced strategies to inform fMRI analysis are needed. Independent Component Analysis (ICA) has been applied to the EEG to select an “epileptic component” of the EEG for fMRI analysis. The results showed improved sensitivity compared to IED base approaches although strict validation was available only in a few of these patients (Jann et al. 2008;
Marques et al. 2009). ICA has also been used in “data-driven” analysis of the fMRI signal to reveal interictal haemodynamic signatures without reference to the EEG (Rodionov et al. 2007). Moreover intracranial electrodes can record abundant epileptic activity can be recorded directly from cortical electrodes while not being detected with scalp electrodes (Alarcon et al. 1994; Nunez&Silberstein 2000; Tao et al. 2005) so that precise modelling of the BOLD baseline is difficult.
21 Figure 2.2: EEG-correlated fMRI
27 year-old man with non-lesional epilepsy and complex partial seizures starting with jerking of the right hand :
a) EEG recorded inside a 3T MR scanner with continuous slice acquisition shows prominent MR gradient-induced artifacts preventing analysis of the raw data.
b) EEG corrected for gradient-induced artefacts reveals the presence of significant cardioballistogram (arrows).
c) Subsequent EEG correction for cardioballistogram showing frequent right frontal Interictal Epileptiform Discharges (IED, arrows).
d) Results of EEG-fMRI analysis (after estimation of the General Linear Model to reveal brain regions where the variance of the BOLD signal recorded with fMRI is statistically explained by the modelled BOLD response to IED). Images are coregistered to axial slices of T1-weighted MRI of the individual patient with intracranial depth electrodes.
There is a widespread network of BOLD changes (yellow-red clusters : positive BOLD changes, maximum in the supplementary motor cortex, yellow arrow ; blue-white clusters : negative changes, maximum in the medial parietal cortex, white arrow) extending beyond the frontal lobe and in both hemisphere. Notably, there are negative BOLD changes in the thalamus and in the medial parietal cortex (precuneus), the latter corresponding to modulation in the default mode network time-locked to the IED.
From Vulliemoz S, Michel CM, Daunizeau J, Lemieux L, Duncan JS ; The combination of EEG souce imaging and EEG-correlated functional MRI to map epileptic networks; Epilepsia 2010 Apr 51(4): 491-505
a
b
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d
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22 2.5
Combination of ESI and EEG-fMRI
The combined analysis of electro-physiological and haemodynamic measurements always requires the awareness that the two datasets reflect observables differentially linked to the underlying neural activity and therefore present intrinsic discrepancies. For example, fMRI responses reflecting high metabolic activity can have no EEG correlate due to brain architecture such as deep-seated sources, source orientation tangential to the scalp, opposing source orientation in sulci or concentric neuronal architecture (Connors&Gutnick 1990). Further, a non-synchronised increase in neuronal activity would cause a metabolic increase without EEG change. On the other hand, an EEG pattern without fMRI correlate is conceivable if a small part of a neuronal population behaves in a highly synchronised pattern without significant metabolic increase.
Furthermore, the BOLD signal is due to oxygenation changes in both the micro-vascular tissue bed and the downstream venous pooling system, leading to potential responses in draining veins remote from the neural source. In anesthetised monkeys, sensory cortex mapping with fMRI and microelectrode arrays showed an overlap of 55% (Disbrow et al.
2000). while in patients with epilepsy, intracranial EEG studies showed that IED sources and IED-correlated fMRI responses share spatial proximity but not exact concordance (Benar et al. 2006; Grova et al. 2008; Vulliemoz et al. 2009) and the changes in neuronal activity related to distant BOLD responses is largely unknown, partly because these sites might not be sampled by intracranial electrodes. The coupling between neuronal activation, perfusion and oxygenation seemed to be preserved in the irritative zone (Stefanovic et al. 2005), including during epileptic discharges (Carmichael et al. 2008a;
Hamandi et al. 2008a), but this coupling seems to be altered in electrographic seizures (Bahar et al. 2006). Structural brain lesions, notably of cerebro-vascular origin, can affect neuro-vascular coupling (Rossini et al. 2004). This should be considered when modelling the BOLD response in regions potentially affected by abnormal haemodynamic properties (vascular lesions, vascular malformations or tumours). Finally, there is puzzling evidence of regional cerebral blood flow changes prior to the onset of a stimulus and unrelated to intra-cranially recorded neuronal activity (Sirotin&Das 2009).
Such changes have also been found prior to focal or generalised spikes detected by scalp electrodes (Hawco et al. 2007; Moeller et al. 2008; Jacobs et al. 2009) suggesting early neurovascular changes that precede the spikes and that are so far undetected by scalp EEG.
23
3 Experimental studies
3.1
Synopsis
In this experimental section, this thesis presents seven studies published in or currently submitted to peer-reviewed journals. In all these publications the applicant was one of the main authors (first or last) or a major contributor.
First, two studies investigate the reliability of EEG-fMRI as a localising tool of focal epileptic activity and the ability of the technique to predict post-operative seizure freedom. Invasive validation with intracranial EEG and/or the resection zone in operated patients was used as gold standard.
- In Chapter 4: validation of EEG-fMRI is investigated using concordance with the resected zone and post-operative seizure controls in 10 operated patients. BOLD changes concordant with the resection zone were associated with a better outcome than discordant findings.
- In Chapter 5: a larger group of 23 patients was studied, all suffering from epilepsy caused by a focal cortical dysplasia, a frequent cause of medically refractory epilepsy. EEG-fMRI findings were compared to intracranial EEG results. Similarly to the previous study, focal findings concordant with the seizure onset zone identified with intracranial EEG were predictive of a good post-operative outcome while discordant findings predicted a poor outcome or were associated with intracranial EEG findings that led to rejection of surgical treatment.
The next three studies propose different combination of EEG-fMRI with spatio-temporal EEG analysis and electrical source imaging to guide fMRI analysis and improve the specificity or sensitivity of EEG-fMRI studies in patients with epilepsy:
- In Chapter 6, simultaneous ESI and EEG-fMRI showed that the high temporal resolution of ESI allowed discriminating between BOLD changes related to the onset vs propagation of interictal activity, thereby increasing the specificity of EEG-fMRI.
- Chapter 7 describes a new strategy to improve the sensitivity of EEG-fMRI studies for localising epileptic activity by refining the modelling of interictal epileptic activity. ESI was used to estimate the continuous activity of the epileptic source during EEG- fMRI. This activity was then used to map brain regions that show haemodynamic fluctuations that correlates with the estimated source timecourse. Comparatively to
24 the conventional EEG-fMRI analysis, the sensitivity of the techniques showed clinically meaningful improvements in 7/15 cases.
- In Chapter 8, another new method is proposed to tackle the frequent problem of the the absence of epileptic discharges in the EEG recorded during fMRI Epilepsy- specific EEG maps are extracted from the clinical long-term EEG and the presence of this map in the EEG recorded during fMRI is used to guide fMRI analysis. All cases were validated with intracranial EEG and/or resection zone in post-operative seizure free patients. Concordant and clinically meaninful results were found in 78%
of these datasets of difficult cases that were previously inconclusive.
The last two studies report pioneering work of the first simultaneous intracranial EEG and fMRI in patients with epilepsy. Preliminary safety studies have shown that the interactions between intracranial electrodes and MR imaging were compatible with safe recording (Carmichael et al. 2007; Carmichael et al. 2008b). The possibility of simultaneous intracranial EEG and fMRI recordings represents a unique tool to explore whole-brain haemodynamic changes related to very focal epileptic activity as recorded with the spatial resolution of intracranial EEG. Such technological development would also allow for a precise study of the neurovascular coupling of physiological (spontaneous brain oscillations, task-related activity) and pathological neuronal activity in the human brain.
- Chapter 9 reports BOLD changes related to focal interictal epileptic activity recorded with intracranial electrodes. This whole-brain mapping informed by the high spatial and temporal resolution of intracranial EEG was very complementary to the reduced spatial coverage of intracranial EEG. It allowed a better understanding of the epileptic networks in these patients and provided hypotheses to explain the persistence seizures of post-operatively in one patient.
- Chapter 10 investigates in closer detail the safety aspects and data quality in these first recordings in humans. Despite the interaction of both equipment, the technique was safe and allowed to record BOLD changes at close proximity of the recording intracranial electrodes, as well as remotely.
25
4 EEG correlated functional MRI and postoperative outcome in focal epilepsy.
This paper has been published in :
J Neurol Neurosurg Psychiatry. 2010 Aug;81(8):922-7. Epub 2010 Jun 14
by Thornton R, Laufs H, Rodionov R, Cannadathu S, Carmichael DW, Vulliemoz S, Salek-Haddadi A, McEvoy AW, Smith SM, Lhatoo S, Elwes RD, Guye M, Walker MC, Lemieux L, Duncan JS.
26
EEG correlated functional MRI and postoperative outcome in focal epilepsy
Rachel Thornton,
1,2Helmut Laufs,
1,2,3Roman Rodionov,
1,2Sajitha Cannadathu,
1,2David W Carmichael,
1,2Serge Vulliemoz,
1,2Afraim Salek-Haddadi,
1,2Andrew W McEvoy,
1,2Shelagh M Smith,
1,2Samden Lhatoo,
4Robert D C Elwes,
5Maxime Guye,
6Matthew C Walker,
1,2Louis Lemieux,
1,2John S Duncan
1,2ABSTRACT
BackgroundThe main challenge in assessing patients with epilepsy for resective surgery is localising seizure onset. Frequently, identification of the irritative and seizure onset zones requires invasive EEG. EEG correlated functional MRI (EEG-fMRI) is a novel imaging technique which may provide localising information with regard to these regions. In patients with focal epilepsy, interictal epileptiform discharge (IED) correlated blood oxygen dependent level (BOLD) signal changes were observed in approximately 50% of patients in whom IEDs are recorded. In 70%, these are concordant with expected seizure onset defined by non-invasive electroclinical information. Assessment of clinical validity requires post- surgical outcome studies which have, to date, been limited to case reports of correlation with intracranial EEG. The value of EEG-fMRI was assessed in patients with focal epilepsy who subsequently underwent epilepsy surgery, and IED correlated fMRI signal changes were related to the resection area and clinical outcome.
MethodsSimultaneous EEG-fMRI was recorded in 76 patients undergoing presurgical evaluation and the locations of IED correlated preoperative BOLD signal change were compared with the resected area and postoperative outcome.
Results21 patients had activations with epileptic activity on EEG-fMRI and 10 underwent surgical resection. Seven of 10 patients were seizure free following surgery and the area of maximal BOLD signal change was concordant with resection in six of seven patients. In the remaining three patients, with reduced seizure frequency post-surgically, areas of significant IED correlated BOLD signal change lay outside the resection.
42 of 55 patients who had no IED related activation underwent resection.
ConclusionThese results show the potential value of EEG-fMRI in presurgical evaluation.
INTRODUCTION
In refractory focal epilepsy, surgical resection has the best chance of a good outcome if seizure onset is identified and remote from eloquent cortex.1The challenge of presurgical evaluation rests in accurate delineation of these regions.
High quality structural MRI has increased the identification of underlying pathology in epilepsy but successful resective surgery is increasingly possible in the absence of MRI abnormalities,2 3 and the epileptogenic zone may extend beyond the margin of abnormal tissue where pathology is
seen.1Standard non-invasive investigations can fail to localise seizure onset and invasive EEG recording is often necessary, which is expensive and has associated morbidity.4Intracranial recording requires careful patient selection and 70e90% of such patients will subsequently be offered surgical resection.5 There is a pressing need therefore for non-invasive techniques to identify these regions and assist in the planning of invasive recordings.
Fluorodeoxyglucoseepositron emission tomog- raphy and ictal-interictal single photon emission CT are helpful but lack the spatial resolution of MRI. Neurophysiological approaches (high density EEG and magnetoencephalography) have shown concordance with intracranial recordings and postoperative outcome (ie, have some positive predictive value6 7) but despite excellent temporal resolution are limited by the accuracy of source localisation.
EEG correlated functional MRI (EEG-fMRI), whereby EEG and fMRI are acquired simulta- neously, reveals regions of blood oxygen level dependent (BOLD) signal changes associated with interictal (IED) and ictal epileptiform discharges which may provide information about the epileptic network. The methodology combines the spatial resolution of MRI with the temporal resolution of EEG and applying EEG-fMRI to presurgical evalu- ation has been an important motivation for the technique’s development.8e12
To date, clinical validation of EEG-fMRI has consisted of studies comparing IED correlated BOLD signal change with invasive and non-invasive methods of localising the seizure onset zone,9 11e15 reporting up to 70% concordance (colocalisation of areas of maximal positive BOLD signal activation and presumed seizure onset at a lobar level) between IED-related BOLD activations and electroclinical seizure onset in patients with focal epilepsy.
Comparison of novel localisation techniques in focal epilepsy with intracranial EEG, the current gold standard, is considered the best method for validation16 but the approach has drawbacks.
Intracranial EEG records directly from regions of interest but has reduced spatial coverage owing to the limited number of electrodes which can be implanted. The problem of source reconstruction found in scalp EEG is not abolished as many regions of interest cannot be accurately sampled using current methods. Nevertheless, it remains one of the best methods of identifying the likely irritative and epileptogenic zones before resection. In EEG-fMRI
<Additional figures are published online only. To view these files please visit the journal online (http://jnnp.bmj.
com).
1Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
2National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Trust, London, UK
3Department of Neurology and Brain Imaging Centre, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
4Department of Neurology, North Bristol NHS Trust, Frenchay Hospital, Bristol, UK
5Department of
Neurophysiology, Kings College Hospital, London, UK
6Centre de Re´sonance Magne´tique Biologique et Me´dicale (CRMBM), UMR CNRS 6612 and Service de Neurophysiologie Clinique, INSERM U 751,CHU Timone, AP-HM, Faculte´ de Me´decine de Marseille, Universite´ de la Me´diterrane´e, Marseille, France Correspondence to Dr R Thornton, UCL, Institute of Neurology, MRI Unit, National Society for Epilepsy, Chesham Lane, Chalfont St Peter, Buckinghamshire SL9 0RJ, UK;
r.thornton@ion.ucl.ac.uk Received 1 October 2009 Revised 17 December 2009 Accepted 24 December 2009 Published Online First 14 June 2010
922 J Neurol Neurosurg Psychiatry2010;81:922e927. doi:10.1136/jnnp.2009.196253
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research, concordance of activations with the irritative zone recorded during invasive monitoring have been reported in small groups, an important step in establishing the tech- nique’s clinical utility.12 14 17One group specifically addressed the use of EEG-fMRI in surgical planning,18 carrying out studies in a group of 29 patients previously rejected for surgery with frequent IEDs. They reported useful EEG-fMRI results in eight patients, four of whom were considered for surgical resection, and suggested that EEG-fMRI may contribute to the surgical decision making process when standard methods did not identify a surgical target.18
Here we compared EEG-fMRI results in a group of patients undergoing surgery with postoperative outcome, assessing whether resection of a region exhibiting IED correlated BOLD activation was associated with postoperative seizure freedom.
METHODS Patients
Seventy-six consecutive patients with refractory focal epilepsy undergoing presurgical evaluation with IEDs recorded during video telemetry underwent EEG-fMRI between December 2005 and May 2008. The EEG-fMRI results did not form any part of the surgical decision making process and were undertaken independently from other investigations without any reduction in medication.
Clinical course
Patients underwent electroclinical assessment, including video EEG, clinical examination and structural MRI (National Hospital for Neurology and Neurosurgery Epilepsy protocol).
The decision regarding electroclinical localisation and subse- quent resection was made by the clinical team and undertaken with curative intent. Six patients underwent anterior temporal lobe resection and four underwent neocortical resection (two frontal, one parietal and one occipital).
The extent of resection, histopathological diagnosis and Inter- national League Against Epilepsy (ILAE) outcome19were recorded 1 year postoperatively. ILAE outcome is measured by a graded scale summarised as follows: 1¼seizure free, 2¼auras only, 3¼seizures on a maximum of 3 days per year, 4¼>50% reduction in seizure frequency, 5¼50% reduction to 100% increase in seizure frequency, 6¼>100% increase in seizure frequency.
EEG-fMRI acquisition
All patients underwent EEG-fMRI for between 35 and 60 min at 1.5 or 3 T. Patients lay still in the scanner with their eyes closed and with no instruction regarding vigilance. EEG was recorded continuously during fMRI using MR compatible systems (Brain Products, Munich, Germany) along with a scanner synchroni- sation signal and ECG. Sets of 404 T2* weighted single shot gradient echo, echo planar images (EPI; TE/TR 30/3000 ms at 3 T; TE/TR 0.5/3000 ms at 1.5 T),flip angle 90843 (at 3T) and 21 (at 1.5T), interleaved slices (thickness: 3 mm at 3 T; 5 mm at 1.5 T), FOV 24324 cm2, 642) were acquired continuously on GE MR scanners (GE Medical Systems, Milwaukee, Wisconsin, USA).
Offline MRI and pulse related artefacts were removed from the EEG trace20 21and events marked.
fMRI processing and analysis
The fMRI time series were realigned, spatially smoothed with a cubic Gaussian kernel of 8 mm full width at half maximum and analysed using a general linear model in SPM5 (http://www.fil.
ion.ucl.ac.uk/SPM) to identify IED related BOLD changes.
Separate sets of regressors were formed for each type of IED
allowing identification of specific BOLD effects. Discharges were represented as zero duration events (unit impulse, or ‘V’, func- tions) convolved with the canonical haemodynamic response function its temporal and dispersion derivatives, resulting in three regressors for each event type.22 Ictal events were modelled as three‘blocks’representing earliest electrographic change, clinical seizure onset and postictal change on the EEG.
Motion related effects were included in the general linear model as 24 regressors representing six scan realignment parameters and a Volterra expansion of these,23 and Heaviside step functions for large motion effects.24 Additional regressors were included for pulse related signal changes.25
F contrasts were used across three regressors corresponding to each event type with a threshold of p<0.05 corrected for multiple comparisons (family-wise error) considered significant.
A T contrast (p<0.001 uncorrected for multiple comparison) assessed whether the haemodynamic response function was positive or negative. BOLD responses were considered positive when a positive haemodynamic response function (HRF) was plotted for a given cluster. A less stringent significance threshold was used to explore the data (p<0.001, uncorrected). EPI data were coregistered to the preoperative T1 weighted images to create activation map overlays.26 Clusters of significant BOLD change were labelled anatomically on high resolution EPI images and coregistered with preoperative structural T1 images.
Postoperative imaging
Postoperative T1 weighted MRI was acquired and coregistered with the preoperative images allowing visualisation of fMRI activation maps in relation to the area of resection. Concordance was defined for the cluster of BOLD activation containing the global maximum.
RESULTS
Seventy-six patients underwent EEG-fMRI recordings. Of these 76 patients, 43 had temporal lobe epilepsy, 26 had frontal lobe epilepsy and seven had posterior epilepsies. Fifty-two (68%) of these subsequently underwent surgical resection. Thirty-four of 52 (65%) reached 1 year follow-up of whom 10 (33%) had significant activation on EEG-fMRI. A further 11 had significant activation on EEG-fMRI but did not undergo surgery owing to an extensive epileptogenic zone or overlap with motor function (n¼5), intraoperative complications (n¼1), patient choice (n¼1) or awaiting further evaluation (n¼4). In 36/52 (69%) patients who were operated and 13/24 (54%) who were not operated, no IEDs were recorded. The mean number of IEDs during the EEG- fMRI studies was 29.3 across all 76 patients (89.3 in those who had any IED). The median number of IEDs in the group who had BOLD activations and underwent resection was 329 (range 22e635).
Clinical data and EEG-fMRI results are summarised in table 1.
Two representative cases are presented infigures 1 and 2. The remainder are available in the supplementary web material (available online).
DISCUSSION
This series of patients with refractory focal epilepsy demon- strated good correspondence between the localisation of IED related BOLD changes, the area of resection and seizure outcome, with useful information obtained in 10/34 patients in whom resections were carried out and the requisite follow-up period reached. In six of the seven cases that were seizure free postoperatively, the area of resection included the locus of
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