ios press brain mechanisms of altered consciousness in

Behavioural Neurology 24 (2011) 35–41 35DOI 10.3233/BEN-2011-0312IOS Press

Brain mechanisms of altered consciousness infocal seizures

Andrew P. Bagshawa,b and Andrea E. Cavannac,d,∗

aSchool of Psychology, University of Birmingham, Birmingham, UKbBirmingham University Imaging Centre, Birmingham, UKcDepartment of Neuropsychiatry, University of Birmingham and BSMHFT, Birmingham, UKdInstitute of Neurology, UCL, London, UK

Abstract. Consciousness is a central concept in epileptology, relevant to the understanding of both focal and generalized seizures.Within focal seizures, impairment of consciousness has long been considered as the main criterion differentiating complex partialseizures (CPS) from simple partial seizures With the development of improved tools for investigating human brain function,new insights into the brain mechanisms of altered consciousness in CPS have become available. This paper reviews the existingliterature on how the currently available methods can be used to address the fundamental issue of how CPS alter consciousness.

Keywords: Epilepsy, consciousness, focal seizures, complex partial seizures, default mode network

1. How is consciousness altered in complex partialseizures?

That consciousness is altered during complex par-tial seizures (CPS) can be clearly observed clinicallyand by patients and their carers, leading to impairmentof consciousness being used as the major distinctionbetween CPS and simple partial seizures (SPS) [11].However, the answer to the question of exactly howconsciousness is altered during CPS is complicated bythe fundamental issue of defining what is meant by‘consciousness’, a term that is more easily debated byphilosophers than employed clinically by neurologists.What is often defined clinically as ‘loss of conscious-ness’ can be caused by much more specific disruptionsof normal brain function. Standard clinical examina-tion during and immediately after a CPS generally re-lies upon an assessment of the patient’s responsivenessand ability to perform simple language, memory andmotor tasks (e.g. response to verbal commands, object

∗Corresponding author: Andrea Eugenio Cavanna, MD, Depart-ment of Neuropsychiatry, University of Birmingham and BSMHFT,Barberry Building, 25 Vincent Drive, Birmingham B15 2FG, UK.E-mail: [email protected].

naming, reaching for an object etc.). Selective impair-ment of these systems as a result of primary or prop-agated seizure activity does not necessarily imply anyalteration in the patient’s level of consciousness, but thepatient’s unresponsiveness could easily be interpretedas such. Added to this definitional issue, the neurosci-entific study of the brain mechanisms underlying con-sciousness is itself an active field, and one which isfar from being resolved [8,12]. The available evidencesuggests that consciousness is mediated by a distribut-ed network of regions, collectively termed the ‘neu-ral correlates of consciousness’ (NCC), which must beperforming individually and collectively in order forconsciousness to be preserved. Therefore, despite theintrinsic difficulty in defining what is precisely meantby consciousness, particularly in a neurological sense,the suggestion would be that alterations in conscious-ness during CPS occur when seizure activity developsfrom a focus and propagates to more extensive brainregions which are involved in the general maintenanceof the conscious state.

However, while this provides a conceptual frame-work within which to examine the link between brainactivity and behaviour, the exact mechanisms by whichthis disruption of the NCC occurs is not clear. With the

ISSN 0953-4180/11/$27.50 2011 – IOS Press and the authors. All rights reserved

36 A.P. Bagshaw and A.E. Cavanna / Brain mechanisms of altered consciousness in focal seizures

advent of improved tools for investigating human brainfunction, new insights into these issues are available,and the focus of this review will be on summarisinghow the available methods can be used to address thefundamental issue of how CPS alter consciousness. Forexample, recent studies have determined that the brainis intrinsically organised into a number of ‘resting-statenetworks’ (RSNs), often quite distributed sets of re-gions whose activity is correlated even in the absenceof a task [14]. It seems that these networks, at leastone of which has been linked with cognitive processesthat are fundamental to consciousness, can be disruptedby epilepsy, even in the absence of a seizure [28,40].With the application of these advanced neuroimagingtechniques, allied with improvements in the way inwhich traditional tools such as intracranial EEG (iEEG)are analysed, a much more detailed understanding ofthe neurobiological mechanisms responsible for con-sciousness and its disruption by epilepsy is possible.However, to date, no single technique can provide thehigh spatiotemporal resolution coupled with access toactivity from throughout the brain that would ideallybe needed to study effects as widespread and complexas are likely to be responsible for alterations to con-sciousness. In addition, as mentioned above, standardclinical examination of a patient’s state ictally and pos-tictally does not provide detailed information about thenature of any alterations of consciousness. Tools suchas the Ictal Consciousness Inventory, a twenty pointquestionnaire that can be used to examine the effect ofCPS on the level and contents of consciousness, pro-vide a much more specific way of identifying the pre-cise behavioural effects of the seizure [9]. The levelof consciousness depends on the integrity of the retic-ular activating system and thalamocortical pathways,while the contents of consciousness can be affectedby disruption of more restricted systems, the precisedetails of which will depend on the focus of the pa-tient’s epilepsy. Detailed examination of the experi-ential effects of seizures, coupled with state-of-the-artneuroimaging techniques and analysis, not only hasthe potential to inform clinical management but also toserve as a tool for understanding the neural substrates ofconsciousness itself. Perhaps most importantly from aclinical viewpoint, if the underlying brain mechanismsresponsible for these alterations in consciousness canbe understood, the possibility of developing treatmentsto reduce the negative effects of seizures on patients’lives can be considered. Although clearly a complexproblem, these goals provide the motivation to devel-op methods which can uncover the link between brainfunction and behaviour, and understand how a pathol-ogy as diverse as epilepsy can affect brain function.

2. How can the brain mechanisms of alteredconsciousness be investigated?

Like most other higher order brain functions, con-sciousness arises from the coordinated activity of a dis-tributed network of cortical and subcortical regions. Assuch, the ideal method to identify the NCC (i.e. theminimum set of regions necessary for consciousness)would provide information from all regions of the brainwith millimetre spatial and millisecond temporal pre-cision [12]. Unfortunately, no such method currentlyexists, but the techniques that are available have beenused to address some of the most important questionsregarding the nature of the brain mechanisms that me-diate altered consciousness in CPS. Although it is in-tuitively obvious that since the effects of interest oc-cur during seizures, it is during seizures that patientsshould be studied, some very interesting observationshave also been made interictally, both by observing thegenerators of interictal discharges and by examiningthe dynamics of the epileptic brain at rest.

The technique that has been most widely used in theinvestigation of CPS is single photon emission comput-ed tomography (SPECT). SPECT involves the injec-tion of a radionuclide (most commonly99mTc-HMPAO(hexamethylpropylene amine oxime), which gives im-ages that are sensitive to cerebral blood flow) as soonas possible following the start of a seizure. The ra-dionuclide very quickly becomes fixated in the braintissues, with a regional distribution that is proportionalto the blood flow, and hence the neuronal activity, at thetime of injection. The patient is subsequently taken tothe scanner following the end of the seizure, where theradioactive decay of the labelled compound is detectedand reconstructed into an image which provides infor-mation about its distribution. The main advantages ofSPECT are that it can be used ictally, and that it pro-vides full brain sensitivity. The disadvantages are thatit involves a considerable radiation dose, and so can-not be used repeatedly in individual subjects, and has arelatively low spatial and temporal resolution, meaningthat the dynamic interactions between regions cannotbe investigated.

At the other end of the temporal scale, EEG mea-sures the coordinated post-synaptic activity of relative-ly widespread, synchronous neuronal populations withmillisecond precision. When recorded non-invasivelyfrom the scalp the ability to identify the precise re-gions generating the signal is difficult, but during pre-surgical evaluation it is relatively common practice torecord EEG data intracranially (iEEG) [8]. This pro-

A.P. Bagshaw and A.E. Cavanna / Brain mechanisms of altered consciousness in focal seizures 37

vides a much more precise idea of the spatial location ofthe activity, as well as retaining the primary advantageof EEG, namely its high temporal resolution. Thereis increasing evidence that the coordination betweenregions is mediated by oscillatory electrical activity,meaning that examination of the EEG provides an ex-cellent opportunity to determine the extent to whichregions are functionally connected [35]. The disadvan-tage of iEEG is that the number of implanted electrodesis limited, and restricted to regions about which thereis a clear clinical hypothesis, meaning that in practicethere are limitations about the extent to which networkactivity can be assessed with iEEG. However, it can bean extremely powerful tool in selected patients.

Functional MRI (fMRI) has become one of the mostwidely used methods to study the human brain sinceits inception in the early 1990s. Its main advantageis that it has high spatial resolution and can providewhole brain coverage, meaning that it is an ideal toolto study the widespread, distributed networks that areoften implicated particularly in higher order brain func-tions. However, it measures neuronal activity only in-directly via the haemodynamic response (HR), whichalso imposes a limit on the temporal resolution thatcan be achieved – the HR to even a very brief stimu-lus takes approximately five seconds to peak and doesnot return to its pre-stimulus level for another 10–15seconds. Although fMRI has been used to examine thehaemodynamic effects of seizures, the confined spaceavailable in the MRI scanner coupled with the relative-ly low likelihood of actually observing a seizure in thetime available for scanning mean that interictal fMRI ismore common [15,24,34]. Often this is combined withEEG to specifically examine interictal discharges [18],but another approach is to investigate spontaneous fluc-tuations of the fMRI signal across multiple brain re-gions, something for which fMRI is ideally suited. Ofparticular interest in this regard is the observation fromthe study of control subjects that the human brain isorganised into a number of RSNs [14]. These RSNscan be identified by observing the correlations in theactivity of the brain when it is not subjected to anytask, and there is increasing evidence that these net-works can be disrupted by epilepsy [28,40]. RSNs havebeen identified which link with intrinsic correlations ofsensorimotor, visual, auditory, language and attentionsystems, and each seems to be related to a particularpattern of activity on the scalp EEG [29]. Perhaps mostrelevant to the current topic, a ‘default mode network’(DMN) has been defined as consisting of regions in thefrontal and parietal lobes, the cingulate gyrus and the

thalamus [32]. This network of regions is generallydeactivated whenever tasks requiring goal-directed at-tention are performed, and some of the cognitive pro-cesses that are fundamental to consciousness have beenlinked with activity in the DMN (e.g. conceptual pro-cessing, self-reflection) [10,20]. Interestingly, some ofthe regions that have been implicated in alterations ofconsciousness in patients with CPS overlap with thosein the DMN [10,17].

Finally, although epilepsy and epileptic seizures areintrinsically features of abnormal brain function, in-formation can also be extracted by investigating brainstructure using MRI. Even when no obvious lesion canbe detected by visual inspection as in the norm clinical-ly, more sophisticated methods of quantitative analysiscan sometimes identify subtle structural abnormalities,for example associated with abnormal signal intensity,cortical thickness etc [13]. In addition, new techniquessuch as diffusion tensor imaging (DTI) allow the un-derlying properties of the white matter connections be-tween regions to be probed, which feasibly could beused to investigate the integrity of the links between theregions comprising the NCC [23].

With a topic as complex as consciousness, and thelimitations of the available tools for investigating thehuman brain, it is perhaps not surprising that a fullunderstanding of the mechanisms by which CPS canaffect the level and contents of a patient’s conscious-ness has yet to be formulated. However, considerableprogress has been made, meaning that some firm con-clusions can be drawn about how and why CPS lead totheir observed behavioural effects.

3. What are the mechanisms of alteredconsciousness in CPS?

A seizure originating in and subsequently confinedto the medial temporal lobe is likely to result in thedisruption of processes subserved by those structures,in particular memory. This might lead to some ictaland postictal amnesia, but would be unlikely to resultin other deficits. Thus, the observation that seizuresoriginating from a focus can lead to alterations of con-sciousness (i.e. the observation that CPS exist) suggeststhat in certain circumstances focal seizures can affectmore distant, and potentially more widespread, brainstructures. The involvement of regions remote from theepileptogenic focus has been noted in a number of stud-ies with various methodologies [5,26,31,36,38],but theprecise relationship between this often widespread ac-


tivity and alterations in consciousness remains unclear.What are the NCC, the regions necessary for the main-tenance of the conscious state, and what are the neu-robiological mechanisms by which they are disruptedduring and after seizures?

The majority of the information about the regionsthat comprise the NCC, which are most straightfor-wardly identified during seizures, comes from SPECTstudies. A number of these have suggested that CPSare associated with widespread, bilateral cortical andsubcortical increases and decreases in blood flow [5,36]. The most common pattern involves increases in thetemporal lobe ipsilateral to the seizure focus, as well asbilateral subcortical midline structures, in particular themedial thalamus, basal ganglia and upper brainstem. Inaddition to these increases in blood flow (hyperperfu-sion), CPS demonstrate marked decreases in blood flow(hypoperfusion) in the bilateral orbitofrontal cortex,an-terior and posterior cingulate regions and frontal andparietal association cortices. This pattern of increas-es and decreases in blood flow is specific to seizureswhich involve disruption of consciousness (i.e. CPS),with SPS showing much more limited changes primari-ly involving the temporal lobe itself [5]. These regions,then, could be characterised as the NCC. By analysingsignal correlations across the different activated anddeactivated regions, it is possible to get an idea of thehow they are connected, leading to the observation thatfronto-parietal hypoperfusion is correlated with mid-line subcortical structures, including the thalamus [5].This has lead to the ‘network inhibition hypothesis’ [4,16], which suggests that propagation of seizure activityto subcortical structures that are needed for cortical ac-tivation disrupts their normal function and consequent-ly the cortex is deactivated, entering a state that mayhave similarities with sleep. Support for such a hypoth-esis comes from the observation of slow wave activity,which is also observed in sleep, in the thalamus andfronto-parietal regions during CPS [6,22].

While SPECT is able to localise the regions affect-ed during CPS, and hence to identify the network thatforms the NCC, its ability to investigate the functionalconnections between these regions is limited by its lowtemporal resolution. Given that the activity within anetwork must be temporally coordinated if the networkis to function correctly, a direct assessment of how re-gions are coordinated is likely to shed light on how theymight become disrupted as a result of seizures. Twomain approaches have been taken to address this issue,namely iEEG and fMRI. As discussed above, iEEGhas ideal temporal resolution and is also a relatively

unambiguous measure of brain activity, compared tothe haemodynamic changes that form the basis of thefMRI signal. However, the electrodes are placed pure-ly on clinical grounds, and there are relatively few ofthem, meaning that the activity of regions involved inthe NCC cannot always be measured. Despite this,in selected cases there may be clinical reasons for im-planting a relatively large number of electrodes, andif the trajectory of an electrode is opportune it maystill be possible to record from some structures of in-terest, even if they are not the target. In one exampleof this, Guye et al. [22] were able to select 13 TLEpatients with electrode contacts in the cortex and thethalamus from a total of 82 who had undergone iEEG.This allowed them to study thalamocortical couplingduring CPS and to observe that patients with mesialTLE (mTLE) who experienced early loss of conscious-ness during CPS also had a higher degree of thalam-ocortical synchrony. The idea that abnormal thalamo-cortical synchrony might have a role in alterations ofconsciousness during CPS was supported by more re-cent work from the same group, which found that in-creased synchrony in structures outside of the temporallobe was strongly correlated with the degree to whichconsciousness was altered [2].

MRI techniques can also be used to shed light onthese issues. In particular, as discussed above, fMRIis ideally suited to the study of widespread networksand the connectivity between the individual regions ofthe network. Of particular relevance, it is becomingincreasingly widely accepted that the DMN is disrupt-ed in both generalised and partial epilepsy. The DMN,originally identified from the observation of commonregions of deactivation across multiple tasks, is posit-ed to represent baseline brain activity related to self-oriented mental activity [20,32]. Regions associatedwith the DMN have been observed to be deactivatedin response to interictal epileptic discharges (IEDs) ingeneralised [1,19] and partial [25,27,33,39], suggest-ing a mechanism whereby interictal discharges maydisrupt normal brain function. In addition, even in theabsence of IEDs, the spontaneous activity of the DMNhas been observed to be disrupted in TLE [40]. With itsrelatively good temporal resolution, fMRI can be usedto explicitly probe the relationship between the signalfluctuations in different regions (i.e. functional connec-tivity). This has indicated that patients with mesialTLE have increased connectivity within the temporallobes compared to control subjects, but decreased con-nectivity in fronto-parietal networks [28]. A similarconclusion regarding the functional connectivity of the


temporal lobes has also been reached via iEEG [3], andanalysis of structural MRI data also points to abnormalstructural connectivity in patients with partial epilep-sy [13]. Advanced mathematical tools such as graphtheory allow the degree of connectivity between thenodes of a network to be explicitly quantified [38], andmay in the future provide a framework to characteriseand summarise the alterations to connectivity causedby epilepsy [21,28]. One of the advantages of graphtheoretical analysis is that it is able to identify partic-ularly well-connected regions of a network, so called‘hubs’. Interestingly, several studies have identified theprecuneus/posterior cingulate region as a hub region,consistent with its high baseline metabolic rate andseemingly important position within the DMN [32].Such observations, linked with the previous discussionabout the regions involved in the NCC, may suggestthat the involvement of the posterior cingulate region isparticularly important in determining whether a seizurewill result in alterations of consciousness [10]. A studyinto the functional connectivity of generalised spike-wave discharges, which can also lead to loss of con-sciousness, similarly suggested that the precuneus isfundamentally important [37], although similar analy-ses have yet to be performed in partial epilepsy. The de-velopment of these analysis tools, which can be explic-itly used to probe how spatially distributed regions co-ordinate their activity, has considerable potential to en-able non-invasive neuroimaging techniques to be usedto understand distributed network processes.

4. Conclusions

The available evidence from multiple methods of in-vestigation provides a coherent picture as to how activ-ity from focal seizures is able to lead to global disrup-tions in consciousness. Within this framework, seizureactivity spreads from its site of origin into wider brainregions, causing abnormally enhanced synchrony inregions responsible for the maintenance of the con-scious state, which may serve to mimic the patternmore normally seen during sleep. A widespread net-work of regions has been identified which are neces-sary for consciousness, involving bilateral subcorticalmidline structures, in particular the medial thalamus,basal ganglia and upper brainstem, as well as bilater-al orbitofrontal cortex, anterior and posterior cingulateregions and frontal and parietal association cortices.Several of these regions overlap with the DMN, andthe observation that patients with partial epilepsy have

modified resting state brain activity, particularly in theDMN, suggests that there is an inherent modificationof normal thalamocortical connections, potentially be-cause of the cumulative effect of seizures. The seizureactivity may then be able to take advantage of theseconnectional anomalies to interfere with DMN activity,leading to the clinical observation of a CPS. However,the precise nature of the relationship between the re-gions of the NCC and the DMN remains unclear, mak-ing this a plausible though unproven hypothesis. Afurther complication is that almost all of the studies inpartial epilepsy have been conducted in patients withmTLE, and although similar mechanisms would be ex-pected to occur in other CPS, the data to support this issparse.

Within this general framework, several lines of in-vestigation remain for future studies. Although restingfMRI studies are relatively straightforward to perform,and connect with a considerable literature from controlsubjects, their link with ictal SPECT and iEEG resultsin the same patients remains to be clarified. Similarly,although there are several tools to characterise the na-ture of ictal alterations in consciousness, they are of-ten not used in neuroimaging studies, meaning that aprecise and detailed understanding of the behaviouraleffects of seizures in specific patients is not available.New methods of connectivity analysis such as graphtheory may help to quantify the nature of the disruptionscaused by epilepsy, and can be used to identify partic-ularly important regions within a network. With thesedevelopments leading to more precise understanding ofthe neural mechanisms underlying alterations to con-sciousness in CPS, the next step will be to identify waysin which this spread of activity can be disrupted andconsciousness retained.

References

[1] J.S. Archer, D.F. Abbott, A.B. Waites and G.D. Jackson, fMRI‘deactivation’ of the posterior cingulate during generalizedspike and wave,Neuroimage20 (2003), 1915–1922.

[2] M. Arthuis, L. Valton, J. Regis, P. Chauvel, F. Wendling,L. Naccache, C. Bernard and F. Bartolomei, Impaired con-sciousness during temporal lobe seizures is related to increasedlong-distance cortical-subcortical synchronization,Brain 132(2009), 2091–2101.

[3] G. Bettus, F. Bartolomei, S. Confort-Gouny, E. Guedj, P.Chau-vel, P.J. Cozzone, J.P. Ranjeva and M. Guye, Role of rest-ing state functional connectivity MRI in presurgical investiga-tion of mesial temporal lobe epilepsy,Journal of NeurologyNeurosurgery and Psychiatry(2010), in press.

[4] H. Blumenfeld, Epilepsy and consciousness, in:The neurolo-gy of consciousness, S. Laureys and G. Tononi, eds, Elsevier,Amsterdam, 2009.


[5] H. Blumenfeld, K.A. McNally, S.D. Vanderhill, A.L. Paige, R.Chung, K. Davis, A.D. Norden, R. Stokking, C. Studholme,E.J. Novotny, I.G. Zubal and S.S. Spencer, Positive and nega-tive network correlations in temporal lobe epilepsy,CerebralCortex14 (2004), 892–902.

[6] H. Blumenfeld, M. Rivera, K.A. McNally, K. Davis, D.D.Spencer and S.S. Spencer, Ictal neocortical slowing in tempo-ral lobe epilepsy,Neurology63 (2004), 1015–1021.

[7] E. Bullmore and O. Sporns, Complex brain networks: graphtheoretical analysis of structural and functional systems, Na-ture Reviews Neuroscience10 (2009), 186–198.

[8] A.E. Cavanna and F. Monaco, Brain mechanisms of alteredconscious states during epileptic seizures,Nature ReviewsNeurology5 (2009), 267–276.

[9] A.E. Cavanna, M. Mula, S. Servo, G. Strigaro, G. Tota, D.Barbagli, L. Collimedaglia, M. Viana, R. Cantello and F.Monaco, Measuring the level and contents of consciousnessduring epileptic seizures: the Ictal Consciousness Inventory,Epilepsy and Behavior13 (2008), 184–188.

[10] A.E. Cavanna and M.R. Trimble, The precuneus: a review ofits functional anatomy and behavioural correlates,Brain 129(2006), 564–583.

[11] Commission on Classification and Terminology of the Interna-tional League Against Epilepsy, Proposal for revised clinicaland electroencephalographic classification of seizures,Epilep-sia 22 (1981), 489–501.

[12] F. Crick and C. Koch, Consciousness and Neuroscience,Cere-bral Cortex8 (1998), 97–107.

[13] K. Dabbs, J. Jones, M. Seidenberg and B. Hermann, Neu-roanatomical correlates of cognitive phenotypes in temporallobe epilepsy,Epilepsy and Behavior15 (2009), 445–451.

[14] J.S. Damoiseaux, S.A. Rombouts, F. Barkhof, P. Scheltens,C.J. Stam, S.M. Smith and C.F. Beckmann, Consistent resting-state networks across healthy subjects,Proceedings of theNational Academy of Sciences USA103 (2006), 13848–13853.

[15] C. Di Bonaventura, A.E. Vaudano, M. Carnı, P. Pantano, V.Nucciarelli, G. Garreffa, B. Maraviglia, M. Prencipe, L. Boz-zao, M. Manfredi and A.T. Giallonardo, EEG/fMRI study ofictal and interictal epileptic activity: methodological issuesand future perspectives in clinical practice,Epilepsia47(Suppl5) (2006), 52–58.

[16] D.J. Englot and H. Blumenfeld, Consciousness and epilepsy:why are complex-partial seizures complex?,Progress in BrainResearch177 (2009), 147–170.

[17] P. Fransson and G. Marrelec, The precuneus/posterior cingu-late cortex plays a pivotal role in the default mode network:Evidence from a partial correlation network analysis,Neu-roimage42 (2008), 1178–1184.

[18] J. Gotman, Epileptic networks studied with EEG-fMRI,Epilepsia49(Suppl 3) (2008), 15236–15240.

[19] J. Gotman, C. Grova, A.P. Bagshaw, E. Kobayashi, Y.Aghakhani and F. Dubeau, Generalized epileptic dischargesshow thalamocortical activation and suspension of the defaultstate of the brain,Proceedings of the National Academy ofSciences USA102 (2005), 15236–15240.

[20] D.A. Gusnard and M.E. Raichle, Searching for a baseline:functional imaging and the resting human brain,Nature Re-views Neuroscience2 (2001), 685–694.

[21] M. Guye, G. Bettus, F. Bartolomei and P.J. Cozzone, Graphtheoretical analysis of structural and functional connectivityMRI in normal and pathological brain networks,MagneticResonance Materials in Physics, Biology and Medicine(2010)in press.

[22] M. Guye, J. Regis, M. Tamura, F. Wendling, A. McGonigal,P. Chauvel and F. Bartolomei, The role of corticothalamiccoupling in human temporal lobe epilepsy,Brain 129 (2006),1917–1928.

[23] H. Johansen-Berg and T.E.J. Behrens, Diffusion MRI: fromquantitative measurement to in-vivo neuroanatomy, AcademicPress, London, 2009.

[24] E. Kobayashi, A.P. Bagshaw, C.G. Benar, Y. Aghakhani, F. An-dermann, F. Dubeau and J. Gotman, Temporal and extratempo-ral BOLD responses to temporal lobe interictal spikes,Epilep-sia 47 (2006), 343–354.

[25] E. Kobayashi, A.P. Bagshaw, C. Grova, F. Dubeau and J. Got-man, Negative BOLD responses to epileptic spikes,HumanBrain Mapping27 (2006), 488–497.

[26] E. Kobayashi, A.P. Bagshaw, A. Jansen, F. Andermann, E.An-dermann, J. Gotman and F. Dubeau, Intrinsic epileptogenici-ty in polymicrogyric cortex suggested by EEG-fMRI BOLDresponses,Neurology12 (2005), 1263–1266.

[27] H. Laufs, U. Lengler, K. Hamandi, A. Kleinschmidt and K.Krakow, Linking generalized spike-and-wave discharges andresting state brain activity by using EEG/fMRI in a patientwith absence seizures,Epilepsia47 (2006), 444–448.

[28] W. Liao, Z. Zhang, Z. Pan, D. Mantini, J. Ding, X. Duan, C.Luo, Z. Wang, Q. Tan, G. Lu and H. Chen, Default mode net-work abnormalities in mesial temporal lobe epilepsy: A studycombining fMRI and DTI,Human Brain Mapping(2010), inpress.

[29] D. Mantini, M.G. Perrucci, C. Del Gratta, G.L. Romani andM. Corbetta, Electrophysiological signatures of resting statenetworks in the human brain,Proceedings of the NationalAcademy of Sciences USA104 (2007), 13170–13175.

[30] C.M. Michel, G. Lantz, L. Spinelli, R.G. De Peralta, T. Landisand M. Seeck, 128-channel EEG source imaging in epilepsy:clinical yield and localization precision,Journal of ClinicalNeurophysiology21 (2004), 71–83.

[31] S.G. Mueller, K.D. Laxer, N. Cashdollar, D.L. Flenniken, G.B.Matson and M.W. Weiner, Identification of abnormal neuronalmetabolism outside the seizure focus in temporal lobe epilep-sy,Epilepsia45 (2004), 355–366.

[32] M.E. Raichle, A.M. MacLeod, A.Z. Snyder, W.J. Powers, D.A.Gusnard and G.L. Shulman, A default mode of brain function,Proceedings of the National Academy of Sciences USA98(2001), 676–682.

[33] A. Salek-Haddadi, L. Lemieux, M. Merschhemke, K.J. Fris-ton, J.S. Duncan and D.R. Fish, Functional magnetic reso-nance imaging of human absence seizures,Annals in Neurol-ogy53 (2003), 663–667.

[34] L. Tyvaert, P. LeVan, F. Dubeau and J. Gotman, Noninva-sive dynamic imaging of seizures in epileptic patients,HumanBrain Mapping30 (2009), 3993–4011.

[35] P.J. Uhlhaas, F. Roux, E. Rodriguez, A. Rotarska-Jagiela andW. Singer, Neural synchrony and the development of corticalnetworks,Trends in Cognitive Sciences14(2) (Feb 2010), 72–80.

[36] W. Van Paesschen, P. Dupont, G. Van Driel, H. Van BilloenandA. Maes, SPECT perfusion changes during complex partialseizures in patients with hippocampal sclerosis,Brain 126(2003), 1103–1111.

[37] A.E. Vaudano, H. Laufs, S.J. Kiebel, D.W. Carmichael, K.Hamandi, M. Guye, R. Thornton, R. Rodionov, K.J. Friston,J.S. Duncan and L. Lemieux, Causal hierarchy within thethalamo-cortical network in spike and wave discharges,PLoSOne4 (2009), e6475.


[38] P. Vermathen, G. Ende, K.D. Laxer, J.A. Walker, R.C. Knowl-ton, N.M. Barbaro, G.B. Matson and M.W. Weiner, Tem-poral lobectomy for epilepsy: recovery of the contralateralhippocampus measured by (1)H MRS,Neurology59 (2002),633–636.

[39] A.B. Waites, R.S. Briellmann, M.M. Saling, D.F. AbbottandG.D. Jackson, Functional connectivity networks are disrupted

in left temporal lobe epilepsy,Annals in Neurology59 (2006),335–343.

[40] Z. Zhang, G. Lu, Y. Zhong, Q. Tan, W. Liao, Z. Wang, Z. Wang,K. Li, H. Chen and Y. Liu, Altered spontaneous neuronalactivity of the default-mode network in mesial temporal lobeepilepsy,Brain Research1323 (2010), 152–160.

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