temporal lobe epilepsy ( tle ) is the most common form of focal epilepsy , where the epileptogenic area is located at some part of the temporal lobe . mesial tle ( mtle ) refers to those cases where the suspected source of epileptogenic activity is located in the mesial area of the temporal lobe , and lateral tle ( ltle ) , instead , where the focus is located in the lateral side . mtle is often associated with structural lesions and/or functional deficiency in one or several ( dual pathology ) mesial structures of the temporal lobe , with hippocampal sclerosis ( hs ) as the most common underlying abnormality . however , pathological findings of damage in the amygdala and parahippocampal region , which in turn is subdivided into the entorhinal cortex ( ec ) , perirhinal cortex ( pc ) , and parahippocampal cortex ( ppc ) , are also reported [ 3 , 4 ] . a significant minority of mtle patients have no pathological findings on magnetic resonance imaging ( mri ) , even though lateralization may be correctly performed by neurophysiological methods [ 5 , 6 ] . normal underlying mesial structures play a key role in our understanding of the pathogenesis of mtle , as they oblige us to ask whether mesial sclerosis ( ms ) is either the cause or the effect in mtle . pathophysiology in mtle can be explained according to two models : ( 1 ) the  focal  model suggests that a single pathological region in the mesial temporal lobe is responsible for seizure origin , establishing a link between the presence of ms and the region of seizure onset . ( 2 ) the  network  model states that seizures in mtle result from an alteration of limbic network , which implies atrophy in other structures different from hippocampus ; this model suggests that the abnormal interaction between ec , hippocampal formation , and subiculum may be responsible for the seizures . in a high percentage of mtle patients ( 60%80% ) , clinical seizures can not be eliminated by drug treatment . in such cases , surgery is the only curative / palliative alternative . even with the advent of imaging techniques that are now routinely applied in the preevaluation of drug - resistant tle patients , neurophysiological assessment remains the main diagnostic method at the time of locating epileptogenic areas . besides traditional electroencephalography ( eeg ) , invasive and semi - invasive neurophysiological methods are justified in most cases when imaging techniques fail in the localization / lateralization of the epileptic focus . traditional neurophysiological analysis , whether noninvasive , semi - invasive , or fully invasive , depends mainly on the analysis of interictal epileptogenic discharges ( ied ) , which are the hallmark of epileptic activity . however , ied appears in the so - called irritative area , which often does not coincide with the true epileptogenic area . thus , ictal neurophysiological patterns , such as spikes and sharp waves , must be studied in order to obtain a correct diagnosis . moreover , as we have recently highlighted , analysis of ied in a neurophysiological signal , although very valuable , can only account for a very low percentage of the full information carried by a pathological signal . in order to obtain such recordings , v - eeg ( eeg combined with an invasive technique and video recording ) is used in most centers . this approach requires hospital admission for several days in order to record and analyze a suitable quantity of seizures to locate the focus . in this work we analyze foramen ovale electrodes ( foes ) recordings in seven tle patients with normal presurgical mri , without taking into account ied activity . very recently we have shown   the existence of interictal mesial synchronization imbalance in tle patients , mostly with pathologic findings in mri studies . in the present work , by using part of the already developed methodology , we extend the preceding work in several directions . we analyze , for the first time , both interictal and ictal mesial synchronization in tle patients . we use here a homogenous sample of seven nonlesional tle patients , in order to discard the causality relation of lesion - desynchronization . six out of seven patients presented mtle , as assessed by previously evaluating foes ictal ied analysis ; the remaining patient presented ltle , thus , the issue of mesial synchronization imbalance against mesial or lateral tle is also addressed . by analyzing records of ictal and interictal activity in a homogenous sample of nonlesional tle patients we were able to provide new information regarding the synchronization imbalance in this pathology , as we will show below . mean age was  39.2  9  years , and time of these intractable epilepsies was 21.4  13.7 years . the ethics committee of hospital de la princesa approved the study , and all the patients gave their informed consent . patients were evaluated before surgery according to the local protocol , as published elsewhere [ 13 , 14 ] , namely , interictal single - photon emission computer tomography ( spect ) , mri 1.5 t , scalp eeg , and v - eeg using 19 scalp electrodes according to the international 1020 system . none of the patients presented pathologic findings in the presurgical mri studies , and , in some cases , this was corroborated by histopathology . table 1 shows the clinical information and results of the presurgical studies ( spect , mri , and v - eeg ) routinely performed in the sample . during the v - eeg recording , antiepileptic drugs were progressively discontinued from the second day to the fourth day ( approximately one - third of the dose per day ) . six - contact platinum foes [ 1517 ] ( ad - tech , racine , usa ) with 1  cm center - to - center spacing , were inserted bilaterally under general anesthesia . the most rostral electrode in the foramen ovale was termed foe no . 1 and the most occipital electrode foe no . digital eeg and foe data were acquired at 500  hz , filtered at 0.560  hz for both scalp and foe recording , and exported at 200  hz to ascii format ( xltek , canada ) . multivariate nonoverlapping temporal windows of 2048 data points were used . in the cases of preseizure and seizure analysis , multivariate records of 512 data points were used in order to achieve better temporal resolution ; 512 points at 200  hz yield temporal windows of approximately 2.5 seconds each . all derivations in scalp and foe electrodes were referenced to ( fz + cz + pz)/3 , thus 28 electrodes were used:(1a)fp1,f3,f7,t3,c3,p3,t5,o1 .  left  scalp(1b)fp2,f4,f8,t4,c4,p4,t6,o2 . right  foe postprocessing calculations were performed using fortran and r. interactions between areas covered by electrodes were quantified using the pearson correlation coefficient . we converted correlation values , 1  ij  1 , between each pair of electrodes i and j , into distances , 0  d(i , j )  1.4 . distances serve in the construction of dendograms and provide a more intuitive notion of desynchronization , a central issue in this work . the greater the distance between two recorded areas , the more desynchronized the corresponding neurophysiological activity is . we use the distance matrix to construct dendograms by applying the classic agglomerative single - linkage algorithm . in order to quantify the degree of synchronization between foes on each side , we summed up the distances between pairs of foe , d(i , j ) , for the left and right sides , and divided the result by two ( due to the symmetric character of the distance matrix ) : 
 ( 2)asl=12i=16j=16d(i , j ) ,  asr=12i=16j=16d(i , j ) . we termed the measure defined above average synchronization ( as ) , which turns out to be a simple yet robust measure of synchronization between all the electrodes on each mesial side . the measure actually is a spatial average over the mesial sites recorded by each foe . as we have shown elsewhere , interictal synchronization imbalance exists between both mesial sides in tle patients . this imbalance will be quantified with 
 ( 3)lias  =  aslasr , 
 as a lateralization index . as higher levels of asl imply greater distances between the left foes and , thus , higher desynchronization . a positive lias implies higher desynchronization on the left side , and , conversely , a negative lias implies greater desynchronization on the right side . figure 1 shows a typical distance matrix between each pair of electrodes ( patient no . 5 ) . in figure 1(a ) , we plot the distance matrix of a single 2.5  sec temporal window during the pre - ictal stage , that is , five minutes before the start of the seizure . darker areas correspond to higher synchronization or tighter interactions between electrodes : the difference between right foes ( rf1rf6 ) and left foes ( lf1lf6 ) is apparent . the right foes seem to be better synchronized than the left foes . on the left temporal side , tighter synchronization was observed only between three electrodes , lf1 , lf2 , and lf3 , which seem to be more synchronized with the right electrodes . on the other side , figure 1(b ) which corresponds to a 2.5  sec temporal window during a seizure , the tight interactions between the entire foe group are striking . in order to view the above results in a different but equivalent way there are three foes on the left mesial side , namely , lf4 , lf5 , and lf6 , and these are  high  in the distance axis , which in turn implies that they are poorly connected with other electrodes . the figure shows that all the mesial electrodes except those mentioned above are tightly grouped in one or two clusters . therefore , one can conclude that , in this situation , the left mesial area is more desynchronized than the right one , due to the poor connection of the areas covered by electrodes lf4lf6 . the greater synchronization between all of the mesial electrodes is striking and is seen as the deep position of the entire foe group in the dendogram , which in turn is also subdivided into two different clusters , one for the right foe and another for the left .   in order to follow desynchronization activity during the whole recording for each patient , we used ( 2 ) and ( 3 ) . 5 during the period before the onset of the seizure ( solid vertical line ) and also during the seizure . the upper panel displays the number of channels whose recorded activity was 2.5 standard deviations above baseline activity , as recorded in the first 5 minutes of the interictal record . at onset , activity in the entire foe group begins to increase , and , after a few seconds , the 12 foe channels are highly excited . the second panel from the top shows asl with a smooth reduction in desynchronization activity or , equivalently , an increase in synchronization until the end of the seizure . one can observe from this figure that even when the seizure has stopped , the asl does not recover its preseizure value . the third panel from the top shows the asr , that is , desynchronization activity on the right side , whose behavior is similar to that on the left side . the main difference between both sides seems to be the deepest drop in the right desynchronized activity toward the end of the seizure . the last panel shows the difference between both desynchronization measures , that is , ( 3 ) . desynchronization activity is greater on the left side than on the right one during the preseizure period . once the seizure starts , lias behaves erratically , increasing the imbalance toward the positive value in the first part of the seizure , but decreasing and inverting to a negative value ( around minute 32 ) in the second and final part of the seizure . figure 4 shows lias for every patient with mtle , as assessed by ictal video - eeg , that is , patients no . although it is difficult to extract a typical pattern of evolution of lias during the seizure from these six cases , some suggestions may be made . for instance , it seems that there is a difference between right and left temporal seizures . in left - sided cases , desynchronization increases ipsilaterally at seizure onset . 4 , with an abrupt increase in the imbalance around minute 14 . patient no . nevertheless , in all four cases , the imbalance during the seizure seems to begin with an increase in the imbalance followed by a decrease , which seems to end with a reversal of the imbalance , that is , minute 32 for patient no . 2 , minute 16 for patient no . 4 , minute 35 for patient no . 7 , and minute 32 for patient no . 5 .   on the other hand , patients with left mtle ( no . 1 and no . 3 ) do not show any significant change during the seizure , except for the high variability observed . 6 , which , accordingly with the video - eeg evaluation , is a lateral left tle . little imbalance exists prior to onset , with lias crossing zero imbalance randomly . during the seizure , desynchronization was initially greater on the right side , although it suddenly became negative around minute 21 . we calculated mean values of lias for each complete foe recording and for each patient in three different situations . during the interictal stage , we used recordings of approximately one hour , during both the awake and sleep states . we also used a preictal recording of ten minutes prior to the seizure onset . the recordings in these cases were inappropriate for the numerical analysis we performed . except for case no . the imbalance lias always coincided with the v - eeg evaluation , which is the gold standard for lateralization in tle . it is noteworthy that lias correctly lateralizes in each different situation , although with a different power . for the case of patient 6 , however , lias yielded a right imbalance , although with a much lower value , which in the case of the preictal stage is almost zero . we showed the existence of desynchronized activity in mesial structures ipsilateral to the epileptic side in mtle patients . the only patient with ltle showed little or no imbalance in desynchronized activity . our findings came from a cluster analysis of foes records in a sample of normal mri patients . mri in our hospital is routinely performed using a 1.5  t device , and the images are visually inspected by expert neurorradiologists . new advances in mri technologies , such as increased strength of magnetic fields to 3 t , improve diagnostic information compared with standard 1.5 t studies [ 21 , 22 ] . in addition , volumetric and quantitative postprocessing image analysis yields better information [ 2 , 23 ] in some cases . however , it is also true that visual inspection of standard mri images by a dedicated epileptologist expert , as was the case in our center , can account for 8090% of hippocampal atrophy [ 2 , 24 ] . second , little attention was paid to the detection of abnormalities in mesial structures other than the hippocampus , mostly due to the tradition of regarding hippocampal sclerosis as the main cause of mesial epilepsy . nonetheless , several authors report that abnormalities in the ec have been found in tle patients with   and without   hippocampal abnormalities . we may resume the above comments stating that no abnormalities in the hippocampus and extrahippocampal areas in our patients were found , at least at the level of routine presurgical evaluations carried out in an average epilepsy center . these semi - invasive electrodes , which are introduced into the cisterna ambiens , record activity from extrahippocampal areas . it is reasonable to assume that the most anterior three to four electrodes record activity from ec , because this area forms the lateral wall of the cisterna ambiens . probably , the rest of the electrodes pick activity up from parahippocampal or perirhinal cortex , though the most frequent epileptiform activity arises from the most facial area . synchronized activity , we were able to demonstrate the existence of higher levels of desynchronization activity ipsilateral to the epileptogenic side than the contralateral one . as anticipated in the past [ 28 , 29 ] , a decrease in synchronization facilitates seizure onset ; therefore , desynchronization facilitates seizure onset in one of these nonhippocampal structures . the state of desynchronization activity could be regarded as a state of increased susceptibility for pathological synchronization , thereby representing a possibly lowered threshold for seizure activity [ 28 , 29 ] . this point is important in regard to the seizure 's dynamic . in studying the seizure evolution , low levels of synchronization , assessed by measuring zero - lag correlated activity at the seizure onset , two hypotheses were advanced : whether desynchronized neuronal activity during seizure spreading is due to delays in reaching different cortical areas or the initial ictal desynchronization is caused by the already desynchronized preictal activity . our results clearly favor the second hypothesis , implying that interictal desynchronization would be essential for initial ictal desynchronization , at least in the mesial cases . in the unique case with ltle , mesial desynchronized activity achieves similar levels at both sides and therefore plays no role in the seizure onset . this would be expected because the seizure onset zone , as located by v - eeg in this ltle patient , is at the lateral side of the temporal lobe . traditionally , the functional connectivity underlying seizure generation in mtle highlights the importance of a circuit composed of the ec , parahippocampus , and hippocampus , with special emphasis on the last one . once epileptogenic activity arises at some part of this circuit , it spreads to other structures , such as the amygdala or neocortex . however , recent anatomical findings and our own electrophysiological results place the hippocampus in a comparable position as the ec and amygdala , thus establishing a functional network of interactions . a deficit in communication between these areas , for instance , lowering levels of synchronization between them , would promote epileptogenic activity . once anomalous information is generated in this network , it would then spread to other mesial and lateral structures , reaching the neocortex ( and thalamus ) and becoming generalized . failure in the network would be due to underlying structural pathology , such as hippocampal sclerosis or ec atrophy , which is the case in lesional tle . in normal mri patients , as in the case studied here , failure in the network may be due to abnormal communication between underlying normal structures . first , the lateralization power displayed in cases of mtle was achieved with a semi - invasive methodology , and second the methodology described here would reduce analysis time drastically . in one or two hours of interictal activity , it would be possible to draw reliable conclusions regarding lateralization , without the need to record actual seizure activity .
although temporal lobe epilepsy ( tle ) is traditionally associated with both hypersynchronous activity in the form of interictal epileptic discharges and hippocampal sclerosis , recent findings suggest that desynchronization also plays a central role in the dynamics of this pathology . the objective of this work is to show the imbalance existing between mesial activities in patients suffering from mesial tle , with normal mesial structures . 
 foramen ovale recordings from six patients with mesial tle and one with lateral tle were analyzed through a cluster analysis and synchronization matrices . 
 none of the patients present findings in the mri presurgical evaluation . 
 numerical analysis was carried out in three different situations : awake and sleep interictal and also during the preictal stage . 
 high levels of desynchronization ipsilateral to the epileptic side were present in mesial tle patients . 
 low levels of desynchronization were present in the lateral tle patient during the interictal stage and almost zero in the preictal stage . implications of these findings in relation with seizure spreading are discussed .