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Purpose: Photosensitive epilepsy (PSE) is the most common form of reflex epilepsy presenting with electroencephalography (EEG) paroxysms elicited by intermittent photic stimulation (IPS). To investigate whether the neuronal network undergoes dynamic changes before and during the transition to an EEG epileptic discharge, we estimated EEG connectivity patterns in photosensitive (PS) patients with idiopathic generalized epilepsy.
Methods: EEG signals were evaluated under resting conditions and during 14 Hz IPS, a frequency that consistently induces photoparoxysmal responses (PPRs) in PS patients. Partial directed coherence (PDC), a linear measure of effective connectivity based on multivariate autoregressive models, was used in 10 PS patients and 10 controls. Anterior versus posterior (F3, F4, C3, C4, and P3, P4, O1, O2) and interhemispheric connectivity patterns (F4, C4, P4, O2, and F3, C3, P3, O1) were estimated with focus on beta and gamma band activity.
Key Findings: PDC analysis revealed an enhanced connectivity pattern in terms of both the number and strength of outflow connections in the PS patient group. Under resting condition, the greater connectivity in the PS patients occurred in the beta band, whereas it mainly involved the gamma band during IPS (i.e., the frequencies ranging from 40–60 Hz that include the higher harmonics of the stimulus frequency). Both at rest and during IPS, the differences between the PS patients and controls were due primarily to clearly increased connectivity involving the anterior cortical regions.
Significance: Our findings indicate that PS patients are characterised by abnormal EEG hyperconnectivity, primarily involving the anterior cortical regions under resting conditions and during IPS. This suggests that, even if the occipital cortical regions are the recipient zone of the stimulus and probably hyperexcitable, the anterior cortical areas are prominently involved in generating the hypersynchronization underlying the spike-and wave discharges elicited by IPS.
Photosensitive epilepsy (PSE), the most common reflex epilepsy in humans, characterizes genetically determined epileptic syndromes (Kasteleijn-NolstTrenité, 1998; Zifkin & Kasteleijn-NolstTrenité, 2000; Stephani et al., 2004). Patients with PSE show electroencephalography (EEG) paroxysms in response to intermittent photic stimulation (IPS), an activation procedure that is applied routinely as a functional test during EEG examinations to enhance preexisting abnormalities or induce abnormal findings. Because of this, PSE offers a highly reproducible model for investigating the dynamic changes in neuronal activity that may occur before and during the transition to an EEG epileptic discharge.
It is known that IPS elicits a physiologic “photic driving” response in normal subjects, which consists of rhythmic EEG activity that is maximal over the posterior regions, time-locked to the stimulus, and has a frequency that is identical or harmonically related to that of the stimulus. However, in photosensitive (PS) patients, IPS can induce a photoparoxysmal response (PPR), a highly inheritable EEG trait characterized by the occurrence of spikes or spike-wave complexes (Fisher et al., 2005). This PPR may occur over the posterior scalp regions, but more frequently has a generalized distribution and can evolve into a self-sustained discharge that outlasts the stimulus itself (Waltz et al., 1992). The PPR and seizures triggered by IPS may be the only epileptic event in some patients (Guerrini & Genton, 2004; Lu et al., 2008); however, in most patients, the photosensitive trait appears as an age-dependent penetrance within a picture of idiopathic generalized epilepsies (IGEs) (Waltz & Stephani, 2000).
Although photosensitive EEG characteristics have been known for a long time, little is known about the mechanisms generating them or the relationship between physiologic and pathologic responses during IPS. The findings of previous electrophysiologic studies suggest that the PPR originates in the cortex and involves the synchronization of large neuronal networks (Wilkins et al., 1979; Binnie et al., 1984; Harding & Fylan, 1999). Evidence indicates that the control of excitation and synchronization is defective in photosensitive patients as a result of their impaired control of contrast gain mechanisms (Porciatti et al., 2000) and/or enhanced synchrony in the gamma band (30–120 Hz), which is harmonically related to the IPS frequencies, before the onset of PPRs (Parra et al., 2003).
In a previous study (Visani et al., 2010) of coherence between occipital and frontal derivations, we found abnormal intrahemispheric and interhemispheric gamma band synchronization in PS patients even at rest. Coherence is a validated means of studying EEG coupling affected by two major limitations: It is a bivariate measure and consequently cannot distinguish direct from indirect linear relationships in a multivariate system, and it does not take into account the direction of the information flow.
To overcome these intrinsic limitations of bivariate and undirected measures, Baccalà and Sameshima (2001) introduced partial directed coherence (PDC), a connectivity estimator in the frequency domain that is based on multivariate autoregressive (MVAR) models and provides a linear measure of causality indicating the direction and strength of the interactions between multiple coupled variables.
We used MVAR modeling and PDC to investigate the connectivity patterns in the beta and gamma bands of healthy participants and PS patients under resting conditions and during 14 Hz IPS. The aim of the study was to evaluate whether intrinsic connectivity patterns differentiate the networks of PS patients and healthy controls, and what changes occur immediately before the appearance of PPR during IPS.
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The results obtained in patients with photoparoxysmal EEG responses indicate an enhanced connectivity pattern mainly involving the frontocentral cortical regions. This led to significantly more and stronger outflow connections that involved beta frequencies under resting conditions and gamma activity during IPS. The different topographical patterns of connectivity between the PS patients and controls under resting conditions and during the stimulus trains indicate that specific changes in the neuronal network predispose toward the generation of synchronous paroxysmal activities and particularly paroxysmal responses to IPS.
We found that the functional alteration affecting the cortical network of PS patients under resting conditions was reflected by significantly enhanced connectivity in the 13–18 Hz beta band, the regional distribution of which was different from that observed in the controls. In the patients, the source was homogeneously distributed on the anterior and posterior electrodes as a result of enhanced interactions leaving the anterior electrodes, whereas the prominent out-going beta connectivity of the controls was on the parietooccipital electrodes. This may be in line with the findings of Kondakor et al. (2005) that, studying the Omega complexity of IGE patient’s EEG studies, indicated greater synchrony in the anterior regions of IGE patients than in those of controls.
The involvement of prominent anterior beta connectivity in the propensity to generate generalized epileptic discharges in PS patients may be due to the neuronal network (possibly inhibitory interneurons) trying to normalize cortical malfunctioning, as has been hypothesized in the case of other neurologic disorders (Chiang et al., 2009; de Haan et al., 2009). However, it is more likely that the changes in connectivity are related to the inherited cell/circuitry changes that certainly occur in photosensitive epileptic syndromes. It is well known that most epilepsies commonly associated with photosensitivity (as well as the “pure” photosensitive epilepsies) have a genetic origin, even though the specific inherited determinant is still insufficiently defined or limited to a small number of patients/families (Stephani et al., 2004; Kasteleijn-NolstTrenité, 2006; Weber & Lerche, 2008). Furthermore, genetic backgrounds are also associated with different patterns of EEG connectivity in healthy subjects, give rise to different connectivity phenotypes (Smit et al., 2010), and lead to ontogenetic changes. Using the synchronization likelihood index, Boersma et al. (2011) have recently found that connectivity in various frequency bands (including beta frequencies) decrease with age in children, possibly because of a tendency to simplify and optimize synaptic connections in order to create a less “expensive” network. This physiologic process of circuitry rearrangement may be delayed or defective in PS patients, thereby leading to different cortical coupling at a juvenile age when photosensitivity is maximally expressed.
The specific role of beta frequencies in connecting the anterior cortical regions of PS patients under resting conditions does not have an obvious explanation. Both beta and gamma frequencies have been attributed to cortical or thalamocortical networks of inhibitory interneurons (Porjesz et al., 2002), and so the enhanced beta band connectivity may reflect an attempt by the system to control the intrinsic hyperexcitability of cortical circuitry prone to generate paroxysmal activity. However, cortical circuitries including both inhibitory and excitatory neurons may also generate a wide range of oscillations (Kopell et al., 2000; van Aerde et al., 2009). Interestingly, the beta band showing enhanced connectivity in our PS patients included the most epileptogenic frequencies of photic stimuli that are consistently capable of evoking paroxysmal EEG activity (Fisher et al., 2005), and may predispose the generation of a pathologic response to IPS. The marked involvement of the central region in the enhanced connectivity of PS patients may be due to the magnification of the natural aptitude of the sensorimotor cortex to generate beta rhythms (Niedermayer, 1996).
Further evaluations of the signal recorded on the anterior regions revealed that there was also a different pattern of connectivity between the left and right anterior hemispheres in the 26–40 Hz gamma band, which corresponds to twice the frequency of the beta band responsible for the stronger connectivity pattern in PS patients. The outflow connections of the patients differed from those of controls because of the left hyperconnectivity observed in patients. Studies comparing the two hemispheres have previously detected differences in EEG coherence between patients with psychiatric disorders or mental impairment and healthy controls at rest and during photic driving (Lazarev et al., 2010; Sankari et al., 2010), which suggest that the intrahemispheric connections undergo compensatory adjustments. Moreover, asymmetrical connectivity unevenly develops and declines in healthy subjects of different ages, and the left anterior regions undergo the main changes (Zhu et al., 2011). The peculiar left “dominance” found in the anterior cortical region of PS patients may also be attributable to the same distorted (genetic and developmental) mechanism that explains the differences between the anterior and posterior cortical areas. The greater propensity of the dominant hemisphere to generate hyperexcitability phenomena has been demonstrated in large populations of patients with focal epilepsies (Gatzonis et al., 2002; Aurlien et al., 2007), and we have found that patients with juvenile myoclonus epilepsy are more likely to generate jerk-locked spikes in the dominant hemisphere (Panzica et al., 2001).
The pattern of beta band connectivity differentiating PS patients and healthy controls under resting conditions did not survive IPS administration, and the same was true of the asymmetrical gamma connectivity between the right and left anterior electrodes in the low gamma band.
The clearest and most significant finding distinguishing PS patients from healthy controls during the EEG epochs heralding the occurrence of paroxysmal EEG discharges occurred in a “medium” gamma band (40–60 Hz), predominantly in the frequencies centered on higher stimulus harmonics. The difference in this frequency window replicated the topography of the beta band under resting conditions, which again suggests that the same neuronal networks sustain both forms of connectivity and are influenced by IPS to generate faster (gamma) oscillations. The main differences in gamma band connectivity related to the frontal electrodes, which are known to be particularly involved in generating high frequency oscillations (Rosanova et al., 2009).
The issue of the EEG contamination by muscular activity has been discussed in various articles dealing with gamma EEG activities (see Dalal et al., 2011 for a review); therefore, we accurately excluded signals with obvious or suspected artifacts. Moreover, because we compared the connectivity patterns obtained in PS patients and controls who underwent identical procedures, it can be assumed that possible contamination would be similarly distributed. Eventually, most the differences observed in PDC during IPS were in frequency bands centered on harmonics of the stimulus frequency, whereas muscular activity would produce rather more distributed background noise.
The involvement of gamma activities in epileptic events has been investigated previously using different techniques in patients with severe focal epilepsies (Guggisberg et al., 2008) and attributed to decreased GABA inhibition at the dendrite level (Wendling et al., 2002). Parra et al. (2003) found significantly enhanced gamma oscillations in PS patients during IPS and suggested that a high degree of synchronization in the gamma band plays a pathogenic role in generating PPR. In line with this, we found a greater trend toward the generation of synchronous gamma activities in PS patients in a previous study based on coherence analysis (Visani et al., 2010), which suggests that gamma activity plays a role in the interhemispheric and intrahemispheric pathologic synchronization heralding PPR.
The present PDC study confirms the role of gamma activity in the generation of PPR, and we suggest that the activation of a network that generates gamma activity capable of coupling the anterior cortices of both hemisphere heralds the generation of paroxysmal activity.
There were no significant differences between the PS patients and healthy controls in terms of the pattern of connectivity in the occipital and parietal cortices (the specific recipient areas of light stimuli) except for a narrow frequency band centered on the IPS harmonic at 42 Hz. This seems to conflict with the hypothesis that the occipital cortex plays a role in generating PPR. Neurophysiologic evaluations such as transcranial magnetic stimulation (TMS) (Siniatchkin et al., 2007; Shepherd & Siniatchkin, 2009), evoked potentials (Guerrini et al., 1998; Porciatti et al., 2000), or fMRI (Chiappa et al., 1999; Moeller et al., 2009a,b) have indicated the increased involvement of the primary recipient occipital cortices of light stimuli in PS patients. However, most of these works (and other hemodynamic and neurophysiologic studies) found that extraoccipital cortices and subcortical structures are also involved in the hyperexcitability mechanism (Kapucu et al., 1996; Chiappa et al., 1999; Inoue et al., 1999; Holmes et al., 2010). Frontal or premotor cortices are certainly involved in the direct generation of spike and wave discharges, including those evoked by PS in patients with generalized epilepsies, as has been directly demonstrated by inspectional EEG analyses (Niedermeyer, 1996; Kasteleijn-NolstTrenité, 1998) or quantitative methods (Gotman, 1981; Takasaka et al., 1989; Visani et al., 2010).
It is also worth noting that the lack of any significant difference in the PDC from the EEG signals recorded in the posterior cortical regions of PS patients and controls is also probably due to the particular characteristics of this measure. Unlike coherence and other linear and nonlinear bivariate methods, PDC allows a multichannel analysis that is capable of detecting the direction of the interactions between paired derivations after removing the contribution of all the other signals, thus revealing the direct connections (Baccalà & Sameshima, 2001; Astolfi et al., 2006; Baccalà et al., 2006). The topographical patterns generated by PDC can, therefore, probably detect the connections more specifically and reveal the causal interdependences within the neuronal network.
In this scenario, it can be hypothesized that PPR requires a hyperexcitable occipital recipient zone, whereas the network originating spike-and wave discharges involves hyperconnected frontocentral cortices. Physiologically, beta frequencies are involved in the coordination of distributed neural activities over longer-range distances (Kopell et al., 2000), whereas gamma oscillations play a major role in coupling local neuronal assemblies and enable synchronization over relatively short distances (Fries et al., 2007). The abnormally synchronized beta bands observed at rest in the anterior cortical regions of PS patients may reflect defectively controlled high-frequency oscillatory processes that couple local and distant neuronal populations in an extended network and pathologically predispose toward generalized epileptic discharges. Under these conditions, IPS may act as an appropriate stimulus to engage the network in generating the connected (gamma) frequencies, ultimately leading to PPR as result of widespread intrahemispheric and interhemispheric transfers, possibly involving cortico-thalamo-cortical pathways or structurally defective connections due to subtle maldevelopments similar to that found in juvenile myoclonic epilepsy (Vulliemoz et al., 2011).