The Insula and Its Epilepsies

Trebaul L., Deman P., Tuyisenge V., Jedynak M., Hugues E., Rudrauf D., Bhattacharjee M., Tadel F., Chanteloup-Foret B., Saubat C., Reyes Mejia G.C., Adam C., Nica A., Pail M., Dubeau F., et. al.

In patients with pharmaco-resistant focal epilepsies investigated with intracranial electroencephalography (iEEG), direct electrical stimulations of a cortical region induce cortico-cortical evoked potentials (CCEP) in distant cerebral cortex, which properties can be used to infer large scale brain connectivity. In 2013, we proposed a new probabilistic functional tractography methodology to study human brain connectivity. We have now been revisiting this method in the F-TRACT project (f-tract.eu) by developing a large multicenter CCEP database of several thousand stimulation runs performed in several hundred patients, and associated processing tools to create a probabilistic atlas of human cortico-cortical connections. Here, we wish to present a snapshot of the methods and data of F-TRACT using a pool of 213 epilepsy patients, all studied by stereo-encephalography with intracerebral depth electrodes. The CCEPs were processed using an automated pipeline with the following consecutive steps: detection of each stimulation run from stimulation artifacts in raw intracranial EEG (iEEG) files, bad channels detection with a machine learning approach, model-based stimulation artifact correction, robust averaging over stimulation pulses. Effective connectivity between the stimulated and recording areas is then inferred from the properties of the first CCEP component, i.e. onset and peak latency, amplitude, duration and integral of the significant part. Finally, group statistics of CCEP features are implemented for each brain parcel explored by iEEG electrodes. The localization (coordinates, white/gray matter relative positioning) of electrode contacts were obtained from imaging data (anatomical MRI or CT scans before and after electrodes implantation). The iEEG contacts were repositioned in different brain parcellations from the segmentation of patients' anatomical MRI or from templates in the MNI coordinate system. The F-TRACT database using the first pool of 213 patients provided connectivity probability values for 95% of possible intrahemispheric and 56% of interhemispheric connections and CCEP features for 78% of intrahemisheric and 14% of interhemispheric connections. In this report, we show some examples of anatomo-functional connectivity matrices, and associated directional maps. We also indicate how CCEP features, especially latencies, are related to spatial distances, and allow estimating the velocity distribution of neuronal signals at a large scale. Finally, we describe the impact on the estimated connectivity of the stimulation charge and of the contact localization according to the white or gray matter. The most relevant maps for the scientific community are available for download on f-tract. eu (David et al., 2017) and will be regularly updated during the following months with the addition of more data in the F-TRACT database. This will provide an unprecedented knowledge on the dynamical properties of large fiber tracts in human.

Fei P., Soucy J., Obaid S., Boucher O., Bouthillier A., Nguyen D.K.

Operculoinsular epilepsy (OIE) can be challenging to diagnose. While the value of SPECT cerebral blood flow and PET F-FDG studies for presurgical evaluation of patients with medial temporal lobe epilepsy (MTLE) is well established, it remains unclear whether they can help identify an operculoinsular epileptic focus. This study assesses the value of interictal/ictal regional cerebral blood flow (rCBF) SPECT and FDG PET for OIE diagnosis.Eighteen patients with proven OIE who underwent interictal/ictal rCBF SPECT and/or FDG-PET prior to epilepsy surgery were identified from our clinical database and were compared with a group of 18 patients who underwent MTLE surgery. Regional cerebral blood flow SPECT and FDG PET images were reevaluated visually by an expert reader blind to clinical data.Interictal/ictal rCBF SPECT correctly identified an operculoinsular focus in 11 (65%) of 17 OIE patients and was misleading in 3 cases (18%). Secondary activation in areas connected to the insula was often observed. In the MTLE group, the area of maximal increased perfusion was congruent in 12 (75%) of 16 patients and extended to the ipsilateral insula in 1 patient. FDG PET findings were concordant with the epileptic focus in 8 (47%) of 17 OIE patients and were misleading in 4 (24%), whereas they were concordant in all MTLE patients.Interictal/ictal rCBF SPECT can identify a concordant operculoinsular focus in a significant proportion of OIE patients and offers a valuable diagnostic tool in nonlesional cases. By contrast, the value of interictal FDG PET in this population is more equivocal.

Herrero J.L., Khuvis S., Yeagle E., Cerf M., Mehta A.D.

Whereas the neurophysiology of respiration has traditionally focused on automatic brain stem processes, higher brain mechanisms underlying the cognitive aspects of breathing are gaining increasing interest. Therapeutic techniques have used conscious control and awareness of breathing for millennia with little understanding of the mechanisms underlying their efficacy. Using direct intracranial recordings in humans, we correlated cortical and limbic neuronal activity as measured by the intracranial electroencephalogram (iEEG) with the breathing cycle. We show this to be the direct result of neuronal activity, as demonstrated by both the specificity of the finding to the cortical gray matter and the tracking of breath by the gamma-band (40–150 Hz) envelope in these structures. We extend prior observations by showing the iEEG signal to track the breathing cycle across a widespread network of cortical and limbic structures. We further demonstrate a sensitivity of this tracking to cognitive factors by using tasks adapted from cognitive behavioral therapy and meditative practice. Specifically, volitional control and awareness of breathing engage distinct but overlapping brain circuits. During volitionally paced breathing, iEEG-breath coherence increases in a frontotemporal-insular network, and during attention to breathing, we demonstrate increased coherence in the anterior cingulate, premotor, insular, and hippocampal cortices. Our findings suggest that breathing can act as an organizing hierarchical principle for neuronal oscillations throughout the brain and detail mechanisms of how cognitive factors impact otherwise automatic neuronal processes during interoceptive attention. NEW & NOTEWORTHY Whereas the link between breathing and brain activity has a long history of application to therapy, its neurophysiology remains unexplored. Using intracranial recordings in humans, we show neuronal activity to track the breathing cycle throughout widespread cortical/limbic sites. Volitional pacing of the breath engages frontotemporal-insular cortices, whereas attention to automatic breathing modulates the cingulate cortex. Our findings imply a fundamental role of breathing-related oscillations in driving neuronal activity and provide insight into the neuronal mechanisms of interoceptive attention.

Allen L.A., Harper R.M., Kumar R., Guye M., Ogren J.A., Lhatoo S.D., Lemieux L., Scott C.A., Vos S.B., Rani S., Diehl B.

Background Sudden unexpected death in epilepsy (SUDEP) is common among young people with epilepsy. Individuals who are at high-risk of SUDEP exhibit regional brain structural and functional connectivity (FC) alterations compared with low-risk patients. However, less is known about network-based FC differences among critical cortical and sub-cortical autonomic regulatory brain structures in temporal lobe epilepsy (TLE) patients at high-risk of SUDEP. Methods 32 TLE patients were risk-stratified according to the following clinical criteria: age of epilepsy onset, duration of epilepsy, frequency of generalized tonic-clonic seizures and presence of nocturnal seizures, resulting in 14 high-risk and 18 low-risk cases. Resting-state functional magnetic resonance imaging (rs-fMRI) signal time courses were extracted from 11 bilateral cortical and sub-cortical brain regions involved in autonomic and other regulatory processes. After computing all pairwise correlations, FC matrices were analysed using the network-based statistic. FC strength among the 11 brain regions was compared between the high- and low-risk patients. Increases and decreases in FC were sought, using high-risk > low-risk and low-risk > high-risk contrasts (with covariates age, gender, lateralisation of epilepsy and presence of hippocampal sclerosis). Results High-risk TLE patients showed a subnetwork with significantly reduced FC (t = 2.5, p = .029) involving the thalamus, brainstem, anterior cingulate, putamen and amygdala, and a second subnetwork with significantly elevated FC (t = 2.1, p = .031), which extended to medial/orbital frontal cortex, insula, hippocampus, amygdala, subcallosal cortex, brainstem, thalamus, caudate, and putamen. Conclusions TLE patients at high-risk of SUDEP showed widespread FC different between key autonomic regulatory brain regions compared to those at low-risk. The altered FC revealed here may help to shed light on the functional correlates of autonomic disturbances in epilepsy and mechanisms involved in SUDEP. Furthermore, these findings represent possible objective biomarkers which could help to identify high-risk patients and enhance SUDEP risk stratification via the use of non-invasive neuroimaging, which would require validation in larger cohorts, with extension to patients with other epilepsies and subjects who succumb to SUDEP.

Obaid S., Zerouali Y., Nguyen D.K.

In this review, authors discuss the semiology and noninvasive investigations of insular epilepsy, an underrecognized type of epilepsy, which may mimic other focal epilepsies. In line with the various functions of the insula and its widespread network of connections, insular epilepsy may feature a variety of early ictal manifestations from somatosensory, visceral, olfactory, gustatory, or vestibular manifestations. Depending on propagation pathways, insular seizures may also include altered consciousness, dystonic posturing, complex motor behaviors, and even autonomic features. Considering the variability in seizure semiology, recognition of insular epilepsy may be challenging and confirmation by noninvasive tests is warranted although few studies have assessed their value. Detection of an insular lesion on MRI greatly facilitates the diagnosis. Scalp EEG findings in frontocentral and/or temporal derivations will generally allow lateralization of the seizure focus. Ictal single-photon computed tomography has moderate sensitivity, whereas positron emission tomography has lower sensitivity. Among newer techniques, magnetoencephalography is highly beneficial, whereas proton magnetic resonance spectroscopy currently has limited value.

Mazzola L., Mauguière F., Isnard J.

Stereotactic stimulations of the insular cortex through intracranial electrodes aim at characterizing the semiology of insular seizures. These stimulations, carried out in the context of Stereo-Electro-Encephalography (SEEG) during presurgical monitoring of epilepsy, reproduce the ictal symptoms observed during the development of insular seizures.The authors reviewed the results of insular stimulations performed in 222 patients admitted between 1997 and 2015 for presurgical SEEG exploration of atypical temporal or perisylvian epilepsy. Stimulations (50 Hz, trains of 5 seconds, pulses of 0.5 ms, intensity 0.2-3.5 mA) were carried out using transopercular electrodes implanted orthogonal to midsagittal plane.Out of a total of 669 stimulations, 550 were clinically eloquent in the absence of any postdischarge (237 and 313, respectively, in the right and left insulae). Somatosensory responses (61% of evoked sensations) including pain and visceral sensations (14.9%) were the most frequent, followed by auditory sensations (8%), vestibular illusions (7.5%), speech impairment (5%), gustatory, (2.7%), and olfactory (1%) sensations. Although these responses showed some functional segregation (in particular a privileged pain representation in the postero-superior quadrant), there was a clear spatial overlap between representations of the different modalities.Symptoms evoked by insular stimulations are multiple. None of them can be considered as absolutely specific to the insular cortex, but the occurrence in given seizure of a somatosensory symptom such as pain or of a laryngeal spasm associated with vestibular, auditory, aphasic, or olfacto-gustatory symptoms points to a discharge development in the insular cortex, which is the only cortical region where stimulations demonstrate such a multimodal representation.

Alomar S., Mullin J.P., Smithason S., Gonzalez-Martinez J.

OBJECTIVEInsular epilepsy is relatively rare; however, exploring the insular cortex when preoperative workup raises the suspicion of insular epilepsy is of paramount importance for accurate localization of the epileptogenic zone and achievement of seizure freedom. The authors review their clinical experience with stereoelectroencephalography (SEEG) electrode implantation in patients with medically intractable epilepsy and suspected insular involvement.METHODSA total of 198 consecutive cases in which patients underwent SEEG implantation with a total of 1556 electrodes between June 2009 and April 2013 were reviewed. The authors identified patients with suspected insular involvement based on seizure semiology, scalp EEG data, and preoperative imaging (MRI, PET, and SPECT or magnetoencephalography [MEG]). Patients with at least 1 insular electrode based on the postoperative 3D reconstruction of CT fused with the preoperative MRI were included.RESULTSOne hundred thirty-five patients with suspected insular epilepsy underwent insular implantation of a total of 303 electrodes (1–6 insular electrodes per patient) with a total of 562 contacts. Two hundred sixty-eight electrodes (88.5%) were implanted orthogonally through the frontoparietal or temporal operculum (420 contacts). Thirty-five electrodes (11.5%) were implanted by means of an oblique trajectory either through a frontal or a parietal entry point (142 contacts). Nineteen patients (14.07%) had insular electrodes placed bilaterally. Twenty-three patients (17.04% of the insular implantation group and 11.6% of the whole SEEG cohort) were confirmed by SEEG to have ictal onset zones in the insula. None of the patients experienced any intracerebral hemorrhage related to the insular electrodes. After insular resection, 5 patients (33.3%) had Engel Class I outcomes, 6 patients (40%) had Engel Class II, 3 patients (20%) had Engel Class III, and 1 patient (6.66%) had Engel Class IV.CONCLUSIONSInsula exploration with stereotactically placed depth electrodes is a safe technique. Orthogonal electrodes are implanted when the hypothesis suggests opercular involvement; however, oblique electrodes allow a higher insular sampling rate.

Levy A., Yen Tran T.P., Boucher O., Bouthillier A., Nguyen D.K.

Operculo-insular seizures are heterogeneous and may resemble seizures originating from the temporal, frontal, or parietal lobe. Although surface and invasive EEG recordings are often necessary to detect operculo-insular seizures, electrophysiological features of operculo-insular epilepsies remain poorly characterized. This study describes the EEG findings of patients with operculo-insular epilepsy.We reviewed electrophysiological data of all patients (n = 9) with operculo-insular seizures revealed by intracranial EEG and for whom operculo-insular epilepsy was confirmed by good seizure outcome after resective or radiosurgery at our center between 2005 and 2013. Patients were divided according to whether their seizure focus involved the anterior (group 1; n = 4) or posterior (group 2; n = 5) portion of the insula.Interictal scalp EEG was lateralizing and showed distinct topographical spike patterns between groups: frontal and temporal in group 1, temporal in group 2. Intracranial recordings showed abundant spikes limited to the operculo-insular region or involving distant areas in the frontal/temporal (group 1) and temporal/parietal lobes (group 2). Ictal intracranial EEG revealed discharges limited to the insula or simultaneously involving extrainsular contacts at onset, notably the orbitofrontal cortex (group 1) and the frontal and parietal opercula (group 2), and propagating to the frontal and temporal lobes in group 1 and to parietal and temporal lobes in group 2.Spike distribution and seizure propagation in operculo-insular epilepsy follows an anterior-to-posterior pattern mirroring an anterior or posterior insular focus localization. When presented with frontal and/or temporal epileptiform abnormalities, an operculo-insular focus should be considered.

von Lehe M., Parpaley Y.

Focal epilepsy originating from the insular cortex is rare. One reason is the small amount of cortical tissue compared with other lobes of the brain. However, the incidence of insular epilepsy might be underestimated because of diagnostic difficulties. The semiology and the surface EEG are often not meaningful or even misleading, and elaborated imaging might be necessary. The close connections of the insular cortex with other potentially epileptogenic areas, such as the temporal lobe or frontal/central cortex, is increasingly recognized as possible reason for failure of epilepsy surgery for temporal or extratemporal seizures. Therefore, some centers consider invasive EEG recording of the insular cortex not only in case of insular epilepsy but also in other focal epilepsies with nonconclusive results from the presurgical work-up. The surgical approach to and resection of insular cortex is challenging because of its deep location and proximity to highly eloquent brain structures. Over the last decades, technical adjuncts like navigation tools, electrophysiological monitoring and intraoperative imaging have improved the outcome after surgery. Nevertheless, there is still a considerable rate of postoperative transient or permanent deficits, in some cases as unavoidable and calculated deficits. In most of the recent series, seizure outcome was favorable and comparable with extratemporal epilepsy surgery or even better. Up to now, the data volume concerning long-term follow-up is limited. This review focusses on the surgical challenges of resections to treat insular epilepsy, on prognostic factors concerning seizure outcome, on postoperative deficits and complications. Moreover, less invasive surgical techniques to treat epilepsy in this highly eloquent area are summarized.

Salado A.L., Koessler L., De Mijolla G., Schmitt E., Vignal J., Civit T., Tyvaert L., Jonas J., Maillard L.G., Colnat-Coulbois S.

Hagiwara K., Jung J., Bouet R., Abdallah C., Guénot M., Garcia-Larrea L., Mauguière F., Rheims S., Isnard J.

For a decade it has been known that the insular lobe epilepsy can mimic frontal lobe epilepsy. We aimed to clarify the pattern of functional coupling occurring during the frontal presentation.We analyzed five insular lobe epilepsy patients. Frontal semiology was predominant for three of them, whereas insular semiology was predominant for the two others. We applied the non-linear regression analysis to stereoelectroencephalography-recorded seizures. A directed functional coupling index was calculated during clonic discharge periods that were accompanied either with frontal or insular semiology.We found significant functional coupling between the insula and mesial frontal/cingulate regions, with the former being a leader region for seizures propagation. Extra-insular regions showed significantly less or even no coupling with the mesial hemispheric regions. The three patients with frontal semiology showed strong couplings with the mesial frontal as well as cingulate regions, including the medial orbitofrontal cortex, pre-SMA/SMA, and the anterior to posterior cingulate. The two patients with the insular semiology only showed couplings between the insula and cingulate regions.The frontal semiology was expressed by strong functional couplings between the insula and mesial frontal regions.The insular origin of seizure should be considered in cryptogenic mesial frontal epilepsies.

Geller E.B., Skarpaas T.L., Gross R.E., Goodman R.R., Barkley G.L., Bazil C.W., Berg M.J., Bergey G.K., Cash S.S., Cole A.J., Duckrow R.B., Edwards J.C., Eisenschenk S., Fessler J., Fountain N.B., et. al.

Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin.Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events.There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices).Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Jobst B.C., Kapur R., Barkley G.L., Bazil C.W., Berg M.J., Bergey G.K., Boggs J.G., Cash S.S., Cole A.J., Duchowny M.S., Duckrow R.B., Edwards J.C., Eisenschenk S., Fessler A.J., Fountain N.B., et. al.

Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin.Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset.There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices.Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Namkung H., Kim S., Sawa A.

Supported by recent human neuroimaging studies, the insula is re-emerging as an important brain area not only in the physiological understanding of the brain, but also in pathological contexts in clinical research. In this opinion article, we briefly introduce the anatomical and histological features of the human insula. We then summarize the physiological functions of the insula and underscore its pathological roles in psychiatric and neurological disorders that have long been underestimated. We finally propose possible strategies through which the role of the insula may be further understood for both basic and clinical neuroscience.

Aitouche Y., Gibbs S.A., Gilbert G., Boucher O., Bouthillier A., Nguyen D.K.

Recent studies suggest that a nonnegligible proportion of drug-resistant epilepsy surgery candidates have an epileptogenic zone that involves the insula. We aimed to examine the value of proton magnetic resonance spectroscopy (1 H-MRS) in identifying patients with insular cortex epilepsy.Patients with possible nonlesional drug-refractory insular epilepsy underwent a voxel-based 1 H-MRS study prior to an intracranial electroencephalographic (EEG) study. Patients were then divided into two groups based on invasive EEG findings: the insular group with evidence of insular seizures and the noninsular group with no evidence of insular seizures. Sixteen age-matched healthy controls were also scanned for normative data.Twenty-two epileptic patients were recruited, 12 with insular seizures and 10 with extra-insular seizures. Ipsilateral and contralateral insular N-acetyl-aspartate concentrations ([NAA]) and NAA/Cr ratios were found to be similar in both patient groups. No significant differences in [NAA] or NAA/Cr ratios were found between the insular group, noninsular group, and healthy controls. [NAA] and NAA/Cr asymmetry indices correctly lateralized the seizure focus in only 16.7% and 0% of patients, respectively.Our preliminary findings suggest that 1 H-MRS fares poorly in identifying patients with nonlesional insular epilepsy.

Yevoo P.E., Fontanini A., Maffei A.

Ouchida S., Nikpour A., Wilson D.N., Fairbrother G.

Epilepsy is a chronic neurological condition with various etiologies, and recurrent unprovoked seizures characterize it. Hypersalivation is a recognized symptom of insular-opercular epilepsies. A wide range of symptoms can occur during a seizure, including hypersalivation, autonomic responses, oropharyngeal sensations, visceral sensations, somatosensory disturbances, and emotional manifestations. In this case study, we examine a unique scenario of a patient who experienced predominantly salivary seizures. Hypersalivation, pill-rolling movements, and lip-smacking characterized these seizures. Importantly, the patient became seizure-free after undergoing radiofrequency thermocoagulation (RFTC) with the assistance of Stereoelectroencephalography (SEEG). Our discussion will focus on the treatment approach involving SEEG-guided RFTC and the careful identification of the brain cortex responsible for triggering excessive salivation during seizures.

Baumgartner M.E., Tomlinson S.B., Galligan K., Kennedy B.C.

The increasingly widespread use of stereo-EEG in the pre-surgical evaluation has led to greater recognition of the insula as both a source and surgical target for drug-resistant epilepsy. Clinicians have long appreciated the challenges of diagnosing and treating seizures arising from the insula. Insular-onset seizures present with a wide variety of semiologies due to its dense and complex integration with other brain structures, resulting in the insula’s reputation as the “great mimicker.” Surgical access to the insula is guarded by the overlying frontal, temporal, and parietal opercula and requires careful negotiation of the Sylvian fissure, the vascular candelabra of the middle cerebral artery, and protection of crucial white matter structures (e.g., corona radiata). Despite these difficulties, open surgical intervention for insular epilepsy is associated with favorable seizure control rates, surpassing those achieved with less-invasive alternatives (e.g., laser ablation). Technical nuances that minimize the risk of adverse functional outcomes following open insular resection (especially hemiparesis) are of tremendous value to the epilepsy surgeon. Here, we review the literature on hemiparesis secondary to insular resection and detail strategies for achieving safe and thorough resection of the insula, with emphasis placed on the posterior insula. We supplement this review with four illustrative cases in which focal, drug-resistant epilepsy was managed via open insular resection with no resultant permanent hemiparesis. Technical insights accumulated through these cases are highlighted.

Machetanz K., Weinbrenner E., Wuttke T.V., Ethofer S., Helfrich R., Kegele J., Lauxmann S., Alber M., Rona S., Tatagiba M., Lerche H., Honegger J., Naros G.

ObjectiveEpilepsy is considered as a network disorder of interacting brain regions. The propagation of local epileptic activity from the seizure onset zone (SOZ) along neuronal networks determines the semiology of seizures. However, in highly interconnected brain regions such as the insula, the association between the SOZ and semiology is blurred necessitating invasive stereoelectroencephalography (SEEG). Normative connectomes on MRI data enable to link different symptoms and lesion locations to a common functional network. The present study applied connectomics to disentangle epilepsy networks from insular SEEG recordings and to describe their relationship to seizure semiology.MethodsWe retrospectively extracted functional networks by normative connectome analysis from 118 insular contacts depicting epileptic discharges during SEEG in 20 epilepsy patients. The resulting epilepsy networks were correlated to the corresponding semiology by voxel-wise regression and multivariate analyses of variances.ResultsEpileptic foci were found in the posterior insula for somatosensory, other sensory and motor seizures, while cognitive and autonomic symptoms were related to the anterior insula. We identified insular connections to the superior temporal gyrus and heschl gyrus in sensory seizures and projections to the somatosensory cortex in somatosensory seizures. Insula-basal ganglia pathways were found in cognitive seizure manifestations, while insular connectivity to fronto-basal regions were strongest in patients with autonomic seizures.ConclusionThe semiology of seizures is mirrored in the functional connectivity of insular epileptic discharges. Combining SEEG and connectomics could provide additional information about seizure propagation within the epilepsy network and might enable new treatment options in the future like deep brain stimulation.

Joris V., Royer J., Weil A.G.

Kilmer J., Rodrigo S., Petrescu A., Aghakhani N., Herbrecht A., Leroy C., Tournier N., Bottlaender M., Taussig D., Bouilleret V.

AbstractObjectivesResective surgery in drug‐resistant focal epilepsy (DRFE) requires extensive evaluation to localize the epileptogenic zone (EZ). When non‐invasive phase 1 assessments (electroencephalography, EEG; magnetic resonance imaging, MRI; and 18F‐Fluorodeoxyglucose–positron emission tomography, [18F]FDG‐PET) are inconclusive for EZ localization, invasive investigations such as stereo‐EEG (SEEG) are necessary. Epileptogenicity maps (Ems) visualize the EZ using SEEG‐identified ictal high‐frequency oscillations (iHFOs). PET imaging with radioligands targeting the18‐kDa translocator protein (TSPO), a marker of glial activation, may aid EZ localization. This study investigates the correlation between TSPO‐PET imaging and SEEG iHFOs in DRFE to determine the utility of TSPO‐PET in pre‐surgical assessments, especially in complex or non‐lesional cases.MethodsPatients with DRFE and inconclusive phase 1 assessments were recruited from Bicêtre Hospital (AP‐HP) for a prospective study (Eudract 2017–003381‐27). They underwent SEEG and [18F]DPA‐714 (N,N‐diethyl‐2‐(2‐(4‐(2‐(fluoro‐18F)ethoxy)phenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidin‐3‐yl)acetamide) (TSPO radioligand) PET imaging. Statistical parametric mapping (SPM) techniques analyzed significant [18F]DPA‐714‐PET uptake (TSPO‐map) and generated epileptogenicity maps (EM‐map). Correlation analyses at regional and voxel‐of‐interest (VOI) levels assessed the relationship between TSPO‐map and EM‐map.ResultsWe were able to obtain and analyze both maps in 12 of 17 patients recruited. A significant positive correlation between EM‐map and TSPO‐map in focal epilepsies was found regionally (r = .81, p < .00004) and at the VOI level (r = .79, p < .00003). Temporal, insular, parietal, and occipital regions showed particularly strong correspondence. In frontal epilepsies, TSPO‐map was more focal than EM‐map, suggesting increased specificity for SEEG planning. This study also demonstrated the benefit of the TSPO‐map in identifying multiple foci in multifocal epilepsies, with or without lesions.SignificanceThese findings suggest that neuroinflammation may be a molecular substrate of the EZ in non‐lesional focal epilepsy. Identifying the EZ inpatients with complex DRFE and inconclusive MRI/[18F]FDG‐PET imaging is essential to improve resective surgery outcomes. Combining TSPO‐PET imaging with SEEG recordings may help bridge this gap.

Pepper J., Seri S., Walsh A.R., Agrawal S., Macpherson L., Sudarsanam A., Lo W.B.

Stereoelectroencephalography (SEEG) is widely used to characterise epileptic networks and guide resection in paediatric epilepsy surgery programmes. The insula, with its extensive connectivity with temporal and extratemporal structures, has increasingly been seen as a possible surgical target. We report our seizure outcomes after SEEG-guided resection of the insula in a paediatric cohort. From our paediatric epilepsy surgery database of patients aged 0–19 years, we analysed demographic and clinical data of those who underwent SEEG-guided insula cortex resection. In total, 11 children (7 females, 4 males) who underwent SEEG-guided resection were identified. The mean age at first SEEG was 13 years old. Mean age at seizure onset was 4.3 years; seizure frequency ranged from 50/day to 2/week. Four children required 1 SEEG study, 6 children 2 SEEG, and 1 child underwent 3 SEEG recordings. The mean follow-up duration was 2.1 years; at the latest follow-up, three children had Engel I, 2 children Engel III, and 6 children Engel IV. One child classified as an Engel IV outcome for insular surgery had Engel class I after 2 failed insula surgeries, after an occult frontal focal cortical dysplasia was later identified and resected. No major complications were noted. In our paediatric series, one third of the patients undergoing insula cortex surgery after SEEG became seizure free but this may require repeat SEEG implantation, repeat resective surgery and the possibility of changing hypothesis from the insula cortex to nearby foci.

Kudr M., Janca R., Jahodova A., Belohlavkova A., Ebel M., Bukacova K., Maulisova A., Tichy M., Liby P., Kyncl M., Holubova Z., Sanda J., Jezdik P., Mackova K., Ramos Rivera G.A., et. al.

AbstractObjectiveEpilepsy surgery in the operculoinsular cortex is challenging due to the difficult delineation of the epileptogenic zone and the high risk of postoperative deficits.MethodsPre‐ and postsurgical data from 30 pediatric patients who underwent operculoinsular cortex surgery at the Motol Epilepsy Center Prague from 2010 to 2022 were analyzed.ResultsFocal cortical dysplasia (FCD; n = 15, 50%) was the predominant cause of epilepsy, followed by epilepsy‐associated tumors (n = 5, 17%) and tuberous sclerosis complex (n = 2, 7%). In eight patients where FCD was the most likely etiology, the histology was negative. Seven patients (23%) displayed normal magnetic resonance imaging results. Seizures exhibited diverse semiology and propagation patterns (frontal, perisylvian, and temporal). The ictal and interictal electroencephalographic (EEG) findings were mostly extensive. Multimodal imaging and advanced postprocessing were frequently used. Stereo‐EEG was used for localizing the epileptogenic zone and eloquent cortex in 23 patients (77%). Oblique electrodes were used as guides for better neurosurgeon orientation. The epileptogenic zone was in the dominant hemisphere in 16 patients. At the 2‐year follow‐up, 22 patients (73%) were completely seizure‐free, and eight (27%) experienced a seizure frequency reduction of >50% (International League Against Epilepsy class 3 and 4). Fourteen patients (47%) underwent antiseizure medication tapering; treatment was completely withdrawn in two (7%). Nineteen patients (63%) remained seizure‐free following the definitive outcome assessment (median = 6 years 5 months, range = 2 years to 13 years 5 months postsurgery). Six patients (20%) experienced corona radiata or basal ganglia ischemia; four (13%) improved to mild and one (3%) to moderate hemiparesis. Two patients (7%) operated on in the anterior insula along with frontotemporal resection experienced major complications: pontine ischemia and postoperative brain edema.SignificanceEpilepsy surgery in the operculoinsular cortex can lead to excellent patient outcomes. A comprehensive diagnostic approach is crucial for surgical success. Rehabilitation brings a great chance for significant recovery of postoperative deficits.

González-Martínez J.A., Ekman F.R.

Epilepsy, a chronic neurological disorder characterized by recurrent seizures, affects a significant portion of the global population, with drug-resistant epilepsy (DRE) presenting a major treatment challenge. Insular epilepsy, originating from this complex region, exhibits a broad range of symptoms, making diagnosis particularly difficult. Advanced imaging techniques and invasive procedures like stereoelectroencephalography (SEEG) are often crucial for accurately localizing the epileptogenic zone. Surgical resection remains the primary treatment for DRE, with recent advancements in microsurgical techniques and neuroimaging improving outcomes. Additionally, minimally invasive approaches like laser interstitial thermal therapy (LITT) and radiofrequency thermocoagulation (RFTC) offer promising alternatives.

Yevoo P.E., Fontanini A., Maffei A.

SummaryTaste preference is a fundamental driver of feeding behavior influencing dietary choices and eating patterns. Extensive experimental evidence indicates that the gustatory cortex (GC) is engaged in taste perception, palatability and preference. However, our knowledge of the neural and neurochemical signals regulating taste preference is rather limited. Neuromodulators can affect preferences, though their effects on neural circuits for taste are incompletely understood. Neurosteroids are of particular interest in view of reports that systemic administration of the neurosteroid allopregnanolone, a potent modulator of tonic GABAergic inhibition, induces hyperphagia and increases intake of energy rich food in human and animal subjects. Tonic inhibition is a powerful modulator of circuit excitability and is primarily mediated by extrasynaptic GABAAreceptors containing the delta subunit (δ-GABAARs). These receptors are widely distributed in the brain, but information regarding the expression of δ-GABAARs within gustatory circuits is lacking, and their role in taste preference has not been investigated. Here, we focused on GC to investigate whether activation of δ-GABAARs affects sweet taste preference in adult mice. Our data reveal that δ-GABAARs are expressed in multiple cell types within GC. These receptors mediate an allopregnanolone-sensitive tonic current and decrease sweet taste preference by altering the behavioral sensitivity to sucrose concentration in a cell type-specific manner. Our findings demonstrate that taste sensitivity and preference in the adult mammalian brain are modulated by tonic inhibition mediated by neurosteroid-activated δ-GABAARs in GC.

González-Crespo A., Brugada-Bellsolà F., Candela-Cantó S., Calvo J.A., Arboix J.R., Bernal J.H.

Insular epilepsy is a well-known cause of drug-resistant epilepsy (DRE) in the pediatric population. It can be a source of surgical epilepsy treatment failures when not ruled out pre-operatively. Non-invasive methods often provide limited information about its existence, being the invasive methods necessary to diagnose it in the vast majority of cases. The most used is stereoelectroencephalography (SEEG). We report a series of DRE pediatric patients in which insular SEEG was performed to rule out insular epilepsy. We performed a retrospective review of pediatric DRE patients operated on SEEG including insular electrodes between April 2016 and September 2022. We described the different trajectories used (orthogonal or oblique) and surgical techniques. After implantation, we assessed electrodes’ precision using three measures: entry point location error (EPLE), target point location error (TPLE), and target deviation (TD). We also reported complications that occurred with this technique as well as the diagnostic information provided. Overall, 32 DRE patients were operated on SEEG including insular electrodes. Four hundred one electrodes were implanted, 148 (39.91%) of whom were directed to the insula. One hundred twelve followed an orthogonal trajectory, and 36 were oblique. The mean EPLE was 1.45 mm, TPLE was 1.88 mm and TD was 0.71 mm. Three patients suffered from frontal hematoma, two of them diagnosed on post-operative MRI and one who required surgery, with no sequelae. One patient suffered from meningitis treated with antibiotics with no permanent sequelae. Nine patients (28.13%) had the insula included in the epileptogenic zone. Insular epilepsy has to be ruled out in DRE patients when little suspicion is obtained after non-invasive testing. This is especially important in the pediatric population, in which seizure semiology is more difficult to characterize and failures to control epilepsy have devastating consequences in neurocognitive development and scholarship. Given its relative low rate of relevant complications and potential benefits, we should consider widening the inclusion criteria for insular SEEG monitoring.

Tavares T.P., Young J.M., Chen V.V., Kerr E.N., Mamak E., Mahood Q., Smith M.L.

Dudley P., Marquez J.P., Farrell F., Benson J., Rugg-Gunn F., Sidhu M.K., O'Sullivan S., Walker M., Yogarajah M.

ObjectiveIdentify the proportion of patients referred with putative functional seizures (FS) that were subsequently re-diagnosed as epileptic seizures (ES), or an alternative diagnosis, following video telemetry EEG (VTEEG). In addition, describe the characteristics of those seizures.MethodsThe VTEEG reports from patients admitted to the Chalfont Centre for Epilepsy between 2019 and 2022 were reviewed. Pre-VTEEG and post-VTEEG diagnoses were compared to identify whether a diagnostic revision was made from suspected FS to ES or another diagnosis. Diagnostic revision cases were then grouped into cohorts with associated features and reviewed to characterise and describe FS mimics.Results444 VTEEG reports where patients had habitual events were identified. 4.7% of patients were referred with FS and were subsequently diagnosed with ES or another diagnosis. In this group, several cohorts could be identified including frontal lobe epileptic seizures, ES with functional overlay, insular or temporal lobe epileptic seizures associated with autonomic or marked experiential peri-ictal symptoms, and individuals who had both ES and FS but whose ES were revealed on medication withdrawal.ConclusionIn patients referred to a tertiary epilepsy unit, a small minority of cases had seizures diagnosed as functional and reclassified as epileptic or an alternative diagnosis. It is clinically important to be aware of these FS mimics.

Obaid S., Guberman G.I., St-Onge E., Campbell E., Edde M., Lamsam L., Bouthillier A., Weil A.G., Daducci A., Rheault F., Nguyen D.K., Descoteaux M.

IntroductionOperculo-insular epilepsy (OIE) is a rare condition amenable to surgery in well-selected cases. Despite the high rate of neurological complications associated with OIE surgery, most postoperative deficits recover fully and rapidly. We provide insights into this peculiar pattern of functional recovery by investigating the longitudinal reorganization of structural networks after surgery for OIE in 10 patients.MethodsStructural T1 and diffusion-weighted MRIs were performed before surgery (t0) and at 6 months (t1) and 12 months (t2) postoperatively. These images were processed with an original, comprehensive structural connectivity pipeline. Using our method, we performed comparisons between the t0 and t1 timepoints and between the t1 and t2 timepoints to characterize the progressive structural remodeling.ResultsWe found a widespread pattern of postoperative changes primarily in the surgical hemisphere, most of which consisted of reductions in connectivity strength (CS) and regional graph theoretic measures (rGTM) that reflect local connectivity. We also observed increases in CS and rGTMs predominantly in regions located near the resection cavity and in the contralateral healthy hemisphere. Finally, most structural changes arose in the first six months following surgery (i.e., between t0 and t1).DiscussionTo our knowledge, this study provides the first description of postoperative structural connectivity changes following surgery for OIE. The ipsilateral reductions in connectivity unveiled by our analysis may result from the reversal of seizure-related structural alterations following postoperative seizure control. Moreover, the strengthening of connections in peri-resection areas and in the contralateral hemisphere may be compatible with compensatory structural plasticity, a process that could contribute to the recovery of functions seen following operculo-insular resections for focal epilepsy.

Stoupi N.A., Weijs M.L., Imbach L., Lenggenhager B.

IntroductionCurrent evidence indicates a modulating role of respiratory processes in cardiac interoception, yet whether altered breathing patterns influence heartbeat-evoked potentials (HEP) remains inconclusive.MethodsHere, we examined the effects of voluntary hyperventilation (VH) as part of a clinical routine examination on scalp-recorded HEPs in epilepsy patients (N = 80).ResultsUsing cluster-based permutation analyses, HEP amplitudes were compared across pre-VH and post-VH conditions within young and elderly subgroups, as well as for the total sample. No differences in the HEP were detected for younger participants or across the full sample, while an increased late HEP during pre-VH compared to post-VH was fond in the senior group, denoting decreased cardiac interoceptive processing after hyperventilation.DiscussionThe present study, thus, provides initial evidence of breathing-related HEP modulations in elderly epilepsy patients, emphasizing the potential of HEP as an interoceptive neural marker that could partially extend to the representation of pulmonary signaling. We speculate that aberrant CO2-chemosensing, coupled with disturbances in autonomic regulation, might constitute the underlying pathophysiological mechanism behind the obtained effect. Available databases involving patient records of routine VH assessment may constitute a valuable asset in disentangling the interplay of cardiac and ventilatory interoceptive information in various patient groups, providing thorough clinical data to parse, as well as increased statistical power and estimates of effects with higher precision through large-scale studies.