Insular Stimulation Research Articles

Changes in autonomic nervous function and influencing factors in a rat insular cortex electrical kindling model

In mammals, the insular cortex plays an important role in autonomic regulation. In patients with insular epilepsy, seizures are always accompanied by autonomic changes. Accordingly, we aimed to establish an electrical kindling model in autonomic-mediating areas of the insular cortex, and to conduct a long-term observation of epileptic genesis in these animals until sudden unexpected death. To establish this model in adult rats, we implanted stimulation electrodes in the granular cell layer of the insular cortex, which controls the heart rate (HR) and respiratory rate (RR). Subsequently, seizure was induced successfully in 92.3 % of the rats, and typical autonomic changes were observed during these seizures. Interestingly, the model was established more easily in older rats, and the rats in which electrical stimulation led to a greater reduction in the HR. Moreover, death occurred in 25 % of the kindled rats. In conclusion, our kindling model demonstrates the ability of insular cortex stimulation to generate epilepsy. Our model thus offers a practical tool for studies of the role of the insular cortex in sudden unexpected death in epilepsy.

Anterior insular cortex stimulation and its effects on emotion recognition.

With the objective to investigate the role of the insula in recognizing emotion, we performed direct electrical stimulation over the anterior insular cortex during awake surgery while simultaneously delivering an emotional sensitivity task. We registered 18 consecutive patients with brain tumors associated with the insular lobe, who were undergoing tumor resection. An emotional sensitivity task was employed to measure the patients' ability to recognize emotions from facial expressions before, during, and after awake surgery. Furthermore, we performed voxel-based lesion symptom mapping (VLSM) to identify the association between relevant brain lesions and emotion recognition. When we performed direct electrical stimulation over the anterior insular cortex during awake surgery, the results showed that the ability to recognize anger was significantly enhanced with the presence of anterior insular stimulation (p < 0.05). Comparing the performance in the emotional sensitivity task before and after surgery, the performance in the anger condition became worse (p < 0.01), but became better in the sadness condition after surgery (p < 0.01). In the case of anger recognition, lower scores in the correct response index were associated with lesions involving the left insula in the VLSM study. Direct electrical stimulation over the anterior insular cortex enhanced anger recognition in patients with insular tumors. In contrast, accuracy of anger recognition was significantly reduced, and sadness was improved, when the performance of emotional sensitivity was compared pre- and post-surgery. Our findings suggest that the insular cortex is involved in changes in emotion recognition, including anger and sadness recognition by modulating arousal level that is closely connected with interoception.

How the insula speaks to the heart: Cardiac responses to insular stimulation in humans.

Despite numerous studies suggesting the role of insular cortex in the control of autonomic activity, the exact location of cardiac motor regions remains controversial. We provide here a functional mapping of autonomic cardiac responses to intracortical stimulations of the human insula. The cardiac effects of 100 insular electrical stimulations into 47 epileptic patients were divided into tachycardia, bradycardia, and no cardiac response according to the magnitude of RR interval (RRI) reactivity. Sympathetic (low frequency, LF, and low to high frequency powers ratio, LF/HF ratio) and parasympathetic (high frequency power, HF) reactivity were studied using RRI analysis. Bradycardia was induced by 26 stimulations (26%) and tachycardia by 21 stimulations (21%). Right and left insular stimulations induced as often a bradycardia as a tachycardia. Tachycardia was accompanied by an increase in LF/HF ratio, suggesting an increase in sympathetic tone; while bradycardia seemed accompanied by an increase of parasympathetic tone reflected by an increase in HF. There was some left/right asymmetry in insular subregions where increased or decreased heart rates were produced after stimulation. However, spatial distribution of tachycardia responses predominated in the posterior insula, whereas bradycardia sites were more anterior in the median part of the insula. These findings seemed to indicate a posterior predominance of sympathetic control in the insula, whichever the side; whereas the parasympathetic control seemed more anterior. Dysfunction of these regions should be considered when modifications of cardiac activity occur during epileptic seizures and in cardiovascular diseases.

Anterior insular cortex stimulation and its effects on emotion recognition

Anterior insular cortex stimulation and its effects on emotion recognition

The Insula and Its Epilepsies.

Insular seizures are great mimickers of seizures originating elsewhere in the brain. The insula is a highly connected brain structure. Seizures may only become clinically evident after ictal activity propagates out of the insula with semiology that reflects the propagation pattern. Insular seizures with perisylvian spread, for example, manifest first as throat constriction, followed next by perioral and hemisensory symptoms, and then by unilateral motor symptoms. On the other hand, insular seizures may spread instead to the temporal and frontal lobes and present like seizures originating from these regions. Due to the location of the insula deep in the brain, interictal and ictal scalp electroencephalogram (EEG) changes can be variable and misleading. Magnetic resonance imaging, magnetic resonance spectroscopy, magnetoencephalography, positron emission tomography, and single-photon computed tomography imaging may assist in establishing a diagnosis of insular epilepsy. Intracranial EEG recordings from within the insula, using stereo-EEG or depth electrode techniques, can prove insular seizure origin. Seizure onset, most commonly seen as low-voltage, fast gamma activity, however, can be highly localized and easily missed if the insula is only sparsely sampled. Moreover, seizure spread to the contralateral insula and other brain regions may occur rapidly. Extensive sampling of the insula with multiple electrode trajectories is necessary to avoid these pitfalls. Understanding the functional organization of the insula is helpful when interpreting the semiology produced by insular seizures. Electrical stimulation mapping around the central sulcus of the insula results in paresthesias, while stimulation of the posterior insula typically produces painful sensations. Visceral sensations are the next most common result of insular stimulation. Treatment of insular epilepsy is evolving, but poses challenges. Surgical resections of the insula are effective but risk significant morbidity if not carefully planned. Neurostimulation is an emerging option for treatment, especially for seizures with onset in the posterior insula. The close association of the insula with marked autonomic changes has led to interest in the role of the insula in sudden unexpected death in epilepsy and warrants additional study with larger patient cohorts.

Modulating interoception by insula stimulation: A double-blinded tDCS study

Interoception consists in the perception and processing of internal body signals, such as heartbeat. Previous neuroimaging studies revealed that attention to heartbeat activated bilateral insula and premotor regions.In the present double-blind study, we aimed at testing the role of insula in interoception by means of transcranial direct current stimulation (tDCS) interfering with its activity.Sixteen healthy participants responded to a questionnaire to evaluate the tendency to be internally focused and performed a heartbeat counting task before and after tDCS in three sessions (left insula stimulation, right insula stimulation, sham stimulation). Real and reported heartbeat were recorded and used to calculate the accuracy scores.A significant interaction between stimulation condition and time (pre- and post-stimulation) was found due to a significant improvement of the interoceptive accuracy in the sham condition only.Our results demonstrated that stimulation over the insula reduced the possibility to improve the precision with which individuals detect internal signals.

Cortical Structures Associated With Human Blood Pressure Control

A better understanding of the role of cortical structures in blood pressure control may help us understand cardiovascular collapse that may lead to sudden unexpected death in epilepsy (SUDEP). To identify cortical control sites for human blood pressure regulation. Patients with intractable epilepsy undergoing intracranial electrode implantation as a prelude to epilepsy surgery in the Epilepsy Monitoring Unit at University Hospitals Cleveland Medical Center were potential candidates for this study. Inclusion criteria were patients 18 years or older who had electrodes implanted in one or more of the regions of interest and in whom deep brain electrical stimulation was indicated for mapping of ictal onset or eloquent cortex as a part of the presurgical evaluation. Twelve consecutive patients were included in this prospective case series from June 1, 2015, to February 28, 2017. Changes in continuous, noninvasive, beat-by-beat blood pressure parameter responses from amygdala, hippocampal, insular, orbitofrontal, temporal, cingulate, and subcallosal stimulation. Electrocardiogram, arterial oxygen saturation, end-tidal carbon dioxide, nasal airflow, and abdominal and thoracic plethysmography were monitored. Among 12 patients (7 female; mean [SD] age, 44.25 [12.55] years), 9 electrodes (7 left and 2 right) all in Brodmann area 25 (subcallosal neocortex) in 4 patients produced striking systolic hypotensive changes. Well-maintained diastolic arterial blood pressure and narrowed pulse pressure indicated stimulation-induced reduction in sympathetic drive and consequent probable reduction in cardiac output rather than bradycardia or peripheral vasodilation-induced hypotension. Frequency-domain analysis of heart rate and blood pressure variability showed a mixed picture. No other stimulated structure produced significant blood pressure changes. These findings suggest that Brodmann area 25 has a role in lowering systolic blood pressure in humans. It is a potential symptomatogenic zone for peri-ictal hypotension in patients with epilepsy.

S43 Insular semiology: From observation of cases to cortical stimulation

Objectives 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 pre-surgical monitoring of epilepsy, reproduce the ictal symptoms observed during the development of insular seizures. Methods We reviewed the results of insular stimulations performed in 222 patients admitted between 1997 and 2015 for pre-surgical SEEG exploration of atypical temporal or perisylvian epilepsy. Stimulations (50 Hz, trains of 5s, pulses of 0.5 ms, intensity 0.2–3.5 mA) were carried out using trans-opercular electrodes implanted orthogonal to mid-sagittal plane. Results 550 of 669 stimulations were clinically eloquent in the absence of any post-discharge (237 and 313 respectively in right and left insula). 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. Discussion 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 to vestibular, auditory, aphasic, or olfacto-gustatory symptoms points to a discharge development in the insular cortex. Conclusion Inular cortex is the only cortical region where stimulations demonstrate such a multi-modal representation.

Application of RNS in refractory epilepsy: Targeting insula.

SummaryAlthough responsive neurostimulation (RNS) is approved for treatment of resistant focal epilepsy in adults, little is known about response to treatment of specific cortical targets. We describe the experience of RNS targeting the insular lobe. We identified patients who had RNS implantation with at least one electrode within the insula between April 2014 and October 2015. We performed a retrospective review of preoperative clinical features, imaging, electrocardiogram (EEG), intraoperative electrocorticography (ECoG), and postoperative seizure outcome. Eight patients with at least 6 months of postimplant follow‐up were identified. Ictal localization was inconclusive with MRI or scalp EEG findings. Intracranial EEG monitoring or intraoperative ECoG demonstrated clear ictal onsets and/or frequent interictal discharges in the insula. Four patients demonstrated overall 50–75% reduction in seizure frequency. Two patients did not show appreciable seizure improvement. One patient has experienced a 75% reduction of seizure frequency, and another is nearly seizure free postoperatively. There were no reported direct complications of insular RNS electrode placement or stimulation, though two patients had postoperative complications thought to be related to craniotomy (hydrocephalus and late infection). Our study suggests that insular RNS electrode placement in selected patients is relatively safe and that RNS treatment may benefit selected patients with insular epilepsy.

Electrical Stimulations of the Human Insula: Their Contribution to the Ictal Semiology of Insular Seizures.

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.

Important methodological issues regarding the use of transcranial magnetic stimulation to investigate interoceptive processing: a Comment on Pollatos et al. (2016).

Comment on: Changes in interoceptive processes following brain stimulation by Pollatos, Herbert, Mai & Kammer, 2016

Connectivity of the frontal and anterior insular network: a cortico-cortical evoked potential study.

OBJECT The frontal and insular fiber network in humans remains largely unknown. This study investigated the connectivity of the frontal and anterior insular network in humans using cortico-cortical evoked potential (CCEP). METHODS This retrospective analysis included 18 patients with medically intractable focal epilepsy who underwent stereoelectroencephalography and CCEP. Alternating 1-Hz electrical stimuli were delivered to parts of the frontal lobe and anterior insula (prefrontal cortex [PFC], ventrolateral and dorsolateral premotor area [vPM and dPM, respectively], presupplementary motor area [pre-SMA], SMA, frontal operculum, and anterior insula). A total of 40-60 stimuli were averaged in each trial to obtain CCEP responses. The distribution of CCEP was evaluated by calculating the root mean square of CCEP responses. RESULTS Stimulation of the PFC elicited prominent CCEP responses in the medial PFC and PMs over the ipsilateral hemisphere. Stimulation of the vPM and dPM induced CCEP responses in the ipsilateral frontoparietal areas. Stimulation of the pre-SMA induced CCEP responses in the ipsilateral medial and lateral frontal areas and contralateral pre-SMA, whereas stimulation of the SMA induced CCEP responses in the bilateral frontoparietal areas. Stimulation of the frontal operculum induced CCEP responses in the ipsilateral insula and temporal operculum. CCEPs were observed in the ipsilateral medial, lateral frontal, and frontotemporal operculum in the anterior insular stimulation. Stimulation of the vPM and SMA led to the network in the dominant hemisphere being more developed. CONCLUSIONS Various regions within the frontal lobe and anterior insula were linked to specific ipsilateral and contralateral regions, which may reflect distinct functional roles.

Effects of insular stimulation on thermal nociception

Electrical stimulation used for brain mapping in the postero-superior insula can evoke pain. The effects of prolonged high frequency insular stimulation on pain thresholds are unknown. Prolonged high frequency insular stimulation, by virtue of its inhibitory properties on networks, could decrease thermal nociception. Epileptic subjects had electrodes implanted in the insular cortex for the purpose of epileptic focus resection. Thermal and pressure nociceptive thresholds were tested bilaterally on the forearm on two consecutive days. Randomly assigned double-blind high frequency (150Hz) insular stimulation took place for 10min before pain testing either on the first day or on the second day. Six subjects (three females; mean age of 35years) were included. Insular stimulation increased heat pain threshold on the ipsilateral (p=0.003; n=6) and contralateral sides (p=0.047; n=6). Differences in cold pain threshold did not reach statistical significance (ipsilateral: p=0.341, contralateral: p=0.143; n=6), but one subject had a profound decrease in both heat and cold pain responses. Pressure pain threshold was not modified by insular stimulation (ipsilateral: p=0.1123; contralateral: p=0.1192; n=6). Two of the three subjects who had a postero-superior operculo-insulectomy developed central pain with contralateral thermal nociceptive deficit. High frequency inhibitory postero-superior insular stimulation may have the potential to decrease thermal nociception. Together with previous studies, our data support the notion that the integrity of this brain region is necessary for thermal but not pressure nociceptive processing.

Middle short gyrus of the insula implicated in speech production: Intracerebral electric stimulation of patients with epilepsy by an oblique approach using a robotized arm

Introduction Few data exist about of the role of the insula in the processing of speech. The data of this study suggests the involvement of the upper middle short gyrus in speech production. Materials and methods For this study, we included 25 patients suffering from severe drug refractory partial epilepsy were investigated by stereo-electroencephalography (SEEG). At least one electrode was used to explore the insular cortex using an oblique approach (trans-frontal or trans-parietal) and who had a normal insular region. In total, 313 stimulations were performed in 27 insula. Eighty-three responses induced by insular electrical stimulation (ES), eight (9.6%) were reported by five patients as speech arrest (5 responses) and a lowering of voice intensity (3 responses). The stereotactic approach allows us to identify the stimulation sites within the insular cortex in terms of its gyri and sulci. Also, the stimulation sites were anatomically localized via image fusion between pre-implantation 3D MRI and post-implantation 3D CT scans revealing the electrode contacts. Results Eight responses were reported as speech disturbances. 7 among them were evoked in 4 patients by stimulation in the middle short gyrus (8.4% of total responses, and 25.9% of responses evoked in the middle short gyrus). The site of the 8th response was in the post-central insular gyrus in the same insular region where the oropharyngeal responses induced by other ES (pharyngeal construction) in this study. The data suggest the involvement of the middle short gyrus of the insula in the procedures of language. These responses were evoked in the non-dominant side four times out of five. This study provides evidence that the middle short gyrus of the insula in both hemispheres responds to ES producing speech disturbances. Conclusion The results of this study are the first to report language disorders in humans evoked by electrical stimulation of the insular cortex during SEEG explorations by electrodes implanted by oblique approach in terms of gyral and sulcal anatomy.

Prolonged QTc interval and insula in patients with ischemic stroke: Inductive or abductive reasoning?

While a great emphasis has been placed on pathophysiological mechanisms underlying the long QT syndromes (LQTS), both congenital and acquired forms, little attention has been focused on the mechanisms whereby a brain damage could induce changes in the QTc interval. Until now, there has been no precise explanation for the frequently observed relationship between acute cerebrovascular events and QTc interval prolongation. Many excellent studies with inductive reasoning proposed QTc effects of insular cortex stimulation [1,2] Few and controversial studies with abductive reasoning investigated an association between prolonged QTc and ischemic insular damage.

Conditioned place preference induced by electrical stimulation of the insular cortex: effects of naloxone

The insular cortex has been related to various sensory, regulatory, and learning processes, which frequently include affective-emotional components. The objective of this study was to investigate the possibility of inducing reinforcing effects by electrical stimulation of this cortical region in Wistar rats. Concurrent conditioned place preference tasks were conducted for this purpose, using two rectangular mazes that differed in dimensions, texture, and spatial orientation. A significant correlation was found in the preferences induced by insular cortex electrical stimulation between the two mazes. Animals showed consistent preference or avoidance behaviors associated with simultaneous insular cortex stimulation. No electrical self-stimulation was achieved. In a second experiment, animals that showed consistent place preference after the simultaneous insular cortex electrical stimulation were administered with 4 mg/ml/kg of naloxone. The results revealed that this opiate antagonist blocked concurrent place preference learning when the task was conducted in a new maze but not when it was conducted in the same maze as that in which the animals had learned the task. These results are discussed in terms of the participation of the insular cortex in various reward and aversion modalities.

Middle short gyrus of the insula implicated in speech production: Intracerebral electric stimulation of patients with epilepsy

Different lines of evidence have suggested an involvement of the insular cortex in speech production. These have included results from lesion studies, functional imaging techniques, and electrical stimulation of the human insular cortex during invasive evaluation of epileptic patients. We evaluated 25 patients who had drug refractory focal epilepsy with at least one electrode stereotactically implanted in the insular cortex. Eight responses to insular cortex electrical stimulation were reported by five patients as speech arrest (five responses) and a lowering of voice intensity (three responses). Data from this study implicate the middle short gyrus of the insula in the production of speech and show the importance of intrainsular electrode implantation during invasive pre-resection evaluation by stereo-electroencephalography (SEEG) when speech arrest occurs early in seizure semiology.

Somatotopic organization of pain responses to direct electrical stimulation of the human insular cortex

The question whether pain encoding in the human insula shows some somatotopic organization is still pending. We studied 142 patients undergoing depth stereotactic EEG (SEEG) exploration of the insular cortex for pre-surgical evaluation of epilepsy. 472 insular electrical stimulations were delivered, of which only 49 (10.5%) elicited a painful sensation in 38 patients (27%). Most sites where low intensity electric stimulation produced pain, without after-discharge or concomitant visually detectable change in EEG activity outside the insula, were located in the posterior two thirds of the insula. Pain was located in a body area restricted to face, upper limb or lower limb for 27 stimulations (55%) and affected more than one of these regions for all others. The insular cortex being oriented parallel to the medial sagittal plane we found no significant difference between body segment representations in the medio-lateral axis. Conversely a somatotopic organization of sites where stimulation produced pain was observed along the rostro-caudal and vertical axis of the insula, showing a face representation rostral to those of upper and lower limbs, with an upper limb representation located above that of the lower limb. These data suggest that, in spite of large and often bilateral receptive fields, pain representation shows some degree of somatotopic organization in the human insula.

Cortico-subcortical organization of language networks in the right hemisphere: An electrostimulation study in left-handers

We have studied the configuration of the cortico-subcortical language networks within the right hemisphere (RH) in nine left-handers, being operated on while awake for a cerebral glioma. Intraoperatively, language was mapped using cortico-subcortical electrostimulation, to avoid permanent deficit. In frontal regions, cortical stimulation elicited articulatory disorders (ventral premotor cortex), anomia (dorsal premotor cortex), speech arrest (pars opercularis), and semantic paraphasia (dorsolateral prefrontal cortex). Insular stimulation generated dysarthria, parietal stimulation phonemic paraphasias, and temporal stimulation semantic paraphasias. Subcortically, the superior longitudinal fasciculus (inducing phonological disturbances when stimulated), inferior occipito-frontal fasciculus (eliciting semantic disturbances during stimulation), subcallosal fasciculus (generating control disturbances when stimulated), and common final pathway (inducing articulatory disorders during stimulation) were identified. These cortical and subcortical structures were preserved, avoiding permanent aphasia, despite a transient immediate postoperative language worsening. Both intraoperative results and postsurgical transitory dysphasia support the major role of the RH in language in left-handers, and provide new insights into the anatomo-functional cortico-subcortical organization of the language networks in the RH-suggesting a “mirror” configuration in comparison to the left hemisphere.

The role of the anterior insular cortex in ictal vomiting: A stereotactic electroencephalography study

Ictal vomiting is a rare manifestation most often associated with right temporal lobe epilepsy. The implication of the anterior insula in the occurrence of this symptom has been suggested based on the role of this region in swallowing and on the observation that electrical insular stimulation can elicit nausea and vomiting. We report the first case, to our knowledge, of a patient presenting with ictal vomiting who underwent bilateral intracranial exploration including insular depth electrodes. The seizure onset zone was localized in the left temporomesial structures, but the occurrence of ictal vomiting correlated in time with a discharge affecting exclusively the anterior part of both insular lobes. It is concluded that the occurrence of ictal vomiting reflects a propagation of the discharge to the insular cortex. Observation of this symptom at the very onset of the seizures in a patient with temporal lobe epilepsy is highly suggestive of an insular seizure onset zone.