Insular Stimulation Research Articles

Transient alteration of awareness triggered by direct electrical stimulation of the brain

BackgroundAwareness is a state of consciousness that enables a subject to interact with the environment. Transient alteration of awareness (AA) is a disabling sign of many types of epileptic seizures. The brain mechanisms of awareness and its alteration are not well known. Objective/HypothesisTransient and isolated AA induced by electrical brain stimulation during a stereoelectroencephalography (SEEG) recording represents an ideal model for studying the associated modifications of functional connectivity and locating the hubs of awareness networks. MethodsWe investigated the SEEG signals-based brain functional connectivity (FC) changes vs background occurring during AA triggered by three thalamic and two insular stimulations in three patients explored by SEEG in the frame of presurgical evaluation for focal drug-resistant epilepsy. The results were compared to the stimulations of the same sites that did not induce clinical changes (negative stimulations). ResultsWe observed decreased node strength in the pulvinar, insula, and parietal associative cortices during the thalamic and insular stimulations that induced AA. The link strengths characterizing functional coupling between the thalamus and the insular, prefrontal, temporal, or parietal associative cortices were also decreased. In contrast, there was an increased synchronization between the precuneus and the temporal lateral cortex. These FC changes were absent during the negative stimulations. ConclusionOur study highlights the role of the pulvinar, insular, and parietal hubs in maintaining the awareness networks and paves the way for invasive or non-invasive neuromodulation protocols to reduce AA manifestations during epileptic seizures.

Insights into interoceptive and emotional processing: Lessons from studies on insular HD-tDCS.

Interoception, the processing of internal bodily signals, is proposed as the fundamental mechanism underlying emotional experiences. Interoceptive and emotional processing appear distorted in psychiatric disorders. However, our understanding of the neural structures involved in both processes remains limited. To explore the feasibility of enhancing interoception and emotion, we conducted two studies using high-definition transcranial direct current stimulation (HD-tDCS) applied to the right anterior insula. In study one, we compared the effects of anodal HD-tDCS and sham tDCS on interoceptive abilities (sensibility, confidence, accuracy, emotional evaluation) in 52 healthy subjects. Study two additionally included physical activation through ergometer cycling at the beginning of HD-tDCS and examined changes in interoceptive and emotional processing in 39 healthy adults. In both studies, HD-tDCS was applied in a single-blind cross-over online design with two separate sessions. Study one yielded no significant effects of HD-tDCS on interoceptive dimensions. In study two, significant improvements in interoceptive sensibility and confidence were observed over time with physical preactivation, while no differential effects were found between sham and insula stimulation. The expected enhancement of interoceptive and emotional processing following insula stimulation was not observed. We conclude that HD-tDCS targeting the insula does not consistently increase interoceptive or emotional variables. The observed increase in interoceptive sensibility may be attributed to the activation of the interoceptive network through physical activity or training effects. Future research on HD-tDCS involving interoceptive network structures could benefit from protocols targeting larger regions within the network, rather than focusing solely on insula stimulation.

Uncovering Interoceptive Human Insular Lobe Function through Intraoperative Cortical Stimulation-A Review.

The insular cortex, a critical hub in the brain's sensory, cognitive, and emotional networks, remains an intriguing subject of study. In this article, we discuss its intricate functional neuroanatomy, emphasizing its pivotal role in processing olfactory information. Through concise exploration, we delve into the insula's diverse connectivity and its involvement in sensory integration, particularly in olfaction. Stimulation studies in humans reveal compelling insights into the insula's contribution to the perception of smell, hinting at its broader implications for cognitive processing. Additionally, we explore an avenue of research in which studying olfactory processing via insular stimulation could unravel higher-level cognitive processes. This innovative approach could help give a fresh perspective on the interplay between sensory and cognitive domains, offering valuable insights into the neural mechanisms underlying cognition and emotion. In conclusion, future research efforts should emphasize a multidisciplinary approach, combining advanced imaging and surgical techniques to explore the intricate functions of the human insula. Moreover, awake craniotomies could offer a unique opportunity for real-time observation, shedding light on its neural circuitry and contributions to higher-order brain functions. Furthermore, olfaction's direct cortical projection enables precise exploration of insular function, promising insights into cognitive and emotional processes. This multifaceted approach will deepen our understanding of the insular cortex and its significance in human cognition and emotion.

Functional Brain Mapping Using Depth Electrodes

ObjectiveThis study investigated the neurological symptoms and stimulus intensities in the stimulation of deep structures and subcortical fibers with the depth electrodes. MethodsSeventeen patients with drug-refractory epilepsy who underwent functional brain mapping with the depth electrodes were enrolled. The 50 Hz electrical stimulation was applied, and the diffusion tensor image was used to identify subcortical fibers. The responsible structures and stimulus intensities for the induced neurological symptoms were evaluated. ResultsNeurological symptoms were induced in 11 of 17 patients. The opercular stimulation elicited the neurological symptoms in six patients at the median threshold of 4.0 mA (visceral/face/hand sensory, hand/throat motor, negative motor and auditory symptoms). The insular stimulation induced the neurological symptoms in four patients at the median threshold of 4.0 mA (auditory, negative motor, and sensory symptoms). The stimulation of subcortical fibers induced in five of nine patients at the median threshold of 4.5 mA. The thresholds of depth electrodes were significantly lower than those of subdural electrodes in eight patients who used both subdural and depth electrodes and induced symptoms with both electrodes. ConclusionThe stimulation of depth electrodes can identify the function of deep structures and subcortical fibers with lower intensities than subdural electrodes.

Insular cortex stimulation alleviates neuropathic pain through changes in the expression of collapsin response mediator protein 2 involved in synaptic plasticity

In recent studies, brain stimulation has shown promising potential to alleviate chronic pain. Although studies have shown that stimulation of pain-related brain regions can induce pain-relieving effects, few studies have elucidated the mechanisms of brain stimulation in the insular cortex (IC). The present study was conducted to explore the changes in characteristic molecules involved in pain modulation mechanisms and to identify the changes in synaptic plasticity after IC stimulation (ICS). Following ICS, pain-relieving behaviors and changes in proteomics were explored. Neuronal activity in the IC after ICS was observed by optical imaging. Western blotting was used to validate the proteomics data and identify the changes in the expression of glutamatergic receptors associated with synaptic plasticity. Experimental results showed that ICS effectively relieved mechanical allodynia, and proteomics identified specific changes in collapsin response mediator protein 2 (CRMP2). Neuronal activity in the neuropathic rats was significantly decreased after ICS. Neuropathic rats showed increased expression levels of phosphorylated CRMP2, alpha amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR), and N-methyl-d-aspartate receptor (NMDAR) subunit 2B (NR2B), which were inhibited by ICS. These results indicate that ICS regulates the synaptic plasticity of ICS through pCRMP2, together with AMPAR and NR2B, to induce pain relief.

Testing the effect of high-definition transcranial direct current stimulation of the insular cortex to modulate decision-making and executive control.

Previous neuroimaging evidence highlighted the role of the insular and dorsal anterior cingulate cortex (dACC) in conflict monitoring and decision-making, thus supporting the translational implications of targeting these regions in neuro-stimulation treatments for clinical purposes. Recent advancements of targeting and modeling procedures for high-definition tDCS (HD-tDCS) provided methodological support for the stimulation of otherwise challenging targets, and a previous study confirmed that cathodal HD-tDCS of the dACC modulates executive control and decision-making metrics in healthy individuals. On the other hand, evidence on the effect of stimulating the insula is still needed. We used a modeling/targeting procedure to investigate the effect of stimulating the posterior insula on Flanker and gambling tasks assessing, respectively, executive control and both loss and risk aversion in decision-making. HD-tDCS was applied through 6 small electrodes delivering anodal, cathodal or sham stimulation for 20 min in a within-subject offline design with three separate sessions. Bayesian statistical analyses on Flanker conflict effect, as well as loss and risk aversion, provided moderate evidence for the null model (i.e., absence of HD-tDCS modulation). These findings suggest that further research on the effect of HD-tDCS on different regions is required to define reliable targets for clinical applications. While modeling and targeting procedures for neuromodulation in clinical research could lead to innovative protocols for stand-alone treatment, or possibly in combination with cognitive training, assessing the effectiveness of insula stimulation might require sensitive metrics other than those investigated here.

Right posterior insular epidural stimulation in rats with neuropathic pain induces a frequency-dependent and opioid system-mediated reduction of pain and its comorbid anxiety and depression

Neuropathic pain (NP) is a sensory, emotional, and persistent disturbing experience caused by a lesion or disease of the somatosensory system which can lead when chronic to comorbidities such as anxiety and depression. Available treatments (pharmacotherapy, neurostimulation) have partial and unpredictable response; therefore, it seems necessary to find a new therapeutical approach that could alleviate most related symptoms and improve patients ‘emotional state’. Posterior Insula seems to be a potential target of neurostimulation for pain relief. However, its effects on pain-related anxiety and depression remain unknown. Using rats with spared nerve injury (SNI), this study aims to elucidate the correlation between NP and anxio-depressive disorders, evaluate potential analgesic, anxiolytic, and antidepressant effects of right posterior insula stimulation (IS) using low (LF-IS, 50 Hz) or high (HF-IS, 150 Hz) frequency and assess endogenous opioid involvement in these effects. Results showed positive correlation between NP, anxiety, and depression. LF-IS reversed anhedonia and despair-like behavior through pain alleviation, whereas HF-IS only reduced anhedonia, all effects involving endogenous opioids. These findings support the link between NP and anxio-depressive disorders. Moreover, IS appears to have analgesic, anxiolytic and antidepressant effects mediated by the endogenous opioid system, making it a promising target for neurostimulation.

Front cover

CNS Neuroscience & TherapeuticsVolume 29, Issue 6 p. i-i COVER IMAGEOpen Access Front cover First published: 11 May 2023 https://doi.org/10.1111/cns.14262AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Graphical Abstract The cover image is based on the Original Article Insular cortex stimulation alleviates neuropathic pain via ERK phosphorylation in neurons by Kyeongmin Kim et al., https://doi.org/10.1111/cns.14126. Volume29, Issue6June 2023Pages i-i RelatedInformation

Insular Role in Blood Pressure and Systemic Vascular Resistance Regulation

ObjectivesThe insula is a brain area involved in the modulation of autonomic responses. Previous studies have focused mainly on its heart rate regulatory function, but its role in vascular control is not well defined. Ictal/postictal blood pressure (BP) fluctuations may have a role in the pathogenesis of sudden unexpected death in epilepsy. This study aims to characterize the insular influence on vascular regulation through direct high-frequency electrical stimulation (E-stim) of different insular regions during stereo-electroencephalographic studies. Materials and MethodsAn observational, prospective study was conducted, involving people with epilepsy who underwent E-stim of depth electrodes implanted in the insular cortex. Patients with anatomical or electrophysiological insular abnormalities, E-stim producing after discharges, or any elicited symptoms were excluded. Variations of BP and systemic vascular resistance (SVR) during the insular stimuli were analyzed, comparing them with those observed during E-stim of control contacts implanted in cortical noneloquent regions and sham stimulations. ResultsFourteen patients were included, five implanted in the right insula and nine in the left. We analyzed 14 stimulations in the right insula, 18 in the left insula, 18 in control electrodes, and 13 sham stimulations. Most right insular responses were hypertensive, whereas most left ones were hypotensive. E-stim of the right insula produced a significant BP and SVR increase, whereas the left insula induced a significant BP decrease without SVR changes. The most remarkable changes were elicited in both posterior insulas, although the magnitude of BP changes was generally low. Control and sham stimulations did not induce BP or SVR changes. ConclusionOur findings on insular stimulation suggest an interhemispheric difference in its vascular regulatory function, with a vasopressor effect of the right insula and a vasodilator effect of the left one.

Acute Effects of High-Frequency Insular Stimulation on Interictal Epileptiform Discharge Rates in Patients with Refractory Epilepsy.

Rationale: Deep brain stimulation (DBS) of several sites, such as the thalamus, has been shown to reduce seizure frequency and interictal epileptiform activity in patients with refractory epilepsy. Recent findings have demonstrated that the insula is part of the 'rich club' of highly connected brain regions. This pilot study investigated short-term effects of high-frequency (HF) insular DBS on interictal epileptiform discharge (IED) rate in patients with refractory epilepsy. Methods: Six patients with drug-resistant epilepsy undergoing an intracranial electroencephalographic study received two sets of 10 min continuous 150 Hz HF-DBS of the insula. For each patient, epileptiform activity was analyzed for a total of 80 min, starting 20 min prior to stimulation set 1 (S1), and ending 20 min after stimulation set 2 (S2). All IEDs were identified and classified according to their anatomic localization by a board-certified epileptologist. The IED rate during the 20 min preceding S1 served as a baseline for comparison with IED rate during S1, S2 and post-stimulation periods. Results: HF-DBS of the anterior insula (aINS) was performed in a patient with an aINS epileptic focus (patient 1). HF-DBS of the posterior insula (pINS) was performed in two patients with a pINS epileptic focus (patients 2 and 4), in one patient with an aINS focus (patient 3), and in two non-insular patients (patients 5 and 6). The total IED (irrespective of their location) rate significantly decreased (p < 0.01) in two patients (patients 1 and 2) during the stimulation period, whereas it significantly increased (p < 0.01) in one patient (patient 6); there was no change in the other three patients. Looking at subsets of spike localization, HF-DBS of the aINS significantly reduced aINS and orbitofrontal IEDs in patient 1 (p < 0.01), while HF-DBS of the pINS had an effect on pINS IEDs (p < 0.01) in both patients with a pINS focus; there was no significant effect of HF-DBS of the insula on IEDs in temporal or other frontal regions. Conclusion: Short-term HF-DBS of the insula had heterogeneous effects on the IED rate. Further work is required to examine factors underlying these heterogeneous effects, such as stimulation frequency, location of IEDs and subregions of the insula stimulated.

Non-invasive insular stimulation for peripheral neuropathic pain: Influence of target or symptom?

ObjectivesThe posterior-superior insula (PSI) has been shown to be a safe and potentially effective target for neuromodulation in peripheral neuropathic pain (PNP) in humans and animal models. However, it remains unknown whether there is a measurable responder profile to PSI stimulation. Two factors were hypothesized to influence the response of repetitive transcranial magnetic stimulation (rTMS) of the PSI: differences in rTMS target (discrete subregions of the PSI) or PNP phenotype. MethodsThis is a secondary analysis from a randomized, double-blind, sham-controlled, cross-over trial assessing PSI-rTMS in PNP (N = 31, 5 days rTMS) (10.1016/j.neucli.2021.06.003). Active PSI-rTMS true responders (>50% pain reduction from baseline after active but not after sham series of treatment) were compared with not true responders, to determine whether they differed with respect to 1) rTMS neuro-navigational target coordinates, and/or 2) specific neuropathic pain symptom inventory (NPSI) clusters (pinpointed pain, evoked pain, and deep pain) at baseline. ResultsMean rTMS target coordinates did not differ between true (n = 45.1%) and not true responders (p = 0.436 for X, p = 0.120 for Y, and p = 0.116 for Z). The Euclidian distance between true and not true responders was 4.04 mm. When comparing differences in responders between NPSI clusters, no participant within the evoked pain cluster was a true responder (p = 0.024). ConclusionResponse to PSI-rTMS may depend on pain cluster subtype rather than on differences in targeting within the PSI.

Epidural Posterior Insular Stimulation Alleviates Neuropathic Pain Manifestations in Rats With Spared Nerve Injury Through Endogenous Opioid System

ObjectivesNeuropathic pain (NP) is defined as constant disabling pain secondary to a lesion or disease of the somatosensory nervous system. This condition is particularly difficult to treat because it often remains resistant to most treatment strategies. Despite the recent diversification of neurostimulation methods, some patients still suffer from refractory pain syndromes. The central role of the posterior insular cortex (PI) in the modulation of pain signaling and perception has been repeatedly suggested. The objective of this study is to assess whether epidural insular stimulation (IS) could reverse NP behavior. Materials and MethodsA total of 53 adult Sprague-Dawley rats received left-sided spared nerve injury (SNI) or Sham-SNI to induce NP symptoms. Afterward, epidural electrodes were implanted over the right PI. After two weeks of postoperative recovery, three groups of SNI-operated rats each received a different stimulation modality: Sham-IS, low-frequency-IS (LF-IS), or high-frequency-IS (HF-IS). Behavioral and functional tests were conducted before and after IS. They comprised the acetone test, pinprick test, von Frey test, and sciatic functional index. An additional LF-IS group received a dose of opioid antagonist naloxone before IS. Intergroup means were compared through independent-samples t-tests, and pre- and post-IS means in the same group were compared through paired t-tests. ResultsWe found a significant reduction of cold allodynia (p = 0.019), mechanical hyperalgesia (p = 0.040), and functional disability (p = 0.005) after LF-IS but not HF-IS. Mechanical allodynia only showed a tendency to decrease after LF-IS. The observed analgesic effects were reversed by opioid antagonist administration. ConclusionThese results suggest a significant reversal of NP symptoms after LF-IS and offer additional evidence that IS might be beneficial in the treatment of resistant NP syndromes through endogenous opioid secretion. Relying on our novel epidural IS model, further fine tuning of stimulation parameters might be necessary to achieve optimal therapeutic effects.

Brain Stimulation Using Responsive Neurostimulation Improves Verbal Memory: A Crossover Case-Control Study.

The effects of brain stimulation on memory formation in humans have shown conflicting results in previous studies. We hypothesized that direct cortical stimulation using an implanted responsive neurostimulation (RNS) system will improve memory. To evaluate whether direct cortical stimulation using RNS improves memory as measured with recall scores of a list-learning task. During outpatient visits, a list-learning task (Hopkins Verbal Learning Test-Revised) was administered to 17 patients with RNS implants. Patients were read a list of 12 semantically related words and asked to recall the list after 3 different learning trials. True or sham stimulations were performed for every third word presented for immediate recall. Most patients had frontotemporal network stimulation-one patient each had insular and parietal stimulations. After a 20-min delay, they were asked to recall the list again, first freely and then through a "yes/no" recognition paradigm. A crossover design was used in which half the patients had true stimulation during the initial visit and half had sham stimulation-followed by crossover to the other group at the next visit. The Hopkins Verbal Learning Test-Revised delayed recall raw score was higher for the stimulation condition compared with the nonstimulation condition (paired t -test, P = .04, effect size d = 0.627). Verbal memory improves by direct cortical stimulation during a list-learning task. The RNS system can be effectively used in memory research using direct cortical stimulation. This study has implications in the development of neurostimulation devices for cognitive enhancement in conditions such as epilepsy, dementia, and traumatic brain injury.

Anterior insula stimulation increases pain threshold in humans: a pilot study.

Chronic pain results in an enormous societal and financial burden. Opioids are the mainstay of treatment, but opioid abuse has led to an epidemic in the United States. Nonpharmacological treatment strategies like deep brain stimulation could be applied to refractory chronic pain if safe and effective brain targets are identified. The anterior insula is a putative mediator of pain-related affective-motivational and cognitive-evaluative cerebral processing. However, the effect of anterior insula stimulation on pain perception is still unknown. Here, the authors provide behavioral and neurophysiological evidence for stimulating the anterior insula as a means of potential therapeutic intervention for patients with chronic pain. Six patients with epilepsy in whom intracerebral electrodes had been implanted for seizure localization were recruited to the study. The direct anterior insula stimulations were performed in the inpatient epilepsy monitoring unit while subjects were fully awake, comfortable, and without sedating medications. The effects of anterior insula stimulation were assessed with quantitative sensory testing for heat pain threshold, nociceptive-specific cutaneous laser-evoked potentials, and intracranial electroencephalogram (EEG) recordings. Control stimulation of noninsular brain regions was performed to test stimulation specificity. Sham stimulations, in which no current was delivered, were also performed to control for potential placebo effects. The safety of these stimulations was evaluated by bedside physicians, real-time intracranial EEG monitoring, and electrocardiogram recordings. Following anterior insula stimulations, the heat pain threshold of each patient significantly increased from baseline (p < 0.001) and correlated with stimulation intensity (regression analysis: β = 0.5712, standard error 0.070, p < 0.001). Significant changes in ongoing intracranial EEG frequency band powers (p < 0.001), reduction in laser pain intensity, and attenuated laser-evoked potentials were also observed following stimulations. Furthermore, the observed behavioral and neurophysiological effects persisted beyond the stimulations. Subjects were not aware of the stimulations, and there were no cardiovascular or untoward effects. Additional, nonpharmacological therapies are imperative for the future management of chronic pain conditions and to mitigate the ongoing opioid crisis. This study suggests that direct stimulation of the anterior insula can safely alter cerebral pain processing in humans. Further investigation of the anterior insula as a potential target for therapeutic neuromodulation is underway.

Stimulation in the Rat Anterior Insula and Anterior Cingulate During an Effortful Weightlifting Task.

When performing tasks, animals must continually assess how much effort is being expended, and gage this against ever-changing physiological states. As effort costs mount, persisting in the task may be unwise. The anterior cingulate cortex (ACC) and the anterior insular cortex are implicated in this process of cost-benefit decision-making, yet their precise contributions toward driving effortful persistence are not well understood. Here we investigated whether electrical stimulation of the ACC or insular cortex would alter effortful persistence in a novel weightlifting task (WLT). In the WLT an animal is challenged to pull a rope 30 cm to trigger food reward dispensing. To make the action increasingly effortful, 45 g of weight is progressively added to the rope after every 10 successful pulls. The animal can quit the task at any point – with the rope weight at the time of quitting taken as the “break weight.” Ten male Sprague-Dawley rats were implanted with stimulating electrodes in either the ACC [cingulate cortex area 1 (Cg1) in rodent] or anterior insula and then assessed in the WLT during stimulation. Low-frequency (10 Hz), high-frequency (130 Hz), and sham stimulations were performed. We predicted that low-frequency stimulation (LFS) of Cg1 in particular would increase persistence in the WLT. Contrary to our predictions, LFS of Cg1 resulted in shorter session duration, lower break weights, and fewer attempts on the break weight. High-frequency stimulation of Cg1 led to an increase in time spent off-task. LFS of the anterior insula was associated with a marginal increase in attempts on the break weight. Taken together our data suggest that stimulation of the rodent Cg1 during an effortful task alters certain aspects of effortful behavior, while insula stimulation has little effect.

The Mysterious Island: Insula and Its Dual Function in Sleep and Wakefulness.

In the recent sleep studies, it was shown that afferentation of many cortical areas switches during sleep to the interoceptive one. However, it was unclear whether the insular cortex, which is often considered as the main cortical visceral representation, maintains the same effective connectivity in both states of vigilance, or processes interoceptive information predominantly in one state. We investigated neuronal responses of the cat insular cortex to electrical stimulations of the intestinal wall delivered during wakefulness and natural sleep. Marked increase was observed in the number of insular neurons responding to this stimulation in sleep comparing to wakefulness, and enlarged amplitudes of evoked local field potentials were found as well. Moreover, most of the cells responding to intestinal stimulation in wakefulness never responded to identical stimuli during sleep and vice versa. It was also shown that applied low intensity intestinal stimulations had never compromised sleep quality. In addition, experiments with microstimulation of the insular cortex and recording of intestinal myoelectric activity demonstrated that effective insula-to-gut propagation also happened only during sleep. On the other hand, the same insular stimulations in wakefulness led to contractions of orofacial muscles. The evoked face movements gradually disappeared in the course of sleep development. These findings demonstrate that pattern of efficient afferent and efferent connections of the insular cortex changes with transition from wakefulness to sleep.

Somatosensory Thalamic Activity Modulation by Posterior Insular Stimulation: Cues to Clinical Application Based on Comparison of Frequencies in a Cat Model

BackgroundThe posterior insula (PI) has been proposed as a potential neurostimulation target for neuropathic pain relief as it represents a key-structure in pain processing. However, currently available data remain inconclusive as to efficient stimulation parameters. ObjectivesAs frequency was shown to be the most correlated parameter to pain relief, this study aims to evaluate the potential modulatory effects of low frequency (LF-IS, 50 Hz) and high-frequency (HF-IS, 150 Hz) posterior insular stimulation on the activity of somatosensory thalamic nuclei. Materials and MethodsEpidural bipolar electrodes were placed over the PI of healthy adult cats, and extracellular single-unit activities of nociceptive (NS), nonnociceptive (NN), and wide dynamic range (WDR) thalamic cells were recorded within the ventral posterolateral nucleus and the medial division of the thalamic posterior complex. Mean discharge frequency and burst firing mode were analyzed before and after either LF-IS or HF-IS. ResultsLF-IS showed a significant thalamic modulatory effects increasing the firing rate of NN cells (p ≤ 0.03) and decreasing the burst firing of NS cells (p ≤ 0.03), independently of the thalamic nucleus. Conversely, HF-IS did not induce any change in firing properties of the three recorded cell types. ConclusionThese data indicate that 50 Hz IS could be a better candidate to control neuropathic pain.

Anterior insula stimulation suppresses appetitive behavior while inducing forebrain activation in alcohol-preferring rats

The anterior insular cortex plays a key role in the representation of interoceptive effects of drug and natural rewards and their integration with attention, executive function, and emotions, making it a potential target region for intervention to control appetitive behaviors. Here, we investigated the effects of chemogenetic stimulation or inhibition of the anterior insula on alcohol and sucrose consumption. Excitatory or inhibitory designer receptors (DREADDs) were expressed in the anterior insula of alcohol-preferring rats by means of adenovirus-mediated gene transfer. Rats had access to either alcohol or sucrose solution during intermittent sessions. To characterize the brain network recruited by chemogenetic insula stimulation we measured brain-wide activation patterns using pharmacological magnetic resonance imaging (phMRI) and c-Fos immunohistochemistry. Anterior insula stimulation by the excitatory Gq-DREADDs significantly attenuated both alcohol and sucrose consumption, whereas the inhibitory Gi-DREADDs had no effects. In contrast, anterior insula stimulation failed to alter locomotor activity or deprivation-induced water drinking. phMRI and c-Fos immunohistochemistry revealed downstream activation of the posterior insula and medial prefrontal cortex, as well as of the mediodorsal thalamus and amygdala. Our results show the critical role of the anterior insula in regulating reward-directed behavior and delineate an insula-centered functional network associated with the effects of insula stimulation. From a translational perspective, our data demonstrate the therapeutic potential of circuit-based interventions and suggest that potentiation of insula excitability with neuromodulatory methods, such as repetitive transcranial magnetic stimulation (rTMS), could be useful in the treatment of alcohol use disorders.

Editors' note: Insular and anterior cingulate cortex deep stimulation for central neuropathic pain: Disassembling the percept of pain

In the article “Insular and anterior cingulate cortex deep stimulation for central neuropathic pain: Disassembling the percept of pain,” Dr. Galhardoni et al. compared the analgesic effects of repetitive transcranial magnetic stimulation (rTMS) of the anterior cingulate cortex (ACC) or the posterior superior insula (PSI) against sham deep rTMS in 98 patients with central neuropathic pain (CNP) after stroke or spinal cord injury in a randomized, double-blinded, sham-controlled, 3-arm parallel study. They found that ACC- and PSI-rTMS were not different from sham-rTMS for pain relief despite a significant increase in heat thresholds after insular stimulation and anxiolytic effects after ACC-rTMS and concluded that different dimensions of pain can be modulated noninvasively by directly stimulating deeper structures without necessarily improving clinical pain. In response, Dr. Zugaib et al. point to their recent work suggesting that PSI-/ACC-rTMS involves more intense stimulation of superficial structures. They argue that the use of linear projection to estimate the stimulation targets—as was the case in the trial—does not correspond to the region of maximum-induced electrical field, which is more superficial, and therefore caution against interpreting the clinical findings as resulting from the stimulation of deep structures as opposed to a combination of stronger superficial and deeper stimulation. They suggest using electric field modeling to guide the coil positioning and adjustment of stimulation intensity. Responding to these comments, Dr. de Andrade et al. defend the precision of their approach, noting that in addition to linear projection-guided PSI stimulation providing antinociceptive effects in patients with CNP and healthy volunteers, direct cortical stimulation of the PSI during stereo-EEG in a previous study showed the same heat-pain changes as described by linear projection-target deep TMS. They also note that stimulation intensity was calculated using the tibialis anterior muscle as a parameter, represented medially in the primary motor cortex, suggesting that a measurable current was likely delivered to the PSI. They argue that computing electric fields would not solve the issue of stimulation intensity, and instead propose that future field models should account for the data from linear projection, validated against sham and active controls, in their algorithms. This exchange highlights the important points of debate in the field of rTMS regarding the most reliable means of targeting deeper structures in the brain, and conversely, identifying the responsible structural mediators of observed stimulation effects. In the article “Insular and anterior cingulate cortex deep stimulation for central neuropathic pain: Disassembling the percept of pain,” Dr. Galhardoni et al. compared the analgesic effects of repetitive transcranial magnetic stimulation (rTMS) of the anterior cingulate cortex (ACC) or the posterior superior insula (PSI) against sham deep rTMS in 98 patients with central neuropathic pain (CNP) after stroke or spinal cord injury in a randomized, double-blinded, sham-controlled, 3-arm parallel study. They found that ACC- and PSI-rTMS were not different from sham-rTMS for pain relief despite a significant increase in heat thresholds after insular stimulation and anxiolytic effects after ACC-rTMS and concluded that different dimensions of pain can be modulated noninvasively by directly stimulating deeper structures without necessarily improving clinical pain. In response, Dr. Zugaib et al. point to their recent work suggesting that PSI-/ACC-rTMS involves more intense stimulation of superficial structures. They argue that the use of linear projection to estimate the stimulation targets—as was the case in the trial—does not correspond to the region of maximum-induced electrical field, which is more superficial, and therefore caution against interpreting the clinical findings as resulting from the stimulation of deep structures as opposed to a combination of stronger superficial and deeper stimulation. They suggest using electric field modeling to guide the coil positioning and adjustment of stimulation intensity. Responding to these comments, Dr. de Andrade et al. defend the precision of their approach, noting that in addition to linear projection-guided PSI stimulation providing antinociceptive effects in patients with CNP and healthy volunteers, direct cortical stimulation of the PSI during stereo-EEG in a previous study showed the same heat-pain changes as described by linear projection-target deep TMS. They also note that stimulation intensity was calculated using the tibialis anterior muscle as a parameter, represented medially in the primary motor cortex, suggesting that a measurable current was likely delivered to the PSI. They argue that computing electric fields would not solve the issue of stimulation intensity, and instead propose that future field models should account for the data from linear projection, validated against sham and active controls, in their algorithms. This exchange highlights the important points of debate in the field of rTMS regarding the most reliable means of targeting deeper structures in the brain, and conversely, identifying the responsible structural mediators of observed stimulation effects.

Author response: Insular and anterior cingulate cortex deep stimulation for central neuropathic pain: Disassembling the percept of pain

We thank Dr. Zugaib et al. for the interest in our work.1 It has been suggested that modeling electric fields within the deep cortical structures would provide more reliable, target-effect conclusions. So far, the use of linear projection to target1 the posterior superior insula (PSI) has provided antinociceptive effects as measured by increases in the heat-pain threshold in patients with central pain2 and in healthy volunteers.3o Importantly, in a unique study,4 direct cortical stimulation of the PSI during stereo-EEG showed exactly4 the same heat-pain changes described by the linear projection-targeted deep transcranial magnetic stimulation (TMS). Taken together, these are very strong arguments for the precision of such an approach. In addition, in the setups cited above, stimulation intensity was calculated using the anterior tibialis muscle as a parameter (with the leg representation buried medially within the primary motor cortex), which attests that a measurable amount of induced electric current was indeed delivered to the PSI. As pointed out by Zugaib and Souza,5 computing electric field would not solve the issue of intensity of stimulation. Because the linear projection-based deep TMS approach proved itself accurate on psychophysical terms, we propose a pragmatic “reverse-modeling” perspective that future electric-field models should take into account the data from linear projection in their algorithms because they have been validated against sham and active controls and provided information on the intensity of stimulation all at once.