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

Abstract

OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Stereotactic electroencephalography in epilepsy patients for mapping of neural circuits related to emotional and psychiatric behaviors: a systematic review

“…60,61 Finally, while this review focused on sEEG research of psychiatric-related behaviors, it is imperative to note that sEEG is a powerful research instrument for studying the spatiotemporal dynamics of neural circuits contributing to other cognitive processes or diseases, such as chronic pain, movement disorders, speech, memory, sleep, and arousal. [62][63][64] Furthermore, the studies included in this review have demonstrated the powerful application of machine learning algorithms to iEEG data, which will strengthen our understanding of the neural networks underlying human behaviors.…”

Revealing the Central Mechanism of Acupuncture for Primary Dysmenorrhea Based on Neuroimaging: A Narrative Review

“…However, this phenomenon is not present in every region of the pain matrix. The insula, as an essential node of the salience network as well as the pain matrix, improves individual brain-based pain sensitivity and increases thresholds for human pain, and is an important part of the brain involved in processing pain [ 50 – 52 ]. The cerebellum is commonly thought to be associated with movement, and the cerebellum supports experimental pain and chronic pain processing with its complex sensory, emotional, and neurocognitive aspects [ 53 , 54 ].…”

The role of endogenous opioid neuropeptides in neurostimulation-driven analgesia

“…Low frequency electrical stimulation of the right pI elicits nociception in humans and primates with some somatotopy ( Ostrowsky et al, 2002 ; Mazzola et al, 2009 ), while high frequency stimulation of pI and aI reduces pain thresholds with no obvious side effects, consistent with insular inactivation ( Denis et al, 2016 ; Liu et al, 2021 ). A form of rTMS in IC has been shown to produce bilateral thermal analgesia in humans without affecting the ability to perceive innocuous thermal or vibrotactile sensations ( Lenoir et al, 2018 ).…”