Electrical stimulation of the insular cortex as a novel target for the relief of refractory pain: An experimental approach in rodents

Insular and anterior cingulate cortex deep stimulation for central neuropathic pain

“…In addition, opioids cause depression of excitatory propagation in the insular cortex in rodents, and insula deep brain stimulation led to opioid-and cannabinoiddependent analgesic effects in a rat model of peripheral neuropathic pain. 19 It has been proposed that the insula has a tonic hyperalgesic effect, with glutamatergic projections to the ipsilateral amygdala and to GABAergic brainstem neurons projecting to descending modulatory nuclei in the brainstem. Thus, its activation during physiologic conditions would couple the aversive component of the nociceptive stimulus with a loss of top-down discriminatory output to the spinal cord, which would gate its tonic inhibitory inputs to ascending somatosensory inputs (i.e., loss of discrimination, loss of descending inhibition; pronociceptive).…”

“…Thus, its activation during physiologic conditions would couple the aversive component of the nociceptive stimulus with a loss of top-down discriminatory output to the spinal cord, which would gate its tonic inhibitory inputs to ascending somatosensory inputs (i.e., loss of discrimination, loss of descending inhibition; pronociceptive). In summary, this model proposes that the insula possesses a pronociceptive role when hyperactive, such as in cases of CNP, and local lesions, local injection of opioids, or high-frequency stimulation by deep brain stimulation 19,41 would decrease its activity and prompt antinociceptive behavior. In this model, the ACC would also be hyperactive in neuropathic pain and would be an important hub in the integration of the affective-emotional components of neuropathic pain.…”

“…The possibility of targeting these deep structures to relieve pain has been tested recently. Insular stimulation in rats under a peripheral neuropathy model caused significant analgesic effects that depended on the availability of opioid and cannabinoid receptors, 19 and high-frequency stimulation of the ACC by optogenetics influenced mood-related responses in rats. 20 In recent years, technologic improvements have allowed the noninvasive modulation of deep cortical structures such as the dentate nucleus, the ACC, 21 and the insula by deep rTMS in awake humans.…”

Anterior insular cortex mediates hyperalgesia induced by chronic pancreatitis in rats

“…Among various brain targets, such as prefrontal cortex and primary motor cortex [64, 65], IC is a newly-identified spot for the intervention of chronic pain. It is well-documented that insular stimulation relieves both experimentally-induced pain [62, 66, 67] and neuropathic pain [68]. The preponderant theory for this is high-frequency stimulation generated neural depolarization blockade [67, 69] or the recruitment of local GABAergic circuit [66], leading to functional inactivation of insular neurons.…”

Composite Pain Biomarker Signatures for Objective Assessment and Effective Treatment

“…While the authors did not suggest that this region alone encodes ongoing pain, as other areas were also reported as periodically active and recent animal work highlights a dominant role for the amygdala in pain unpleasantness, for example, reminding us of pain's complexity and requirement to activate many brain regions (Corder et al, 2019), several results, including the neurochemistry findings discussed above, propose that this region provides potential as a possible biomarker of nociceptive drive and pain intensity. This is perhaps supported by the failure to activate it, unlike most other pain-related brain regions, by empathy, hypnosis, or recalled pain (Fairhurst et al, 2012;Raij et al, 2005;Wager et al, 2013); it is part of the NPS and Pain-Analgesic network; predictive coding identifies its role encoding stimulus intensity (Geuter et al, 2017); it is not encoding saliency (Horing et al, 2018); and there is alteration of pain upon posterior insula modulation (acute and tonic) in animals and humans (Dimov et al, 2018;Garcia-Larrea and Mauguiè re, 2018;Han et al, 2015;Lin et al, 2017). A composite signature reflecting ongoing activity, neurochemical and network coupling changes from various brain regions, such as the dorsal posterior insula combined with other regions, would be interesting to explore in the context of a potential biomarker.…”