Suppression of neuropathic pain and comorbidities by recurrent cycles of repetitive transcranial direct current motor cortex stimulation in mice

Abstract

Transcranial, minimally-invasive stimulation of the primary motor cortex (M1) has recently emerged to show promise in treating clinically refractory neuropathic pain. However, there is a major need for improving efficacy, reducing variability and understanding mechanisms. Rodent models hold promise in helping to overcome these obstacles. However, there still remains a major divide between clinical and preclinical studies with respect to stimulation programs, analysis of pain as a multidimensional sensory-affective-motivational state and lack of focus on chronic phases of established pain. Here, we employed direct transcranial M1 stimulation (M1 tDCS) either as a single 5-day block or recurring blocks of repetitive stimulation over early or chronic phases of peripherally-induced neuropathic pain in mice. We report that repeated blocks of stimulation reverse established neuropathic mechanical allodynia more strongly than a single 5-day regime and also suppress cold allodynia, aversive behavior and anxiety without adversely affecting motor function over a long period. Activity mapping revealed highly selective alterations in the posterior insula, periaqueductal gray subdivisions and superficial spinal laminae in reversal of mechanical allodynia. Our preclinical data reveal multimodal analgesia and improvement in quality of life by multiple blocks of M1 tDCS and uncover underlying brain networks, thus helping promote clinical translation.

Prolonged Suppression of Neuropathic Hypersensitivity upon Neurostimulation of the Posterior Insula in Mice

“…Testing conditioned preference or avoidance behaviors [ 33 ] are difficult in the setting of this study, since tDCS treatment essentially extends over several days and unfolds its beneficial effects over the weeks after completing the last treatment. We therefore tested voluntary avoidance behaviors towards stimuli that are innocuous in control conditions but become noxious following nerve injury using a paradigm of place escape avoidance (PEAP) which we have established and reported on previously [ 9 , 11 ]. Because mice prefer a dark environment, using a light-dark box, we paired a dark chamber with the application of 0.07–0.16 g von Frey mechanical stimuli on the paw ipsilateral to nerve injury and application of the same stimuli to the contralateral unaffected paw in the bright chamber ( Figure 3 A).…”

“…After recovery from electrode implantation, animals were anesthetized again with the medetomidine/midazolam/fentanyl mixture (see above). As described previously [ 9 , 19 ], the sciatic nerve and its three branches (sural, common peroneal, and tibial) were exposed via an incision of the lateral thigh skin and a dissection of the biceps femoris muscle, and the common peroneal and tibial nerves were tightly ligated and cut distally; a 2–4 mm section was removed from the ligation. The sural nerve remained intact during surgery.…”

“…Treatment was initiated at day 3, Day 36 and day 75 post-SNI in Block I, Block II and Block III, respectively. The tDCS protocol was adapted from previous tDCS studies [ 9 , 11 , 20 , 21 , 22 , 23 ]. Animals were anesthetized with 3% isoflurane, the head fixed via the nosepiece of the stereotaxic mask (RWD Life Science Company, China), and a light sedation maintained with 1% isoflurane.…”

“…In order to assess the aversiveness of evoked mechanical stimulation in neuropathic animals, PEAP was performed four days after the last session of tDCS treatment in both blocks, and was modified from previous studies [ 9 , 11 , 32 ]. Briefly, animals were given a unilateral hind paw nociceptive stimulation and were placed in a 22 × 22 × 12 cm chamber atop a mesh floor.…”

“…A majority of previous studies investigating neurostimulation approaches in human subjects and rodent models have focused on the motor cortex [ 5 , 7 , 8 , 9 , 10 ], and a few new studies have also emerged on the prefrontal cortex [ 11 ]. In contrast, the insular cortex has not been tested so far in neurostimulation studies in rodents, and to date there is no knowledge on the potential of therapies specifically targeting the insula in achieving pain relief.…”