Brain Circuits Involved in the Development of Chronic Musculoskeletal Pain: Evidence From Non-invasive Brain Stimulation

Abstract

It has been well-documented that the brain changes in states of chronic pain. Less is known about changes in the brain that predict the transition from acute to chronic pain. Evidence from neuroimaging studies suggests a shift from brain regions involved in nociceptive processing to corticostriatal brain regions that are instrumental in the processing of reward and emotional learning in the transition to the chronic state. In addition, dysfunction in descending pain modulatory circuits encompassing the periaqueductal gray and the rostral anterior cingulate cortex may also be a key risk factor for pain chronicity. Although longitudinal imaging studies have revealed potential predictors of pain chronicity, their causal role has not yet been determined. Here we review evidence from studies that involve non-invasive brain stimulation to elucidate to what extent they may help to elucidate the brain circuits involved in pain chronicity. Especially, we focus on studies using non-invasive brain stimulation techniques [e.g., transcranial magnetic stimulation (TMS), particularly its repetitive form (rTMS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS)] in the context of musculoskeletal pain chronicity. We focus on the role of the motor cortex because of its known contribution to sensory components of pain via thalamic inhibition, and the role of the dorsolateral prefrontal cortex because of its role on cognitive and affective processing of pain. We will also discuss findings from studies using experimentally induced prolonged pain and studies implicating the DLPFC, which may shed light on the earliest transition phase to chronicity. We propose that combined brain stimulation and imaging studies might further advance mechanistic models of the chronicity process and involved brain circuits. Implications and challenges for translating the research on mechanistic models of the development of chronic pain to clinical practice will also be addressed.

Analgesic Effects of Repetitive Transcranial Magnetic Stimulation in Patients With Advanced Non-Small-Cell Lung Cancer: A Randomized, Sham-Controlled, Pilot Study

“…Usually, low frequency (< 1Hz) stimulation has an inhibitory effect on the brain, while high frequency (> 5Hz) stimulation excite neurons ( 11 ). It has been reported that rTMS relieves various types of pain, such as neuropathic pain after spinal cord injury, stroke or postoperative of trigeminal nerve ( 12 ), migraine ( 13 ), fibromyalgia ( 14 ) and chronic musculoskeletal pain ( 15 ). Even less clinical study has been done on the application of rTMS in patients with cancer pain.…”

Anodal-TDCS over Left-DLPFC Modulates Motor Cortex Excitability in Chronic Lower Back Pain

“…Glutamate and GABA are critical to maintaining and regulating many physiological functions and are reported to underlie altered excitability in varying chronic pain conditions [ 62 , 63 ]. The potential for tDCS over DLPFC to modulate ICF and SICI in chronic pain may be due to interconnections between the DLPFC and the periaqueductal gray area and motor cortex [ 64 , 65 , 66 ]. These areas play a key role in descending mechanisms that modulate spinal nociceptive activity [ 64 , 65 , 66 ].…”

“…The potential for tDCS over DLPFC to modulate ICF and SICI in chronic pain may be due to interconnections between the DLPFC and the periaqueductal gray area and motor cortex [ 64 , 65 , 66 ]. These areas play a key role in descending mechanisms that modulate spinal nociceptive activity [ 64 , 65 , 66 ]. A recent meta-analysis reported that while the balance of glutamate and GABA differed between chronic pain conditions, glutamate and GABA play a key role in the pathophysiology of pain processing and modulation [ 63 ].…”

Pain control based on oscillatory brain activity using transcranial alternating current stimulation: An integrative review

“…The brain regions involved in pain processing include the primary and secondary somatosensory cortices; primary motor and supplementary motor cortices; insular cortex; anterior cingulate cortex; thalamus; regions within the prefrontal and parietal cortices; and regions involved in emotion, memory, and fear processing in the amygdala, hippocampus, and subcortical structures, including the basal ganglia (Martucci and Mackey, 2018;Geuter et al, 2020). Among these brain regions, cortical sites near the scalp have been investigated as potential targets to reduce pain by non-invasive brain stimulation (NIBS), which can alter cortical excitability through approaches, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation (O'Connell et al, 2018;Kandiae et al, 2021). Neurophysiological studies using electroencephalography (EEG) and magnetoencephalography (MEG) have demonstrated that neural oscillatory frequencies corresponding to the theta (4-7 Hz), alpha (8-12 Hz), beta (13-29 Hz), and gamma bands (30-100 Hz) are associated with pain processing (Ploner et al, 2017).…”