fMRI evidence of degeneration-induced neuropathic pain in diabetes: Enhanced limbic and striatal activations

Abstract

Persistent neuropathic pain due to peripheral nerve degeneration in diabetes is a stressful symptom; however, the underlying neural substrates remain elusive. This study attempted to explore neuroanatomical substrates of thermal hyperalgesia and burning pain in a diabetic cohort due to pathologically proven cutaneous nerve degeneration (the painful group). By applying noxious 44°C heat stimuli to the right foot to provoke neuropathic pain symptoms, brain activation patterns were compared with those of healthy control subjects and patients with a similar degree of cutaneous nerve degeneration but without pain (the painless group). Psychophysical results showed enhanced affective pain ratings in the painful group. After eliminating the influence of different pain intensity ratings on cerebral responses, the painful group displayed augmented responses in the limbic and striatal structures, including the perigenual anterior cingulate cortex (ACC), superior frontal gyrus, medial thalamus, anterior insular cortex, lentiform nucleus (LN), and premotor area. Among these regions, blood oxygen level-dependent (BOLD) signals in the ACC and LN were correlated with pain ratings to thermal stimulations in the painful group. Furthermore, activation maps of a simple regression analysis as well as a region of interest analysis revealed that responses in these limbic and striatal circuits paralleled the duration of neuropathic pain. However, in the painless group, BOLD signals in the primary somatosensory cortex and ACC were reduced. These results suggest that enhanced limbic and striatal activations underlie maladaptive responses after cutaneous nerve degeneration, which contributed to the development and maintenance of burning pain and thermal hyperalgesia in diabetes.

Imaging signatures of altered brain responses in small-fiber neuropathy

“…Our previous studies documented the influences of skin nerve degeneration on central processing of pain, ie, the level of brain fMRI activation was abnormally augmented in patients with neuropathic pain. 76 Electrophysiologically, the reduction in the magnitude of pain-evoked brain responses paralleled the degree of skin denervation. 17 The present findings extended our previous work, linking the pathological evidence of skin nerve degeneration with imaging signatures of structural and functional disruptions in pain-related regions.…”

“…However, it may be less effective to induce brain activations in patients without thermal hyperalgesia. 76 In this study, only 6 of the 19 patients had thermal hyperalgesia and 4 patients had mechanical allodynia only. As such, applying both mechanical (eg, brush) and thermal (heat and cold) stimulations in fMRI experiments may better detect functional brain responses in these patients with pure mechanical allodynia and facilitate the comparisons of modality-specific differences in fMRI activation patterns.…”

“…Second, our study applied noxious heat stimulation to assess brain functional activations to thermal pain. Thermal testing with contact heat (eg, thermodes) 5,33,55,76 or radiant heat (eg, laser) 7,62 stimuli has been widely used to assess the physiological integrity of temperature-sensitive nociceptive fibers. However, it may be less effective to induce brain activations in patients without thermal hyperalgesia.…”

“…3,69 Using stimulus-activated functional magnetic resonance imaging (fMRI), we documented that patients with painful neuropathy due to diabetes had enhanced striatal and limbic activations to noxious heat. 76 These studies indicate that brain function may be affected when cutaneous nerves are disrupted under experimental or pathological conditions, leading to abnormal recruitment of nociceptive brain regions during pain stimulation. Nevertheless, whether the structural integrity of the brain and task-related functional connectivity are altered after peripheral nerve degeneration has remained elusive.…”

Olfactory Dysfunction in Diabetes

“…These data indicate that there are some definitive alterations in the pain-processing matrix activation pattern in patients with painful neuropathy. 35 Another preliminary study using MRI spectroscopy reported the shift of excitatory-inhibition neurotransmitter balance in favor of excitatory glutamate in the posterior insula of diabetic patients with symptomatic neuropathy. 36 In summary, central manifestations seem to be associated with peripheral and autonomic neuropathy in diabetic patients.…”