Altered resting activity patterns and connectivity in individuals with complex regional pain syndrome

Abstract

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder that typically occurs in the limbs, usually the upper limb. CRPS usually develops from a peripheral event but its maintenance relies on changes within the central nervous system. While functional abnormalities in the thalamus and primary somatosensory cortex (S1) of the brain are some of the most consistently reported brain findings in CRPS, the mechanisms are yet to be explored in full, not least of all how these two regions interact and how they might relate to clinical deficits, such as the commonly reported poor tactile acuity in this condition. This study recruited 15 upper‐limb CRPS subjects and 30 healthy controls and used functional magnetic resonance imaging (fMRI) to investigate infra‐slow oscillations (ISOs) in critical pain regions of the brain in CRPS. As hypothesised, we found CRPS was associated with increases in resting signal intensity ISOs (0.03–0.06 Hz) in the thalamus contralateral to the painful limb in CRPS subjects. Interestingly, there was no such difference between groups in S1, however CRPS subjects displayed stronger thalamo‐S1 functional connectivity than controls, and this was related to pain. As predicted, CRPS subjects displayed poor tactile acuity on the painful limb which, interestingly, was also related to thalamo‐S1 functional connectivity strength. Our findings provide novel evidence of altered patterns of resting activity and connectivity in CRPS which may underlie altered thalamocortical loop dynamics and the constant perception of pain.

Complex Regional Pain Syndrome: Thalamic GMV Atrophy and Associations of Lower GMV With Clinical and Sensorimotor Performance Data

“…Especially for the prefrontal interactions these parts of the thalamus might be related to both pain modulation [discussion see ( 41 )] or effects of the ACC [e.g., ( 11 )] which had been described to be vulnerable to both chronic pain but also stressors in animal research before ( 42 , 43 ). Especially the thalamo-prefrontal axis is an important hub which shows changes in cholinergic neurotransmitters in chronic pain patients ( 41 ) and specifically a decrease connectivity for CRPS patients ( 38 ). At least with respect to the ACC GMV decrease it seems to be highly associated with the duration of CRPS.…”

Possibility of Assessing Pain with Biomarkers in Psychiatric Disorders

“…As expected, CRPS patients showed poor acuity of painful limb touch related to the strength of functional thalamo-S1 connectivity. CRPS subjects displayed stronger thalamo-S1 functional connectivity than controls, and this was related to the intensity of the pain [46].…”

“…N-acetylaspartate (NAA, a marker of neuron density), choline (Cho, an indicator of myelin breakdown products, building the sheaths of nerve cells), and myo-inositol (mI) are considered to be markers of microglial activation. Using the single voxel spectroscopy (SVS) method, it has been possible to assess the differences between both hemispheres of the brain in CRPS patients at the following locations: insula, thalamus, basal ganglia, and postcentral gyrus [11][12][13][14]46] Single voxel 1H-MRS is a noninvasive method for in vivo quantification of several different brain metabolites including N-acetylaspartate (NAA, a marker of neuronal density), choline-containing compounds (Cho, an indicator of myelin breakdown products, building the sheaths of nerve cells), creatine (Cr, energy metabolism marker), myo-inositol (mI, a marker of microglia activation) and glutamate-glutamine (Glx, excitatory neurotransmitter and precursor amino acid). The advantage of this method is that it may provide information about metabolite alterations in the brain, while MRI fails to reveal any morphological abnormalities.…”

Possibility of Assessing Pain with Biomarkers in Psychiatric Disorders

“…N -acetylaspartate (NAA, a marker of neuron density), choline (Cho, an indicator of myelin breakdown products, building the sheaths of nerve cells), and myo-inositol (mI) are considered to be markers of microglial activa-tion. Using the single voxel spectroscopy (SVS) method, it has been possible to assess the differences between both hemispheres of the brain in CRPS patients at the following loca-tions: insula, thalamus, basal ganglia, and postcentral gyrus [11][12][13][14]46] Single voxel 1H-MRS is a noninvasive method for in vivo quantification of several different brain metabolites including N-acetylaspartate (NAA, a marker of neuronal den-sity), choline-containing compounds (Cho, an indicator of myelin breakdown products, building the sheaths of nerve cells), creatine (Cr, energy metabolism marker), myo-inositol (mI, a marker of microglia activation) and glutamate-glutamine (Glx, excitatory neuro-transmitter and precursor amino acid). The advantage of this method is that it may pro-vide information about metabolite alterations in the brain, while MRI fails to reveal any morphological abnormalities.…”

“…In mechanical hyperalgesia: reduction of volume of the bilateral hindlimb area, anterior cingulate cortex, islets [35,36] Jung, 2019 [35]; Seminowicz, 2009 [36] Gray peripheral area (PAG) is activated by most pain mechanisms [42,43] Knudsen, 2011 [42]; Maihoefner, 2004 [43] In CRPS: pain is associated with (I) connectivity between MPFC, cingulate gyrus, lower parietal lobe, (I) connectivity between MPFC and insular cortex; (I) activity in connection between thalamus and primary somatosensory cortex [46] ; gray matter atrophy in right islet, right VMPFC, right nucleus accumbens [44] Jung, 2018 [44]; Di Pietro, 2020 [46] fNIRS (functional near infrared spectroscopy) (I) metabolism of frontal lobes measured by oxygenation and blood flow, fNIRS measurement shown good accuracy in assessing pain in response to thermal nociceptive stimulation [56] Rojas, 2019 [56]…”