The Somatosensory Link in Fibromyalgia: Functional Connectivity of the Primary Somatosensory Cortex Is Altered by Sustained Pain and Is Associated With Clinical/Autonomic Dysfunction

Kim, Jieun; Loggia, Marco L.; Cahalan, Christine; Harris, Richard E.; Beißner, Florian; García, Ronald G.; Kim, Hyungjun; Barbieri, Riccardo; Wasan, Ajay D.; Edwards, Robert R.; Napadow, Vitaly

doi:10.1002/art.39043

Cited by 137 publications

(177 citation statements)

References 53 publications

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“…In fact, a recent neuroimaging meta-analysis noted S1 as part of a network of brain regions regulating autonomic, particularly sympathetic, outflow (Beissner et al, 2013). In addition, our recent study in patients with chronic pain found that pain-evoked increase in S1 connectivity to the anterior/middle insula cortex was associated with reduced cardiovagal modulation (Kim et al, 2015). These studies link S1 with central control of autonomic tone and future studies should explore if, for example, S1-insula connectivity is also associated with both autonomic (e.g.…”

Section: Discussionmentioning

confidence: 80%

Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture

Maeda

Kim

Kettner

et al. 2017

Brain

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129

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Ã These authors contributed equally to this work.Carpal tunnel syndrome is the most common entrapment neuropathy, affecting the median nerve at the wrist. Acupuncture is a minimally-invasive and conservative therapeutic option, and while rooted in a complex practice ritual, acupuncture overlaps significantly with many conventional peripherally-focused neuromodulatory therapies. However, the neurophysiological mechanisms by which acupuncture impacts accepted subjective/psychological and objective/physiological outcomes are not well understood. Eligible patients (n = 80, 65 female, age: 49.3 AE 8.6 years) were enrolled and randomized into three intervention arms: (i) verum electro-acupuncture 'local' to the more affected hand; (ii) verum electro-acupuncture at 'distal' body sites, near the ankle contralesional to the more affected hand; and (iii) local sham electro-acupuncture using non-penetrating placebo needles. Acupuncture therapy was provided for 16 sessions over 8 weeks. Boston Carpal Tunnel Syndrome Questionnaire assessed pain and paraesthesia symptoms at baseline, following therapy and at 3-month follow-up. Nerve conduction studies assessing median nerve sensory latency and brain imaging data were acquired at baseline and following therapy. Functional magnetic resonance imaging assessed somatotopy in the primary somatosensory cortex using vibrotactile stimulation over three digits (2, 3 and 5). While all three acupuncture interventions reduced symptom severity, verum (local and distal) acupuncture was superior to sham in producing improvements in neurophysiological outcomes, both local to the wrist (i.e. median sensory nerve conduction latency) and in the brain (i.e. digit 2/3 cortical separation distance). Moreover, greater improvement in second/third interdigit cortical separation distance following verum acupuncture predicted sustained improvements in symptom severity at 3-month follow-up. We further explored potential differential mechanisms of local versus distal acupuncture using diffusion tensor imaging of white matter microstructure adjacent to the primary somatosensory cortex. Compared to healthy adults (n = 34, 28 female, 49.7 AE 9.9 years old), patients with carpal tunnel syndrome demonstrated increased fractional anisotropy in several regions and, for these regions we found that improvement in median nerve latency was associated with reduction of fractional anisotropy near (i) contralesional hand area following verum, but not sham, acupuncture; (ii) ipsilesional hand area following local, but not distal or sham, acupuncture; and (iii) ipsilesional leg area following distal, but not local or sham, acupuncture. As these primary somatosensory cortex subregions are distinctly targeted by local versus distal acupuncture electrostimulation, acupuncture at local versus distal sites may improve median nerve function at the wrist by somatotopically distinct neuroplasticity in the primary somatosensory cortex following therapy. Our study further suggests that improvements in primary somatosensory cortex ...

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Section: Discussionmentioning

confidence: 80%

Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture

Maeda

Kim

Kettner

et al. 2017

Brain

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129

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“…43,69,72 Furthermore, phasic as well as tonic application of a painful stimulus can produce temporal summation, 3 and both modes of application show a close correlation with psychosocial factors such as catastrophizing. 32 As in the current study, lower pressures are typically required to produce pain in FM patients compared with control subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Our moderately painful (40 of 100) prolonged cuff stimulus produced temporal summation in most patients with FM, consistent with previous studies that observed a modest increase in temporal summation in FM as a group over control subjects with stimulus matching. 43,69,72 The duration of the painful cuff stimulus we used was relatively long compared with some other measures of temporal summation, 5 for the purpose of increasing the likelihood of detecting temporal summation as well as PAS. Although there was some variability in the response to a prolonged cuff stimulus in both groups, FM patients reported increased incidence and severity of PAS compared with control subjects, similar to previous reports.…”

Section: Discussionmentioning

confidence: 99%

Painful After-Sensations in Fibromyalgia are Linked to Catastrophizing and Differences in Brain Response in the Medial Temporal Lobe

Schreiber

Loggia

Kim

et al. 2017

The Journal of Pain

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Fibromyalgia (FM) is a complex syndrome characterized by chronic widespread pain, hyperalgesia, and other disabling symptoms. Although the brain response to experimental pain in FM patients has been the object of intense investigation, the biological underpinnings of painful after-sensations (PAS), and their relation to negative affect have received little attention. In this cross-sectional cohort study, subjects with FM (n = 53) and healthy controls (n = 17) were assessed for PAS using exposure to a sustained, moderately painful cuff stimulus to the leg, individually calibrated to a target pain intensity of 40 of 100. Despite requiring lower cuff pressures to achieve the target pain level, FM patients reported more pronounced PAS 15 seconds after the end of cuff stimulation, which correlated positively with clinical pain scores. Functional magnetic resonance imaging revealed reduced deactivation of the medial temporal lobe (MTL; amygdala, hippocampus, parahippocampal gyrus) in FM patients, during pain stimulation, as well as in the ensuing poststimulation period, when PAS are experienced. Moreover, the functional magnetic resonance imaging signal measured during the poststimulation period in the MTL, as well as in the insular and anterior middle cingulate and medial prefrontal cortices, correlated with the severity of reported PAS by FM patients. These results suggest that the MTL plays a role in PAS in FM patients. Perspective PAS are more common and severe in FM, and are associated with clinical pain and catastrophizing. PAS severity is also associated with less MTL deactivation, suggesting that the MTL, a core node of the default mode network, may be important in the prolongation of pain sensation in FM.

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“…If advancing the understanding of FMS pathophysiology leads to new therapeutic targets and if there is progress in the design and execution of FMS clinical trials, new FDA-approved treatment options should eventually be available. Perhaps a renewed focus on gaining a greater understanding of the mechanism(s) underlying altered resting brain conductivity [35], the role of brain-derived neutrotrophic factor [36], thermoregulation [37] and T-type Ca 2+ channels [38] in FMS will also provide the impetus for new directions in drug development for FMS.…”

Section: Expert Commentarymentioning

confidence: 99%

Recent strategies for drug development in fibromyalgia syndrome

Blumenthal

Malemud

2016

Expert Review of Neurotherapeutics

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The US Federal Drug Administration (FDA) approved 3 medications for treating fibromyalgia syndrome (FMS). There have been no additional FDA approvals since January 2009 and the efficacy of the FDA-approved medications for FMS has been questioned. Areas covered: The "search for studies" tool using clinicaltrials.gov and PubMed were employed. The term, "fibromyalgia" was used for clinicaltrials.gov. The terms employed for PubMed were "Name-of-Drug Fibromyalgia", "Fibromyalgia Treatment" or "Fibromyalgia Drug Treatment." Clinical trials were reviewed if they were prospective and blinded, and if they employed a comparator, either placebo or another pharmaceutical. Expert commentary: Progress toward standardizing the outcome measures for FMS clinical trials have been made but challenges remain. Several pharmaceutical candidates for FMS have been tested since 2009. The results of these studies with potential novel targets for drug development for FMS were reviewed including the results of trials with sodium oxybate, quetiapine, esreboxetine, nabilone, memantine, naltrexone, and melatonin.

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The Somatosensory Link in Fibromyalgia: Functional Connectivity of the Primary Somatosensory Cortex Is Altered by Sustained Pain and Is Associated With Clinical/Autonomic Dysfunction

Cited by 137 publications

References 53 publications

Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture

Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture

Painful After-Sensations in Fibromyalgia are Linked to Catastrophizing and Differences in Brain Response in the Medial Temporal Lobe

Recent strategies for drug development in fibromyalgia syndrome

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