Accepted

The neuropathophysiology of a debilitating chronic urologic pain condition, bladder pain syndrome (BPS), remains unknown. Our recent data suggests withdrawal of cardiovagal modulation in subjects with BPS, in contrast to sympathetic nervous system dysfunction in another chronic pelvic pain syndrome, myofascial pelvic pain (MPP). We evaluated whether comorbid disorders differentially associated with BPS vs MPP shed additional light on these autonomic differences.

Chronic neuropathic pain is known to alter the primary motor cortex (M1) function. Less is known about the normal, physiological effects of experimental neurogenic pain on M1. The objective of this study is to determine how short-interval intracortical inhibition (SICI) is altered in the M1 representation area of a muscle exposed to experimental pain compared to SICI of another muscle not exposed to pain. The cortical representation areas of the right abductor pollicis brevis (APB) and biceps brachii (BB) muscles of 11 subjects were stimulated with a multi-locus transcranial magnetic stimulation device while the resulting motor-evoked potentials (MEPs) were recorded with electromyography. Single- and paired-pulse TMS was administered in seven conditions, including one with the right hand placed in cold water. The stimulation intensity for the conditioning pulses in the paired-pulse examination was 80% of the resting motor threshold (RMT) of the stimulated site and 120% of RMT for both the test and single pulses. The paired-pulse MEP amplitudes were normalized with the mean amplitude of the single-pulse MEPs of the same condition and muscle. SICI was compared between conditions. After the cold pain, the normalized paired-pulse MEP amplitudes decreased in APB, but not in BB, indicating that SICI was potentially increased only in the cortical area of the muscle subjected to pain. These data suggest that SICI is increased in the M1 representation area of a hand muscle shortly after exposure to pain has ended, which implies that short-lasting pain can alter the inhibitory balance in M1.

This controlled trial examined the benefit of a high-frequency transcutaneous electrical nerve stimulation (hfTENS) device (Quell ) for chronic low back pain (CLBP) patients. Thirty-five (N=35) participants were randomly assigned to use the device each day for 3 months (Experimental) and were compared with 33 subjects without the device (treatment-as-usual Control). All patients were instructed to complete baseline questionnaires and were assessed on thresholds of pressure pain and mechanical temporal summation as part of a standardized quantitative sensory test (QST) assessment. The subjects also uploaded smartphone applications (apps) for tracking use of the hfTENS and for daily pain assessment. Each participant completed weekly phone interviews, was prompted to complete daily pain app assessments, and was asked to repeat the baseline questionnaires again after 6 weeks and 3 months. Sixty percent of the subjects were female, 77.9% were Caucasian, and the average age was 46.2. Significant reductions in pain intensity (p<0.01) and activity interference (p<0.025) and significant improvements in pain catastrophizing (p<0.025) were noted in the Experimental subjects compared with the Controls. No group differences were found on depression, anxiety, or pain-related disability. Older subjects with a longer duration of pain tended to use the hfTENS more often. Subjects who showed greater sensitivity based on QST results revealed increased use of the hfTENS (p<0.025) and tended to believe that the hfTENS was more helpful in reducing their back pain, but these findings did not reach significance (p=0.09). Further trials designed to determine the mechanism of action of the hfTENS are needed. This article is protected by copyright. All rights reserved.

Accumulating evidence has shown that complicated brain systems are involved in the development and maintenance of chronic low back pain (cLBP), but the association between brain functional changes and clinical outcomes remains unclear. Here, we used resting-state functional magnetic resonance imaging (fMRI) and multivariate pattern analysis to identify abnormal functional connectivity (FC) between the default mode, sensorimotor, salience, and central executive brain networks in cLBP and tested whether abnormal FCs are related to pain and comorbid symptoms. Fifty cLBP patients and 44 matched healthy controls (HCs) underwent an fMRI scan, from which brain networks were identified by independent component analysis. Multivariate pattern analysis, graph theory approaches, and correlation analyses were applied to find abnormal FCs that were associated with clinical symptoms. Findings were validated on a second cohort of 30 cLBP patients and 30 matched HCs. Results showed that the medial prefrontal cortex/rostral anterior cingulate cortex had abnormal FCs with brain regions within the default mode network and with other brain networks in cLBP patients. These altered FCs were also correlated with pain duration, pain severity, and pain interference. Finally, we found that resting-state FC could discriminate cLBP patients from HCs with 91% accuracy in the first cohort and 78% accuracy in the validation cohort. Our findings suggest that the medial prefrontal cortex/rostral anterior cingulate cortex may be an important hub for linking the default mode network with the other 3 networks in cLBP patients. Elucidating the altered FCs and their association with clinical outcomes will enhance our understanding of the pathophysiology of cLBP and may facilitate the development of pain management approaches.

Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in UCPPS participants was compared to healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from six participating MAPP testing sites were pooled for analysis. UCPPS participants (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in UCPPS patients was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in UCPPS participants revealed that pain sensitivity increased during periods of urological symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement one year later. The finding that individuals with UCPPS demonstrate non-pelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.

Charcot-Marie-Tooth disease (CMT) is most commonly caused by duplication of a chromosomal segment surrounding Peripheral Myelin Protein 22, or PMP22 gene, which is classified as CMT1A. Several candidate therapies reduce Pmp22 mRNA levels in CMT1A rodent models, but development of biomarkers for clinical trials in CMT1A is a challenge given its slow progression and the difficulty in obtaining nerve samples. Quantitative PCR measurements of PMP22 mRNA in dermal nerves were performed using skin biopsies in human clinical trials for CMT1A, but this approach did not show increased PMP22 mRNA in CMT1A patients compared to controls. One complicating factor is the variable amounts of Schwann cells (SC) in skin. The objective of the study was to develop a novel method for precise evaluation of PMP22 levels in skin biopsies that can discriminate CMT1A patients from controls.