S1 Brain Connectivity in Carpal Tunnel Syndrome Underlies Median Nerve and Functional Improvement Following Electro-Acupuncture.

Carpal Tunnel Syndrome (CTS) is a median nerve entrapment neuropathy that alters primary somatosensory cortex (S1) organization. While electro-acupuncture (EA), a form of peripheral neuromodulation, has been shown to improve clinical and neurophysiological CTS outcomes, the role of EA-evoked brain response during therapy (within and beyond S1) for improved outcomes is unknown. We investigated S1-associated whole brain fMRI connectivity during both a resting and sustained EA stimulation state in age-matched healthy controls (N = 28) and CTS patients (N = 64), at baseline and after 8 weeks of acupuncture therapy (local, distal, or sham EA). Compared to healthy controls, CTS patients at baseline showed decreased resting state functional connectivity between S1 and thalamic pulvinar nucleus. Increases in S1/pulvinar connectivity strength following verum EA therapy (combined local and distal) were correlated with improvements in median nerve velocity (r = 0.38, p = 0.035). During sustained local EA, compared to healthy controls, CTS patients demonstrated increased functional connectivity between S1 and anterior hippocampus (aHipp). Following 8 weeks of local EA therapy, S1/aHipp connectivity significantly decreased and greater decrease was associated with improvement in patients' functional status (r = 0.64, p = 0.01) and increased median nerve velocity (r = -0.62, p = 0.013). Thus, connectivity between S1 and other brain areas is also disrupted in CTS patients and may be improved following EA therapy. Furthermore, stimulus-evoked fMRI connectivity adds therapy-specific, mechanistic insight to more common resting state connectivity approaches. Specifically, local EA modulates S1 connectivity to sensory and affective processing regions, linked to patient function and median nerve health.

N6-methylated adenine on the target sites of mamA from Mycobacterium bovis BCG enhances macrophage activation by CpG DNA in mice.

CpG motifs in DNA sequences are recognized by Toll-like receptor 9 and activate immune cells. Bacterial genomic DNA (gDNA) has modified cytosine bases (5-methylcytosine [5 mC]) and modified adenine bases (6-methyladenine [6 mA]). 5 mC inhibits immune activation by CpG DNA; however, it is unclear whether 6 mA inhibits immune activation by CpG DNA. Mycobacterium bovis BCG (BCG) has three adenine methyltransferases (MTases) that act on specific target sequences. In this study, we examined whether the 6 mA at the target sites of adenine MTases affected the immunostimulatory activity of CpG DNA. Our results showed that only 6 mA located at the target sequence of mamA, an adenine MTase from BCG, enhanced interleukin (IL)-12p40 production from murine bone marrow-derived macrophages (BMDMs) stimulated with CpG DNA. Enhancement of IL-12p40 production in BMDMs was also observed when BMDMs were stimulated with CpG DNA ligated to oligodeoxynucleotides (ODNs) harboring 6 mA. Accordingly, we then evaluated whether gDNA from adenine MTase-deficient BCG was less efficient with regard to stimulation of BMDMs. Indeed, gDNA from a mamA-deficient BCG had less ability to activate BMDMs than that from wild-type BCG. We concluded from these results that adenine methylation on ODNs and bacterial gDNA may enhance immune activity induced by CpG DNA.

Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture.

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 ± 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 ± 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 somatotopy can predict long-term clinical outcomes for carpal tunnel syndrome.

Reference Values for the Scalene Interval Width During Varying Degrees of Glenohumeral Abduction Using Ultrasonography.

OBJECTIVE: The aim of this study was to establish reference values for the width of the interval between the anterior and middle scalene muscles using ultrasonography during varying degrees of glenohumeral joint (GH) abduction. Reliability and body mass index (BMI) data were also assessed. METHODS: Interscalene triangles of asymptomatic participants were scanned bilaterally in the transverse plane. Images were obtained at 0°, 90°, and 150° of GH abduction with the participant seated. Width measurements were taken between the anterior and middle scalene muscle borders by bisecting the C6 nerve root as it passed superficial to the posterior tubercle of the C7 transverse process. Intra- and interexaminer reliability and BMI correlation were studied. Statistical significance was defined as P ≤ .05. RESULTS: Images of 42 scalene intervals were included from 21 participants (11 female). Mean participant age was 25.3 ± 3.9 years; mean BMI was 25.4 ± 2.7 kg/m2. Scalene interval measurements at 0°, 90°, and 150° of GH abduction were 4.5 ± 0.5 mm, 4.6 ± 0.5 mm, and 4.4 ± 0.7 mm, respectively, without a significant difference (P = .07). Intraexaminer reliability was excellent (0°: intraclass correlation coefficient [ICC] = 0.82; 90°: ICC = 0.89; 150°: ICC = 0.90). Interexaminer reliability was good to excellent (0°: ICC = 0.59; 90°: ICC = 0.85; 150°: ICC = 0.89). Body mass index was positively correlated only at 0° of GH abduction. CONCLUSIONS: This study establishes previously unreported reference ultrasonography values for the width of the scalene interval. Intraexaminer reliability was excellent at all glenohumeral positions, and interexaminer reliability was determined to be good to excellent. Body mass index was positively correlated only at 0° of GH abduction.

Reliability of the Goutallier classification in quantifying muscle fatty degeneration in the lumbar multifidus using magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to investigate the reliability of the Goutallier classification system (GCS) for grading muscle fatty degeneration in the lumbar multifidus (LM) using magnetic resonance imaging (MRI) examinations. METHODS: Lumbar spine MRI scans were obtained retrospectively from the radiology department imaging system. Two examiners (a chiropractic diagnostic imaging resident and a board certified chiropractic radiologist with 30 years of experience) independently graded each LM at the L4/5 and L5/S1 intervertebral level. ImageJ pixel analysis software (version 1.47; National Institutes of Health, Bethesda, MD) was used independently by 2 observers to quantify the percent fat of the LM and allow correlation between LM percent fat and GCS grade. Twenty-five subject MRIs were randomly selected. Magnetic resonance imaging scans were included if they were obtained using a 1.5 T imaging system and were excluded if there was evidence of spinal infection, tumor, fracture, or postoperative changes. For all tests, P < .05 was defined as significant. RESULTS: Intraobserver reliability grading LM fat ranged from a weighted κ (κw) of 0.71 to 0.93. Mean interobserver reliability grading LM fat was κ(w), 0.76 to κ(w), 0.85. There was a significant (P < .001) correlation between LM percent fat and GCS grade. Furthermore, interobserver reliability in determining percent fat was between intraclass correlation coefficient, 0.73 to intraclass correlation coefficient, 0.90. CONCLUSIONS: In this study, the GCS was reliable in grading LM fatty degeneration and correlated positively with a quantified percent fat value. In addition, ImageJ software (National Institutes of Health) was reliable between raters when quantifying LM percent fat.

Acupuncture-evoked response in somatosensory and prefrontal cortices predicts immediate pain reduction in carpal tunnel syndrome.

The linkage between brain response to acupuncture and subsequent analgesia remains poorly understood. Our aim was to evaluate this linkage in chronic pain patients with carpal tunnel syndrome (CTS). Brain response to electroacupuncture (EA) was evaluated with functional MRI. Subjects were randomized to 3 groups: (1) EA applied at local acupoints on the affected wrist (PC-7 to TW-5), (2) EA at distal acupoints (contralateral ankle, SP-6 to LV-4), and (3) sham EA at nonacupoint locations on the affected wrist. Symptom ratings were evaluated prior to and following the scan. Subjects in the local and distal groups reported reduced pain. Verum EA produced greater reduction of paresthesia compared to sham. Compared to sham EA, local EA produced greater activation in insula and S2 and greater deactivation in ipsilateral S1, while distal EA produced greater activation in S2 and deactivation in posterior cingulate cortex. Brain response to distal EA in prefrontal cortex (PFC) and brain response to verum EA in S1, SMA, and PFC were correlated with pain reduction following stimulation. Thus, while greater activation to verum acupuncture in these regions may predict subsequent analgesia, PFC activation may specifically mediate reduced pain when stimulating distal acupoints.

Acupuncture Evoked Response in Contralateral Somatosensory Cortex Reflects Peripheral Nerve Pathology of Carpal Tunnel Syndrome.

BACKGROUND: Most neuroimaging studies exploring brain response to different acupoints have been performed in healthy adults. OBJECTIVE: The aim of this study was to compare brain responses to acupuncture at local versus distal acupoints in patients with carpal tunnel syndrome (CTS), who have chronic pain, versus healthy controls (HC) and correlate these responses with median nerve function. MATERIALS AND METHODS: Brain response to electroacupuncture (EA; 2Hz) was evaluated with event-related functional MRI (fMRI) in patients with CTS (n=37) and age-matched HC (n=30). EA was applied at acupoints local (PC 7 to TW 5) and distal (SP 6 to LV 4) to the CTS lesions. RESULTS: Brain response in both groups and acupoints included activation of the bilateral secondary somatosensory cortex (S2) and insula, and the contralesional primary somatosensory cortex (cS1). Deactivation was noted in ipsilesional primary somatosensory cortex (S1). A significant difference between local and distal acupoints was found in cS1 for HC, but not CTS. Furthermore, cS1 activation by EA at local acupoints was negatively correlated with median nerve peak sensory latency in HC, but was positively correlated in CTS. No correlation was found for EA at distal acupoints for either group. CONCLUSIONS: Brain response to EA differs between CTS and HC and, for local acupoint stimulation, is associated with median nerve function, reflecting the peripheral nerve pathophysiology of CTS.

Brain correlates of phasic autonomic response to acupuncture stimulation: an event-related fMRI study.

Autonomic nervous system (ANS) response to acupuncture has been investigated by multiple studies; however, the brain circuitry underlying this response is not well understood. We applied event-related fMRI (er-fMRI) in conjunction with ANS recording (heart rate, HR; skin conductance response, SCR). Brief manual acupuncture stimuli were delivered at acupoints ST36 and SP9, while sham stimuli were delivered at control location, SH1. Acupuncture produced activation in S2, insula, and mid-cingulate cortex, and deactivation in default mode network (DMN) areas. On average, HR deceleration (HR-) and SCR were noted following both real and sham acupuncture, though magnitude of response was greater following real acupuncture and inter-subject magnitude of response correlated with evoked sensation intensity. Acupuncture events with strong SCR also produced greater anterior insula activation than without SCR. Moreover, acupuncture at SP9, which produced greater SCR, also produced stronger sharp pain sensation, and greater anterior insula activation. Conversely, acupuncture-induced HR- was associated with greater DMN deactivation. Between-event correlation demonstrated that this association was strongest for ST36, which also produced more robust HR-. In fact, DMN deactivation was significantly more pronounced across acupuncture stimuli producing HR-, versus those events characterized by acceleration (HR+). Thus, differential brain response underlying acupuncture stimuli may be related to differential autonomic outflows and may result from heterogeneity in evoked sensations. Our er-fMRI approach suggests that ANS response to acupuncture, consistent with previously characterized orienting and startle/defense responses, arises from activity within distinct subregions of the more general brain circuitry responding to acupuncture stimuli.

Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation.

OBJECTIVE: Previous vagus nerve stimulation (VNS) studies have demonstrated antinociceptive effects, and recent noninvasive approaches, termed transcutaneous-vagus nerve stimulation (t-VNS), have utilized stimulation of the auricular branch of the vagus nerve in the ear. The dorsal medullary vagal system operates in tune with respiration, and we propose that supplying vagal afferent stimulation gated to the exhalation phase of respiration can optimize t-VNS. DESIGN: Counterbalanced, crossover study. PATIENTS: Patients with chronic pelvic pain (CPP) due to endometriosis in a specialty pain clinic. INTERVENTIONS/OUTCOMES: We evaluated evoked pain analgesia for respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) compared with nonvagal auricular stimulation (NVAS). RAVANS and NVAS were evaluated in separate sessions spaced at least 1 week apart. Outcome measures included deep-tissue pain intensity, temporal summation of pain, and anxiety ratings, which were assessed at baseline, during active stimulation, immediately following stimulation, and 15 minutes after stimulus cessation. RESULTS: RAVANS demonstrated a trend for reduced evoked pain intensity and temporal summation of mechanical pain, and significantly reduced anxiety in N = 15 CPP patients, compared with NVAS, with moderate to large effect sizes (η(2) > 0.2). CONCLUSION: Chronic pain disorders such as CPP are in great need of effective, nonpharmacological options for treatment. RAVANS produced promising antinociceptive effects for quantitative sensory testing (QST) outcomes reflective of the noted hyperalgesia and central sensitization in this patient population. Future studies should evaluate longer-term application of RAVANS to examine its effects on both QST outcomes and clinical pain.

Characterizing acupuncture stimuli using brain imaging with FMRI--a systematic review and meta-analysis of the literature.

BACKGROUND: The mechanisms of action underlying acupuncture, including acupuncture point specificity, are not well understood. In the previous decade, an increasing number of studies have applied fMRI to investigate brain response to acupuncture stimulation. Our aim was to provide a systematic overview of acupuncture fMRI research considering the following aspects: 1) differences between verum and sham acupuncture, 2) differences due to various methods of acupuncture manipulation, 3) differences between patients and healthy volunteers, 4) differences between different acupuncture points. METHODOLOGY/PRINCIPAL FINDINGS: We systematically searched English, Chinese, Korean and Japanese databases for literature published from the earliest available up until September 2009, without any language restrictions. We included all studies using fMRI to investigate the effect of acupuncture on the human brain (at least one group that received needle-based acupuncture). 779 papers were identified, 149 met the inclusion criteria for the descriptive analysis, and 34 were eligible for the meta-analyses. From a descriptive perspective, multiple studies reported that acupuncture modulates activity within specific brain areas, including somatosensory cortices, limbic system, basal ganglia, brain stem, and cerebellum. Meta-analyses for verum acupuncture stimuli confirmed brain activity within many of the regions mentioned above. Differences between verum and sham acupuncture were noted in brain response in middle cingulate, while some heterogeneity was noted for other regions depending on how such meta-analyses were performed, such as sensorimotor cortices, limbic regions, and cerebellum. CONCLUSIONS: Brain response to acupuncture stimuli encompasses a broad network of regions consistent with not just somatosensory, but also affective and cognitive processing. While the results were heterogeneous, from a descriptive perspective most studies suggest that acupuncture can modulate the activity within specific brain areas, and the evidence based on meta-analyses confirmed some of these results. More high quality studies with more transparent methodology are needed to improve the consistency amongst different studies.

Increased c-fos immunoreactivity in the spinal cord and brain following spinal cord stimulation is frequency-dependent.

Spinal cord stimulation (SCS) is an alternative approach for treatment of neuropathic pain when conservative management is ineffective. Previously we showed both 4 Hz and 60 Hz SCS reduces hyperalgesia in an animal model of neuropathic pain. However, the mechanisms underlying the pain reduction by SCS and how different frequencies of SCS produce the analgesic effect are unclear. To elucidate potential sites modulated by SCS we examined distribution of c-fos in Sprague-Dawley rats with spared nerve injury (SNI) and those without injury in response to SCS. SCS was delivered at one of 3 different frequencies (4 Hz, 60 Hz, and 100 Hz) for 30 min 2 weeks after SNI or in animals without SNI. Animals were perfused either 5 min or 2 h after SCS and c-fos protein examined immunohistochemically. The number of c-fos positive cells significantly increased 5 min (35 min after SCS began) after 4 Hz SCS in the NRM, but not PAG in animals with nerve injury. The number of c-fos positive cells was significantly increased bilaterally 2 h after either 4 Hz or 60 Hz SCS in the spinal cord dorsal horn in the cervical enlargement and under the electrode, but not in the lumbar enlargement in animals with nerve injury. In uninjured animals 4 Hz SCS increased c-fos expression at the electrode site and lumbar enlargement when compared to animals implanted with the electrode who did not receive SCS. 100 Hz SCS had no effect on c-fos expression. Thus, at the time points examined in this model, low frequency SCS likely activates supraspinal and spinal mechanisms to produce analgesia, while higher frequencies activate spinal mechanisms.