Pfab F, Nowak-Machen M, Napadow V, Fleckenstein J.
Alternatives to prokinetics to move the pylorus and colon. Curr Opin Clin Nutr Metab Care 2012;15(2):166-73.
AbstractPURPOSE OF REVIEW: Gastrointestinal motility disorders (GMDs) are common in the ICU. When encountering these problems, one typically thinks of prokinetics. This review summarizes current evidence of treatments. RECENT FINDINGS: Prokinetics are not the first-line therapy for GMDs. In fact, the clinical implications of using prokinetic agents are rather controversial. Current evidence on alternative treatment modalities such as fluid and electrolyte management, laxatives, opioid antagonists, purgative enemas, acupuncture, physical therapies and probiotics is growing. SUMMARY: Current state of the art to treat GMDs is primarily focused at the elimination of underlying trigger factors. Fluid and electrolyte management as well as laxatives and peripherally acting μ-opioid receptor antagonists are the recommended first-line therapies that can be complemented with prokinetics. Acupuncture as well as physical modalities, such as massage or warming of the abdomen, is promising with few side-effects and should be considered as well.
pfab_curropinclinnutr_2012.pdf As-Sanie S, Harris RE, Napadow V, Kim J, Neshewat G, Kairys A, Williams D, Clauw DJ, Schmidt-Wilcke T.
Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study. Pain 2012;153(5):1006-14.
AbstractChronic pelvic pain (CPP) is a highly prevalent pain condition, estimated to affect 15%-20% of women in the United States. Endometriosis is often associated with CPP, however, other factors, such as preexisting or concomitant changes of the central pain system, might contribute to the development of chronic pain. We applied voxel-based morphometry to determine whether women with CPP with and without endometriosis display changes in brain morphology in regions known to be involved in pain processing. Four subgroups of women participated: 17 with endometriosis and CPP, 15 with endometriosis without CPP, 6 with CPP without endometriosis, and 23 healthy controls. All patients with endometriosis and/or CPP were surgically confirmed. Relative to controls, women with endometriosis-associated CPP displayed decreased gray matter volume in brain regions involved in pain perception, including the left thalamus, left cingulate gyrus, right putamen, and right insula. Women with CPP without endometriosis also showed decreases in gray matter volume in the left thalamus. Such decreases were not observed in patients with endometriosis who had no CPP. We conclude that CPP is associated with changes in regional gray matter volume within the central pain system. Although endometriosis may be an important risk factor for the development of CPP, acting as a cyclic source of peripheral nociceptive input, our data support the notion that changes in the central pain system also play an important role in the development of chronic pain, regardless of the presence of endometriosis.
Huang W, Pach D, Napadow V, Park K, Long X, Neumann J, Maeda Y, Nierhaus T, Liang F, Witt CM.
Characterizing acupuncture stimuli using brain imaging with FMRI--a systematic review and meta-analysis of the literature. PLoS One 2012;7(4):e32960.
AbstractBACKGROUND: 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.
Napadow V, Kim J, Clauw DJ, Harris RE.
Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia. Arthritis Rheum 2012;64(7):2398-403.
AbstractOBJECTIVE: A major impediment to the development of novel treatment strategies for fibromyalgia (FM) is the lack of an objective marker that reflects spontaneously reported clinical pain in patients with FM. Studies of resting-state intrinsic brain connectivity in FM have demonstrated increased insular connectivity to the default mode network (DMN), a network whose activity is increased during nontask states. Moreover, increased insular connectivity to the DMN was associated with increased spontaneous pain levels. However, as these analyses were cross-sectional in nature, they provided no insight into dynamic changes in connectivity or their relationship to variations in self-reported clinical pain. The purpose of this study was to evaluate longitudinal changes in the intrinsic brain connectivity of FM patients treated with nonpharmacologic interventions known to modulate pain levels in this patient population, and to test the hypothesis that the reduction of DMN-insula connectivity following therapy would correlate with diminished pain.
METHODS: Seventeen FM patients underwent resting-state functional magnetic resonance imaging at baseline and following 4 weeks of a nonpharmacologic intervention to diminish pain. Intrinsic DMN connectivity was evaluated using probabilistic independent components analysis. Longitudinal changes in intrinsic DMN connectivity were evaluated by paired analysis, and correlations between longitudinal changes in clinical pain and changes in intrinsic DMN connectivity were investigated by multiple linear regression analysis. Changes in clinical pain were assessed with the short form of the McGill Pain Questionnaire (SF-MPQ).
RESULTS: Clinical pain as assessed using the sensory scale of the SF-MPQ was reduced following therapy (P=0.02). Intrinsic DMN connectivity to the insula was reduced, and this reduction correlated with reductions in pain (corrected P<0.05).
CONCLUSION: Our findings suggest that intrinsic brain connectivity can be used as a candidate objective marker that reflects changes in spontaneous chronic pain within individual FM patients. We propose that intrinsic connectivity measures could potentially be used in either research or clinical settings as a complementary, more objective outcome measure for use in FM.
napadow_ar_2012.pdf Loggia ML, Edwards RR, Kim J, Vangel MG, Wasan AD, Gollub RL, Harris RE, Park K, Napadow V.
Disentangling linear and nonlinear brain responses to evoked deep tissue pain. Pain 2012;153(10):2140-51.
AbstractPain stimuli evoke widespread responses in the brain. However, our understanding of the physiological significance underlying heterogeneous response within different pain-activated and -deactivated regions is still limited. Using functional magnetic resonance imaging, we evaluated brain responses to a wide range of stimulus intensity levels (1 innocuous, 7 painful) in order to estimate region-specific stimulus-response functions, which we hypothesized could illuminate that region's functional relationship to pain. Linear and nonlinear brain responses to pain were estimated through independent Legendre polynomial transformations of pain ratings within a general linear model. This approach identified at least 5 different, regionally specific activity profiles in the brain. Linearly increasing (eg, primary somatosensory/motor cortex, insulae) and intensity-independent (eg, secondary somatosensory cortex) activation was noted in traditional pain-processing areas, potentially reflecting sensory encoding and all-or-none salience responses, respectively. Multiple activity profiles were seen in areas of the default mode network (DMN): intensity-independent deactivation (eg, posterior cingulate cortex), linearly decreasing (eg, contralateral inferior parietal lobule), and quadratic (U-shaped; eg, medial prefrontal cortex). The latter observation suggests that: (1) different DMN subregions exhibit functional heterogeneity and (2) some DMN subregions respond in a percept-related manner to pain, suggesting closer linkage between the DMN and pain processing than previously thought. Future studies should apply a similar approach using innocuous stimuli of multiple intensities to evaluate whether the response profiles reported here can also be generalized to nonpainful somatosensory processing.
loggia_pain_2012.pdf Napadow V, Edwards RR, Cahalan CM, Mensing G, Greenbaum S, Valovska A, Li A, Kim J, Maeda Y, Park K, Wasan AD.
Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Med 2012;13(6):777-89.
AbstractOBJECTIVE: 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.
napadow_painmed_2012.pdf Pfab F, Valet M, Napadow V, Tölle T-R, Behrendt H, Ring J, Darsow U.
Itch and the brain. Chem Immunol Allergy 2012;98:253-65.
AbstractThe sensation of itch - defined as unpleasant sensation inducing the urge to scratch - is processed by a network of different brain regions contributing to the encoding of sensory, emotional, attention-dependent, cognitive-evaluative and motivational patterns. Patients with atopic eczema show different activation patterns and kinetics compared to healthy volunteers. This review summarizes current studies investigating itch in the brain.
Dhond RP, Ruzich E, Witzel T, Maeda Y, Malatesta C, Morse LR, Audette J, Hämäläinen M, Kettner N, Napadow V.
Spatio-temporal mapping cortical neuroplasticity in carpal tunnel syndrome. Brain 2012;135(Pt 10):3062-73.
AbstractNeuroimaging data demonstrate that carpal tunnel syndrome, a peripheral neuropathy, is accompanied by maladaptive central neuroplasticity. To further investigate this phenomenon, we collected magnetoencephalography data from 12 patients with carpal tunnel syndrome and 12 healthy control subjects undergoing somatosensory stimulation of the median nerve-innervated Digits 2 and 3, as well as Digit 5, which is innervated by the ulnar nerve. Nerve conduction velocity and psychophysical data were acquired to determine whether standard clinical measures correlated with brain response. In subjects with carpal tunnel syndrome, but not healthy controls, sensory nerve conduction velocity for Digits 2 and 3 was slower than Digit 5. However, somatosensory M20 latencies for Digits 2 and 3 were significantly longer than those of Digit 5. The extent of the M20 delay for median nerve-innervated Digit 2 was positively correlated with decreasing nerve conduction velocity and increasing pain severity. Thus, slower peripheral nerve conduction in carpal tunnel syndrome corresponds to greater delays in the first somatosensory cortical response. Furthermore, spectral analysis demonstrated weaker post-stimulus beta event-related desynchronization and earlier and shorter event-related synchronization in subjects with carpal tunnel syndrome. The extent of the decreased event-related desynchronization for median nerve-innervated digits was positively correlated with paraesthesia severity. We propose that ongoing paraesthesias in median nerve-innervated digits render their corresponding sensorimotor cortical areas 'busy', thus reducing their capacity to process external stimulation. Finally, subjects with carpal tunnel syndrome demonstrated a smaller cortical source separation for Digits 2 and 3 compared with healthy controls. This supports our hypothesis that ongoing paraesthesias promote blurring of median nerve-innervated digit representations through Hebbian plasticity mechanisms. In summary, this study reveals significant correlation between the clinical severity of carpal tunnel syndrome and the latency of the early M20, as well as the strength of long latency beta oscillations. These temporal magnetoencephalography measures are novel markers of neuroplasticity in carpal tunnel syndrome and could be used to study central changes that may occur following clinical intervention.
dhond_brain_2012.pdf 
