Publications

2012
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.Abstract

PURPOSE 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.Abstract

Chronic 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.

as-sanie_pain_2012.pdf
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.Abstract

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.

huang_plosone_2012.pdf
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.Abstract
OBJECTIVE: 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.Abstract
Pain 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.Abstract
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.
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.Abstract

The 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.

pfab_chemimmunall_2012.pdf
Loggia ML, Napadow V. Multi-parameter autonomic-based pain assessment: more is more?. Pain 2012;153(9):1779-80. loggia_pain_2012.pdf
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.Abstract
Neuroimaging 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
2011
Kim J, Napadow V, Kuo B, Barbieri R. A combined HRV-fMRI approach to assess cortical control of cardiovagal modulation by motion sickness. Conf Proc IEEE Eng Med Biol Soc 2011;2011:2825-8.Abstract
Nausea is a commonly occurring symptom typified by epigastric discomfort with the urge to vomit. To date, the brain circuitry underlying the autonomic nervous system response to nausea has not been fully understood. Functional MRI (fMRI), together with a point process adaptive recursive algorithm for computation of the high-frequency (HF) index of heart rate variability (HRV) was combined to evaluate the brain circuitry underlying autonomic nervous system response to nausea. Alone, the point process analysis revealed increasing sympathetic and decreasing parasympathetic response during nausea with significant increased heart rate (HR) and decreased HF. The combined HRV-fMRI analysis demonstrated that the fMRI signal in the medial prefrontal cortex (MPFC) and pregenual anterior cingulate cortex (pgACC), regions of higher cortical functions and emotion showed a negative correlation at the baseline and a positive correlation during nausea. Overall, our findings confirm a sympathovagal shift (toward sympathetic) during nausea, which was related to brain activity in regions associated with emotion and higher cognitive function.
Pfab F, Winhard M, Nowak-Machen M, Napadow V, Irnich D, Pawlik M, Bein T, Hansen E. Acupuncture in critically ill patients improves delayed gastric emptying: a randomized controlled trial. Anesth Analg 2011;112(1):150-5.Abstract

BACKGROUND: Malnutrition remains a severe problem in the recovery of critically ill patients and leads to increased in-hospital morbidity and in-hospital stay. Even though early enteral nutrition has been shown to improve overall patient outcomes in the intensive care unit (ICU), tubefeed administration is often complicated by delayed gastric emptying and gastroesophageal reflux. Acupuncture has been successfully used in the treatment and prevention of perioperative nausea and vomiting. In this study we evaluated whether acupuncture can improve gastric emptying in comparison with standard promotility drugs in critically ill patients receiving enteral feeding. METHODS: Thirty mechanically ventilated neurosurgical ICU patients with delayed gastric emptying, defined as a gastric residual volume (GRV) >500 mL for ≥ 2 days, were prospectively and randomly assigned to either the acupoint stimulation group (ASG; bilateral transcutaneous electrical acupoint stimulation at Neiguan, PC-6) or the conventional promotility drug treatment group (DTG) over a period of 6 days (metoclopramide, cisapride, erythromycin). Patients in the ASG group did not receive any conventional promotility drugs. Successful treatment (feeding tolerance) was defined as GRV <200 mL per 24 hours. RESULTS: Demographic and hemodynamic data were similar in both groups. After 5 days of treatment, 80% of patients in the ASG group successfully developed feeding tolerance versus 60% in the DTG group. On treatment day 1, GRV decreased from 970 ± 87 mL to 346 ± 71 mL with acupoint stimulation (P = 0.003), whereas patients in the DTG group showed a significant increase in GRV from 903 ± 60 mL to 1040 ± 211 mL (P = 0.015). In addition, GRV decreased and feeding balance (defined as enteral feeding volume minus GRV) increased in more patients in the ASG group (14 of 15) than in the DTG group (7 of 15; P = 0.014). On treatment day 1, the mean feeding balance was significantly higher in the ASG group (121 ± 128 mL) than in the DTG group (-727 ± 259 mL) (P = 0.005). Overall, the feeding balance improved significantly on all days of treatment in comparison with the DTG group. Patients in the DTG group did not show an increase in feeding balance until day 6. CONCLUSIONS: We introduce a new protocol for acupuncture administration in the critical care setting. We demonstrated that this protocol was more effective than standard promotility medication in the treatment of delayed gastric emptying in critically ill patients. Acupoint stimulation at Neiguan (PC-6) may be a convenient and inexpensive option (with few side effects) for the prevention and treatment of malnutrition in critically ill patients.

pfab_anan_2011.pdf
Witzel T, Napadow V, Kettner NW, Vangel MG, Hämäläinen MS, Dhond RP. Differences in cortical response to acupressure and electroacupuncture stimuli. BMC Neurosci 2011;12:73.Abstract
BACKGROUND: FMRI studies focus on sub-cortical effects of acupuncture stimuli. The purpose of this study was to assess changes in primary somatosensory (S1) activity over the course of different types of acupuncture stimulation. We used whole head magnetoencephalography (MEG) to map S1 brain response during 15 minutes of electroacupuncture (EA) and acupressure (AP). We further assessed how brain response changed during the course of stimulation. RESULTS: Evoked brain response to EA differed from AP in its temporal dynamics by showing clear contralateral M20/M30 peaks while the latter demonstrated temporal dispersion. Both EA and AP demonstrated significantly decreased response amplitudes following five minutes of stimulation. However, the latency of these decreases were earlier in EA (~30 ms post-stimulus) than AP (> 100 ms). Time-frequency responses demonstrated early onset, event related synchronization (ERS), within the gamma band at ~70-130 ms and the theta band at ~50-200 ms post-stimulus. A prolonged event related desynchronization (ERD) of alpha and beta power occurred at ~100-300 ms post-stimulus. There was decreased beta ERD at ~100-300 ms over the course of EA, but not AP. CONCLUSION: Both EA and AP demonstrated conditioning of SI response. In conjunction with their subcortical effects on endogenous pain regulation, these therapies show potential for affecting S1 processing and possibly altering maladaptive neuroplasticity. Thus, further investigation in neuropathic populations is needed.
witzel_bmcneuroscience_2011.pdf
Wasan AD, Loggia ML, Chen LQ, Napadow V, Kong J, Gollub RL. Neural correlates of chronic low back pain measured by arterial spin labeling. Anesthesiology 2011;115(2):364-74.Abstract
BACKGROUND: The varying nature of chronic pain (CP) is difficult to correlate to neural activity using typical functional magnetic resonance imaging methods. Arterial spin labeling is a perfusion-based imaging technique allowing the absolute quantification of regional cerebral blood flow, which is a surrogate measure of neuronal activity. METHODS: Subjects with chronic low back and radicular pain and matched healthy normal subjects, undergoing identical procedures, participated in three sessions: a characterization and training session and two arterial spin labeling sessions. In the first imaging session, CP (if any) was exacerbated using clinical maneuvers; in the second session, noxious heat was applied to the affected leg dermatome, the intensity of which was matched to the pain intensity level of the CP exacerbations for each back pain subject. RESULTS: The clinically significant worsening of ongoing CP (≤ 30%, n = 16) was associated with significant regional blood flow increases (6-10 mm/100 g of tissue/min, P less than 0.01) within brain regions known to activate with experimental pain (somatosensory, prefrontal, and insular cortices) and in other structures observed less frequently in experimental pain studies, such as the superior parietal lobule (part of the dorsal attention network). This effect is specific to changes in ongoing CP as it is observed during worsening CP, but it is not observed after thermal pain application, or in matched, pain-free healthy controls. CONCLUSIONS: Study findings demonstrate the use of arterial spin labeling to investigate the neural processing of CP, and these findings are a step forward in the quest for objective biomarkers of the chronic pain experience.
wasan_anesthesiology_2011.pdf
Langevin HM, Wayne PM, Macpherson H, Schnyer R, Milley RM, Napadow V, Lao L, Park J, Harris RE, Cohen M, Sherman KJ, Haramati A, Hammerschlag R. Paradoxes in acupuncture research: strategies for moving forward. Evid Based Complement Alternat Med 2011;2011:180805.Abstract

In November 2007, the Society for Acupuncture Research (SAR) held an international symposium to mark the 10th anniversary of the 1997 NIH Consensus Development Conference on Acupuncture. The symposium presentations revealed the considerable maturation of the field of acupuncture research, yet two provocative paradoxes emerged. First, a number of well-designed clinical trials have reported that true acupuncture is superior to usual care, but does not significantly outperform sham acupuncture, findings apparently at odds with traditional theories regarding acupuncture point specificity. Second, although many studies using animal and human experimental models have reported physiological effects that vary as a function of needling parameters (e.g., mode of stimulation) the extent to which these parameters influence therapeutic outcomes in clinical trials is unclear. This White Paper, collaboratively written by the SAR Board of Directors, identifies gaps in knowledge underlying the paradoxes and proposes strategies for their resolution through translational research. We recommend that acupuncture treatments should be studied (1) "top down" as multi-component "whole-system" interventions and (2) "bottom up" as mechanistic studies that focus on understanding how individual treatment components interact and translate into clinical and physiological outcomes. Such a strategy, incorporating considerations of efficacy, effectiveness and qualitative measures, will strengthen the evidence base for such complex interventions as acupuncture.

langevin_ecam_2011.pdf
Rosen BR, Napadow V. Quantitative markers for neuropsychiatric disease: give it a rest. Radiology 2011;259(1):17-9.
LaCount LT, Barbieri R, Park K, Kim J, Brown EN, Kuo B, Napadow V. Static and dynamic autonomic response with increasing nausea perception. Aviat Space Environ Med 2011;82(4):424-33.Abstract
BACKGROUND: Nausea is a commonly occurring symptom typified by epigastric discomfort with urge to vomit. The relationship between autonomic nervous system (ANS) outflow and increasing nausea perception is not fully understood. METHODS: Our study employed a nauseogenic visual stimulus (horizontally translating stripes) while 17 female subjects freely rated transitions in nausea level and autonomic outflow was measured (heart rate, HR; heart rate variability, HRV; skin conductance response, SCR; respiratory rate). We also adopted a recent approach to continuous high-frequency (HF) HRV estimation to evaluate dynamic cardiovagal modulation. RESULTS: HR increased from baseline for all increasing nausea transitions, especially transition to strong nausea (15.0 +/- 11.4 bpm), but decreased (-6.6 +/- 4.6 bpm) once the visual stimulus ceased. SCR also increased for all increasing nausea transitions, especially transition to strong nausea (1.76 +/- 1.68 microS), but continued to increase (0.52 +/- 0.65 microS) once visual stimulation ceased. LF/HF HRV increased following transition to moderate (1.54 +/- 2.11 a.u.) and strong (2.57 +/- 3.49 a.u.) nausea, suggesting a sympathetic shift in sympathovagal balance. However, dynamic HF HRV suggested that bursts of cardiovagal modulation precede transitions to higher nausea, perhaps influencing subjects to rate higher levels of nausea. No significant change in respiration rate was found. CONCLUSIONS: Our results suggest that increasing nausea perception is associated with both increased sympathetic and decreased parasympathetic ANS modulation. These findings corroborate past ANS studies of nausea, applying perception-linked analyses and dynamic estimation of cardiovagal modulation in response to nausea.
lacount_asem_2011.pdf
2010
Andrews SS, Addy NJ, Brent R, Arkin AP. Detailed simulations of cell biology with Smoldyn 2.1. PLoS Comput Biol 2010;6(3):e1000705.Abstract
Most cellular processes depend on intracellular locations and random collisions of individual protein molecules. To model these processes, we developed algorithms to simulate the diffusion, membrane interactions, and reactions of individual molecules, and implemented these in the Smoldyn program. Compared to the popular MCell and ChemCell simulators, we found that Smoldyn was in many cases more accurate, more computationally efficient, and easier to use. Using Smoldyn, we modeled pheromone response system signaling among yeast cells of opposite mating type. This model showed that secreted Bar1 protease might help a cell identify the fittest mating partner by sharpening the pheromone concentration gradient. This model involved about 200,000 protein molecules, about 7000 cubic microns of volume, and about 75 minutes of simulated time; it took about 10 hours to run. Over the next several years, as faster computers become available, Smoldyn will allow researchers to model and explore systems the size of entire bacterial and smaller eukaryotic cells.
Andrews SS, Addy NJ, Brent R, Arkin AP. Detailed simulations of cell biology with Smoldyn 2.1. PLoS Comput Biol 2010;6(3):e1000705.Abstract
Most cellular processes depend on intracellular locations and random collisions of individual protein molecules. To model these processes, we developed algorithms to simulate the diffusion, membrane interactions, and reactions of individual molecules, and implemented these in the Smoldyn program. Compared to the popular MCell and ChemCell simulators, we found that Smoldyn was in many cases more accurate, more computationally efficient, and easier to use. Using Smoldyn, we modeled pheromone response system signaling among yeast cells of opposite mating type. This model showed that secreted Bar1 protease might help a cell identify the fittest mating partner by sharpening the pheromone concentration gradient. This model involved about 200,000 protein molecules, about 7000 cubic microns of volume, and about 75 minutes of simulated time; it took about 10 hours to run. Over the next several years, as faster computers become available, Smoldyn will allow researchers to model and explore systems the size of entire bacterial and smaller eukaryotic cells.
Napadow V, LaCount L, Park K, As-Sanie S, Clauw DJ, Harris RE. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum 2010;62(8):2545-55.Abstract
OBJECTIVE: Fibromyalgia (FM) is considered to be the prototypical central chronic pain syndrome and is associated with widespread pain that fluctuates spontaneously. Multiple studies have demonstrated altered brain activity in these patients. The objective of this study was to investigate the degree of connectivity between multiple brain networks in patients with FM, as well as how activity in these networks correlates with the level of spontaneous pain. METHODS: Resting-state functional magnetic resonance imaging (FMRI) data from 18 patients with FM and 18 age-matched healthy control subjects were analyzed using dual-regression independent components analysis, which is a data-driven approach for the identification of independent brain networks. Intrinsic, or resting-state, connectivity was evaluated in multiple brain networks: the default mode network (DMN), the executive attention network (EAN), and the medial visual network (MVN), with the MVN serving as a negative control. Spontaneous pain levels were also analyzed for covariance with intrinsic connectivity. RESULTS: Patients with FM had greater connectivity within the DMN and right EAN (corrected P [P(corr)] < 0.05 versus controls), and greater connectivity between the DMN and the insular cortex, which is a brain region known to process evoked pain. Furthermore, greater intensity of spontaneous pain at the time of the FMRI scan correlated with greater intrinsic connectivity between the insula and both the DMN and right EAN (P(corr) < 0.05). CONCLUSION: These findings indicate that resting brain activity within multiple networks is associated with spontaneous clinical pain in patients with FM. These findings may also have broader implications for how subjective experiences such as pain arise from a complex interplay among multiple brain networks.
napadow_ar_2010.pdf
Hui KKS, Napadow V, Liu J, Li M, Marina O, Nixon EE, Claunch JD, LaCount L, Sporko T, Kwong KK. Monitoring acupuncture effects on human brain by FMRI. J Vis Exp 2010;(38)Abstract
Functional MRI is used to study the effects of acupuncture on the BOLD response and the functional connectivity of the human brain. Results demonstrate that acupuncture mobilizes a limbic-paralimbic-neocortical network and its anti-correlated sensorimotor/paralimbic network at multiple levels of the brain and that the hemodynamic response is influenced by the psychophysical response. Physiological monitoring may be performed to explore the peripheral response of the autonomic nerve function. This video describes the studies performed at LI4 (hegu), ST36 (zusanli) and LV3 (taichong), classical acupoints that are commonly used for modulatory and pain-reducing actions. Some issues that require attention in the applications of fMRI to acupuncture investigation are noted.
hui_jove_2010.pdf

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