Napadow V, Li A, Loggia ML, Kim J, Schalock PC, Lerner E, Tran T-N, Ring J, Rosen BR, Kaptchuk TJ, Pfab F. The brain circuitry mediating antipruritic effects of acupuncture. Cereb Cortex 2014;24(4):873-82.Abstract
Itch is an aversive sensory experience and while systemic therapies, such as acupuncture, have shown promise in alleviating itch in patients suffering from chronic itch, their antipruritic mechanisms are unknown. As several lines of evidence implicate brain-focused mechanisms, we applied functional magnetic resonance imaging and our validated temperature-modulation itch model to evaluate the underlying brain circuitry supporting allergen-induced itch reduction in atopic dermatitis patients by acupuncture, antihistamine, and respective placebo treatments. Brain response to allergen itch demonstrated phase dependency. During an increasing itch phase, activation was localized in anterior insula and striatum, regions associated with salience/interoception and motivation processing. Once itch reached peak plateau, robust activation was noted in prefrontal cognitive and premotor areas. Acupuncture reduced itch and itch-evoked activation in the insula, putamen, and premotor and prefrontal cortical areas. Neither itch sensation nor itch-evoked brain response was altered following antihistamine or placebo acupuncture. Greater itch reduction following acupuncture was associated with greater reduction in putamen response, a region implicated in motivation and habitual behavior underlying the urge to scratch, specifically implicating this region in acupuncture's antipruritic effects. Understanding brain circuitry underlying itch reduction following acupuncture and related neuromodulatory therapies will significantly impact the development and applicability of novel therapies to reduce an itch.
Sclocco R, Kim J, Garcia RG, Sheehan JD, Beissner F, Bianchi AM, Cerutti S, Kuo B, Barbieri R, Napadow V. Brain Circuitry Supporting Multi-Organ Autonomic Outflow in Response to Nausea. Cereb Cortex 2014;Abstract

While autonomic outflow is an important co-factor of nausea physiology, central control of this outflow is poorly understood. We evaluated sympathetic (skin conductance level) and cardiovagal (high-frequency heart rate variability) modulation, collected synchronously with functional MRI (fMRI) data during nauseogenic visual stimulation aimed to induce vection in susceptible individuals. Autonomic data guided analysis of neuroimaging data, using a stimulus-based (analysis windows set by visual stimulation protocol) and percept-based (windows set by subjects' ratings) approach. Increased sympathetic and decreased parasympathetic modulation was associated with robust and anti-correlated brain activity in response to nausea. Specifically, greater autonomic response was associated with reduced fMRI signal in brain regions such as the insula, suggesting an inhibitory relationship with premotor brainstem nuclei. Interestingly, some sympathetic/parasympathetic specificity was noted. Activity in default mode network and visual motion areas was anti-correlated with parasympathetic outflow at peak nausea. In contrast, lateral prefrontal cortical activity was anti-correlated with sympathetic outflow during recovery, soon after cessation of nauseogenic stimulation. These results suggest divergent central autonomic control for sympathetic and parasympathetic response to nausea. Autonomic outflow and the central autonomic network underlying ANS response to nausea may be an important determinant of overall nausea intensity and, ultimately, a potential therapeutic target.

Chae Y, Lee I-S, Jung W-M, Chang D-S, Napadow V, Lee H, Park H-J, Wallraven C. Decreased peripheral and central responses to acupuncture stimulation following modification of body ownership. PLoS One 2014;9(10):e109489.Abstract
Acupuncture stimulation increases local blood flow around the site of stimulation and induces signal changes in brain regions related to the body matrix. The rubber hand illusion (RHI) is an experimental paradigm that manipulates important aspects of bodily self-awareness. The present study aimed to investigate how modifications of body ownership using the RHI affect local blood flow and cerebral responses during acupuncture needle stimulation. During the RHI, acupuncture needle stimulation was applied to the real left hand while measuring blood microcirculation with a LASER Doppler imager (Experiment 1, N = 28) and concurrent brain signal changes using functional magnetic resonance imaging (fMRI; Experiment 2, N = 17). When the body ownership of participants was altered by the RHI, acupuncture stimulation resulted in a significantly lower increase in local blood flow (Experiment 1), and significantly less brain activation was detected in the right insula (Experiment 2). This study found changes in both local blood flow and brain responses during acupuncture needle stimulation following modification of body ownership. These findings suggest that physiological responses during acupuncture stimulation can be influenced by the modification of body ownership.
Loggia ML, Berna C, Kim J, Cahalan CM, Gollub RL, Wasan AD, Harris RE, Edwards RR, Napadow V. Disrupted brain circuitry for pain-related reward/punishment in fibromyalgia. Arthritis Rheumatol 2014;66(1):203-12.Abstract
OBJECTIVE: While patients with fibromyalgia (FM) are known to exhibit hyperalgesia, the central mechanisms contributing to this altered pain processing are not fully understood. This study was undertaken to investigate potential dysregulation of the neural circuitry underlying cognitive and hedonic aspects of the subjective experience of pain, such as anticipation of pain and anticipation of pain relief. METHODS: Thirty-one FM patients and 14 controls underwent functional magnetic resonance imaging, while receiving cuff pressure pain stimuli on the leg calibrated to elicit a pain rating of ~50 on a 100-point scale. During the scan, subjects also received visual cues informing them of the impending onset of pain (pain anticipation) and the impending offset of pain (relief anticipation). RESULTS: Patients exhibited less robust activation during both anticipation of pain and anticipation of relief within regions of the brain commonly thought to be involved in sensory, affective, cognitive, and pain-modulatory processes. In healthy controls, direct searches and region-of-interest analyses of the ventral tegmental area revealed a pattern of activity compatible with the encoding of punishment signals: activation during anticipation of pain and pain stimulation, but deactivation during anticipation of pain relief. In FM patients, however, activity in the ventral tegmental area during periods of pain and periods of anticipation (of both pain and relief) was dramatically reduced or abolished. CONCLUSION: FM patients exhibit disrupted brain responses to reward/punishment. The ventral tegmental area is a source of reward-linked dopaminergic/γ-aminobutyric acid-releasing (GABAergic) neurotransmission in the brain, and our observations are compatible with reports of altered dopaminergic/GABAergic neurotransmission in FM. Reduced reward/punishment signaling in FM may be related to the augmented central processing of pain and reduced efficacy of opioid treatments in these patients.
Yu R, Gollub RL, Spaeth R, Napadow V, Wasan A, Kong J. Disrupted functional connectivity of the periaqueductal gray in chronic low back pain. Neuroimage Clin 2014;6:100-8.Abstract
Chronic low back pain is a common neurological disorder. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. In this study, we investigated brain resting state PAG functional connectivity (FC) differences between patients with chronic low back pain (cLBP) in low pain or high pain condition and matched healthy controls (HCs). PAG seed based functional connectivity (FC) analysis of the functional MR imaging data was performed to investigate the difference among the connectivity maps in the cLBP in the low or high pain condition and HC groups as well as within the cLBP at differing endogenous back pain intensities. Results showed that FC between the PAG and the ventral medial prefrontal cortex (vmPFC)/rostral anterior cingulate cortex (rACC) increased in cLBP patients compared to matched controls. In addition, we also found significant negative correlations between pain ratings and PAG-vmPFC/rACC FC in cLBP patients after pain-inducing maneuver. The duration of cLBP was negatively correlated with PAG-insula and PAG-amygdala FC before pain-inducing maneuver in the patient group. These findings are in line with the impairments of the descending pain modulation reported in patients with cLBP. Our results provide evidence showing that cLBP patients have abnormal FC in PAG centered pain modulation network during rest.
Akeju O, Loggia ML, Catana C, Pavone KJ, Vazquez R, Rhee J, Contreras Ramirez V, Chonde DB, Izquierdo-Garcia D, Arabasz G, Hsu S, Habeeb K, Hooker JM, Napadow V, Brown EN, Purdon PL. Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness. Elife 2014;3:e04499.Abstract
Understanding the neural basis of consciousness is fundamental to neuroscience research. Disruptions in cortico-cortical connectivity have been suggested as a primary mechanism of unconsciousness. By using a novel combination of positron emission tomography and functional magnetic resonance imaging, we studied anesthesia-induced unconsciousness and recovery using the α₂-agonist dexmedetomidine. During unconsciousness, cerebral metabolic rate of glucose and cerebral blood flow were preferentially decreased in the thalamus, the Default Mode Network (DMN), and the bilateral Frontoparietal Networks (FPNs). Cortico-cortical functional connectivity within the DMN and FPNs was preserved. However, DMN thalamo-cortical functional connectivity was disrupted. Recovery from this state was associated with sustained reduction in cerebral blood flow and restored DMN thalamo-cortical functional connectivity. We report that loss of thalamo-cortical functional connectivity is sufficient to produce unconsciousness.
Kim J, Van Dijk KRA, Libby A, Napadow V. Frequency-dependent relationship between resting-state functional magnetic resonance imaging signal power and head motion is localized within distributed association networks. Brain Connect 2014;4(1):30-9.Abstract
Recent studies have highlighted the importance of analyzing spectral power in resting-state functional magnetic resonance imaging (rs-fMRI) data. Significant modulation of power has been ascribed to the performance of cognitive tasks and has been ascribed clinical significance. However, the role of confounding factors such as head motion on spectral power is not fully understood. Specifically, the spatial distribution of frequency-dependent associations between rs-fMRI power and motion is unknown. We utilized a large rs-fMRI dataset (n=1000) to quantify the influence of head motion on spectral power in different frequency bands. We (1) performed regression analyses across the entire sample and (2) computed difference maps between high- and low-motion groups, more consistent with common experimental designs, and both analyses gave similar results. Greater head motion led to reduced spectral power at lower frequencies (0.007-0.05 Hz), but increased power at higher frequencies (0.12-0.167 Hz). Importantly, our whole-brain voxel-wise analysis showed that brain areas in distributed association networks (e.g., default mode and frontoparietal control networks) were most susceptible to head motion. These results were consistent with or without global signal regression (GSR). Additionally, without GSR, we noted a positive correlation with low-frequency power in the pre- and postcentral gyrus (S1/M1), mid-cingulate cortex, and insula and a negative correlation with mid-frequency (0.05-0.12 Hz) power in S1/M1, visual, and lateral temporal cortices. Hence, head motion significantly affects rs-fMRI power and great care must be taken when assigning a diagnostic marker for clinical populations known to present with greater head motion.
Maeda Y, Kettner N, Holden J, Lee J, Kim J, Cina S, Malatesta C, Gerber J, McManus C, Im J, Libby A, Mezzacappa P, Morse LR, Park K, Audette J, Tommerdahl M, Napadow V. Functional deficits in carpal tunnel syndrome reflect reorganization of primary somatosensory cortex. Brain 2014;137(Pt 6):1741-52.Abstract
Carpal tunnel syndrome, a median nerve entrapment neuropathy, is characterized by sensorimotor deficits. Recent reports have shown that this syndrome is also characterized by functional and structural neuroplasticity in the primary somatosensory cortex of the brain. However, the linkage between this neuroplasticity and the functional deficits in carpal tunnel syndrome is unknown. Sixty-three subjects with carpal tunnel syndrome aged 20-60 years and 28 age- and sex-matched healthy control subjects were evaluated with event-related functional magnetic resonance imaging at 3 T while vibrotactile stimulation was delivered to median nerve innervated (second and third) and ulnar nerve innervated (fifth) digits. For each subject, the interdigit cortical separation distance for each digit's contralateral primary somatosensory cortex representation was assessed. We also evaluated fine motor skill performance using a previously validated psychomotor performance test (maximum voluntary contraction and visuomotor pinch/release testing) and tactile discrimination capacity using a four-finger forced choice response test. These biobehavioural and clinical metrics were evaluated and correlated with the second/third interdigit cortical separation distance. Compared with healthy control subjects, subjects with carpal tunnel syndrome demonstrated reduced second/third interdigit cortical separation distance (P < 0.05) in contralateral primary somatosensory cortex, corroborating our previous preliminary multi-modal neuroimaging findings. For psychomotor performance testing, subjects with carpal tunnel syndrome demonstrated reduced maximum voluntary contraction pinch strength (P < 0.01) and a reduced number of pinch/release cycles per second (P < 0.05). Additionally, for four-finger forced-choice testing, subjects with carpal tunnel syndrome demonstrated greater response time (P < 0.05), and reduced sensory discrimination accuracy (P < 0.001) for median nerve, but not ulnar nerve, innervated digits. Moreover, the second/third interdigit cortical separation distance was negatively correlated with paraesthesia severity (r = -0.31, P < 0.05), and number of pinch/release cycles (r = -0.31, P < 0.05), and positively correlated with the second and third digit sensory discrimination accuracy (r = 0.50, P < 0.05). Therefore, reduced second/third interdigit cortical separation distance in contralateral primary somatosensory cortex was associated with worse symptomatology (particularly paraesthesia), reduced fine motor skill performance, and worse sensory discrimination accuracy for median nerve innervated digits. In conclusion, primary somatosensory cortex neuroplasticity for median nerve innervated digits in carpal tunnel syndrome is indeed maladaptive and underlies the functional deficits seen in these patients.
Bai L, Harris RE, Kong J, Lao L, Napadow V, Zhao B. Neurobiological mechanisms of acupuncture 2014. Evid Based Complement Alternat Med 2014;2014:765068. bai_ebcam_2014.pdf
Lee J, Napadow V, Park K. Pain and sensory detection threshold response to acupuncture is modulated by coping strategy and acupuncture sensation. BMC Complement Altern Med 2014;14:324.Abstract
BACKGROUND: Acupuncture has been shown to reduce pain, and acupuncture-induced sensation may be important for this analgesia. In addition, cognitive coping strategies can influence sensory perception. However, the role of coping strategy on acupuncture modulation of pain and sensory thresholds, and the association between acupuncture sensation and these modulatory effects, is currently unknown. METHODS: Electroacupuncture (EA) was applied at acupoints ST36 and GB39 of 61 healthy adults. Different coping conditions were experimentally designed to form an active coping strategy group (AC group), who thought they could control EA stimulation intensity, and a passive coping strategy group (PC group), who did not think they had such control. Importantly, neither group was actually able to control EA stimulus intensity. Quantitative sensory testing was performed before and after EA, and consisted of vibration (VDT), mechanical (MDT), warm (WDT), and cold (CDT) detection thresholds, and pressure (PPT), mechanical (MPT), heat (HPT) and cold (CPT) pain thresholds. Autonomic measures (e.g. skin conductance response, SCR) were also acquired to quantify physiological response to EA under different coping conditions. Subjects also reported the intensity of any acupuncture-induced sensations. RESULTS: Coping strategy was induced with successful blinding in 58% of AC subjects. Compared to PC, AC showed greater SCR to EA. Under AC, EA reduced PPT and CPT. In the AC group, improved pain and sensory thresholds were correlated with acupuncture sensation (VDTchange vs. MI: r=0.58, CDTchange vs. tingling: r=0.53, CPTchange vs. tingling; r=0.55, CPTchange vs. dull; r=0.55). However, in the PC group, improved sensory thresholds were negatively correlated with acupuncture sensation (CDTchange vs. intensity sensitization: r=-0.52, WDTchange vs. fullness: r=-0.57). CONCLUSIONS: Our novel approach was able to successfully induce AC and PC strategies to EA stimulation. The interaction between psychological coping strategy and acupuncture sensation intensity can differentially modulate pain and sensory detection threshold response to EA. In a clinical context, our findings suggest that instructions given to the patient can significantly affect therapeutic outcomes and the relationship between acupuncture intensity and clinical response. Specifically, acupuncture analgesia can be enhanced by matching physical stimulation intensity with psychological coping strategy to acupuncture contexts. TRIAL REGISTRATION: KCT0000905.
Lee J, Napadow V, Kim J, Lee S, Choi W, Kaptchuk TJ, Park K. Phantom acupuncture: dissociating somatosensory and cognitive/affective components of acupuncture stimulation with a novel form of placebo acupuncture. PLoS One 2014;9(8):e104582.Abstract
In a clinical setting, acupuncture treatment consists of multiple components including somatosensory stimulation, treatment context, and attention to needle-based procedures. In order to dissociate somatosensory versus contextual and attentional aspects of acupuncture, we devised a novel form of placebo acupuncture, a visual manipulation dubbed phantom acupuncture, which reproduces the acupuncture needling ritual without somatosensory tactile stimulation. Subjects (N = 20) received both real (REAL) and phantom (PHNT) acupuncture. Subjects were retrospectively classified into two groups based on PHNT credibility (PHNTc, who found phantom acupuncture credible; and PHNTnc, who did not). Autonomic and psychophysical responses were monitored. We found that PHNT can be delivered in a credible manner. Acupuncture needling, a complex, ritualistic somatosensory intervention, induces sympathetic activation (phasic skin conductance [SC] response), which may be specific to the somatosensory component of acupuncture. In contrast, contextual effects, such as needling credibility, are instead associated with a shift toward relative cardiovagal activation (decreased heart rate) during needling and sympathetic inhibition (decreased SC) and parasympathetic activation (decreased pupil size) following acupuncture needling. Visual stimulation characterizing the needling ritual is an important factor for phasic autonomic responses to acupuncture and may undelie the needling orienting response. Our study suggests that phantom acupuncture can be a viable sham control for acupuncture as it completely excludes the somatosensory component of real needling while maintaining the credibility of the acupuncture treatment context in many subjects.
Dolman AJ, Loggia ML, Edwards RR, Gollub RL, Kong J, Napadow V, Wasan AD. Phenotype matters: the absence of a positive association between cortical thinning and chronic low back pain when controlling for salient clinical variables. Clin J Pain 2014;30(10):839-45.Abstract
AIMS/OBJECTIVES/BACKGROUND: Studies have associated chronic low back pain (cLBP) with grey matter thinning. But these studies have not controlled for important clinical variables (such as a comorbid affective disorder, pain medication, age, or pain phenotype), which may reduce or eliminate these associations. METHODS: We conducted cortical thickness and voxel-based morphometry (VBM) analyses in 14 cLBP patients with a discogenic component to their pain, not taking opioids or benzodiazepines, and not depressed or anxious. They were age and gender matched to 14 pain-free controls (PFCs). An ROI-driven analysis (regions of interest) was conducted, using 18 clusters from a previous arterial spin labeling study demonstrating greater regional cerebral blood flow (rCBF) in these cLBP subjects than the PFCs. Cortical thickness and VBM-based gray matter volume measurements were obtained from a structural MRI scan and group contrasts were calculated. RESULTS: Multivariate analysis of variance showed a trend toward cortical thickening in the right paracentral lobule in cLBP subjects (F1,17=3.667, P<0.067), and significant thickening in the right rostral middle frontal gyrus (F1,17=6.880, P<0.014). These clusters were non-significant after including age as a covariate (P<0.891; P<0.279). A whole-brain cortical thickness and VBM analysis also did not identify significant clusters of thinning or thickening. Exploratory analyses identified group differences for correlations between age and cortical thickness of the right rostral middle frontal gyrus (cLBP: R=-0.03, P=0.9; PFCs: R=-0.81, P<0.001), that is, PFCs demonstrated age-related thinning while cLBP patients did not. CONCLUSIONS: Our pilot results suggest that controlling for affect, age, and concurrent medications may reduce or eliminate some of the previously reported structural brain alterations in cLBP.
Maeda Y, Kettner N, Lee J, Kim J, Cina S, Malatesta C, Gerber J, McManus C, Im J, Libby A, Mezzacappa P, Morse LR, Park K, Audette J, Napadow V. Acupuncture Evoked Response in Contralateral Somatosensory Cortex Reflects Peripheral Nerve Pathology of Carpal Tunnel Syndrome. Med Acupunct 2013;25(4):275-284.Abstract

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.

Maeda Y, Kettner N, Lee J, Kim J, Cina S, Malatesta C, Gerber J, McManus C, Im J, Libby A, Mezzacappa P, Morse LR, Park K, Audette J, Napadow V. Acupuncture-evoked response in somatosensory and prefrontal cortices predicts immediate pain reduction in carpal tunnel syndrome. Evid Based Complement Alternat Med 2013;2013:795906.Abstract

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.

Maeda Y, Kettner N, Sheehan J, Kim J, Cina S, Malatesta C, Gerber J, McManus C, Mezzacappa P, Morse LR, Audette J, Napadow V. Altered brain morphometry in carpal tunnel syndrome is associated with median nerve pathology. Neuroimage Clin 2013;2:313-319.Abstract
OBJECTIVE: Carpal tunnel syndrome (CTS) is a common median nerve entrapment neuropathy characterized by pain, paresthesias, diminished peripheral nerve conduction velocity (NCV) and maladaptive functional brain neuroplasticity. We evaluated structural reorganization in brain gray (GM) and white (WM) matter and whether such plasticity is linked to altered median nerve function in CTS. METHODS: We performed NCV testing, T1-weighted structural MRI, and diffusion tensor imaging (DTI) in 28 CTS and 28 age-matched healthy controls (HC). Voxel-based morphometry (VBM) contrasted regional GM volume for CTS versus HC. Significant clusters were correlated with clinical metrics and served as seeds to define associated WM tracts using DTI data and probabilistic tractography. Within these WM tracts, fractional anisotropy (FA), axial (AD) and radial (RD) diffusivity were evaluated for group differences and correlations with clinical metrics. RESULTS: For CTS subjects, GM volume was significantly reduced in contralesional S1 (hand-area), pulvinar and frontal pole. GM volume in contralesional S1 correlated with median NCV. NCV was also correlated with RD and was negatively correlated with FA within U-fiber cortico-cortical association tracts identified from the contralesional S1 VBM seed. CONCLUSIONS: Our study identified clear morphometric changes in the CTS brain. This central morphometric change is likely secondary to peripheral nerve pathology and altered somatosensory afference. Enhanced axonal coherence and myelination within cortico-cortical tracts connecting primary somatosensory and motor areas may accompany peripheral nerve deafferentation. As structural plasticity was correlated with NCV and not symptomatology, the former may be a better determinant of appropriate clinical intervention for CTS, including surgery.
Beissner F, Meissner K, Bär K-J, Napadow V. The autonomic brain: an activation likelihood estimation meta-analysis for central processing of autonomic function. J Neurosci 2013;33(25):10503-11.Abstract
The autonomic nervous system (ANS) is of paramount importance for daily life. Its regulatory action on respiratory, cardiovascular, digestive, endocrine, and many other systems is controlled by a number of structures in the CNS. While the majority of these nuclei and cortices have been identified in animal models, neuroimaging studies have recently begun to shed light on central autonomic processing in humans. In this study, we used activation likelihood estimation to conduct a meta-analysis of human neuroimaging experiments evaluating central autonomic processing to localize (1) cortical and subcortical areas involved in autonomic processing, (2) potential subsystems for the sympathetic and parasympathetic divisions of the ANS, and (3) potential subsystems for specific ANS responses to different stimuli/tasks. Across all tasks, we identified a set of consistently activated brain regions, comprising left amygdala, right anterior and left posterior insula and midcingulate cortices that form the core of the central autonomic network. While sympathetic-associated regions predominate in executive- and salience-processing networks, parasympathetic regions predominate in the default mode network. Hence, central processing of autonomic function does not simply involve a monolithic network of brain regions, instead showing elements of task and division specificity.
Napadow V, Sheehan JD, Kim J, LaCount LT, Park K, Kaptchuk TJ, Rosen BR, Kuo B. The brain circuitry underlying the temporal evolution of nausea in humans. Cereb Cortex 2013;23(4):806-13.Abstract
Nausea is a universal human experience. It evolves slowly over time, and brain mechanisms underlying this evolution are not well understood. Our functional magnetic resonance imaging (fMRI) approach evaluated brain activity contributing to and arising from increasing motion sickness. Subjects rated transitions to increasing nausea, produced by visually induced vection within the fMRI environment. We evaluated parametrically increasing brain activity 1) precipitating increasing nausea and 2) following transition to stronger nausea. All subjects demonstrated visual stimulus-associated activation (P < 0.01) in primary and extrastriate visual cortices. In subjects experiencing motion sickness, increasing phasic activity preceding nausea was found in amygdala, putamen, and dorsal pons/locus ceruleus. Increasing sustained response following increased nausea was found in a broader network including insular, anterior cingulate, orbitofrontal, somatosensory and prefrontal cortices. Moreover, sustained anterior insula activation to strong nausea was correlated with midcingulate activation (r = 0.87), suggesting a closer linkage between these specific regions within the brain circuitry subserving nausea perception. Thus, while phasic activation in fear conditioning and noradrenergic brainstem regions precipitates transition to strong nausea, sustained activation following this transition occurs in a broader interoceptive, limbic, somatosensory, and cognitive network, reflecting the multiple dimensions of this aversive commonly occurring symptom.
Napadow V, Lee J, Kim J, Cina S, Maeda Y, Barbieri R, Harris RE, Kettner N, Park K. Brain correlates of phasic autonomic response to acupuncture stimulation: an event-related fMRI study. Hum Brain Mapp 2013;34(10):2592-606.Abstract
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.
Napadow V, Sheehan J, Kim J, Dassatti A, Thurler AH, Surjanhata B, Vangel M, Makris N, Schaechter JD, Kuo B. Brain white matter microstructure is associated with susceptibility to motion-induced nausea. Neurogastroenterol Motil 2013;25(5):448-50, e303.Abstract
Nausea is associated with significant morbidity, and there is a wide range in the propensity of individuals to experience nausea. The neural basis of the heterogeneity in nausea susceptibility is poorly understood. Our previous functional magnetic resonance imaging (fMRI) study in healthy adults showed that a visual motion stimulus caused activation in the right MT+/V5 area, and that increased sensation of nausea due to this stimulus was associated with increased activation in the right anterior insula. For the current study, we hypothesized that individual differences in visual motion-induced nausea are due to microstructural differences in the inferior fronto-occipital fasciculus (IFOF), the white matter tract connecting the right visual motion processing area (MT+/V5) and right anterior insula. To test this hypothesis, we acquired diffusion tensor imaging data from 30 healthy adults who were subsequently dichotomized into high and low nausea susceptibility groups based on the Motion Sickness Susceptibility Scale. We quantified diffusion along the IFOF for each subject based on axial diffusivity (AD); radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA), and evaluated between-group differences in these diffusion metrics. Subjects with high susceptibility to nausea rated significantly (P < 0.001) higher nausea intensity to visual motion stimuli and had significantly (P < 0.05) lower AD and MD along the right IFOF compared to subjects with low susceptibility to nausea. This result suggests that differences in white matter microstructure within tracts connecting visual motion and nausea-processing brain areas may contribute to nausea susceptibility or may have resulted from an increased history of nausea episodes.
Pfab F, Schalock PC, Napadow V, Athanasiadis GI, Yosipovitch G, Ring J. Complementary integrative approach for treating pruritus. Dermatol Ther 2013;26(2):149-56.Abstract

Complementary and alternative medicine (CAM) is a conservative and increasingly popular approach to treat pruritus for both patients and medical providers. CAM includes natural products, mind-body medicine, and manipulative and body-based practices. In this overview, we summarize current evidence, possible mechanisms and clinical approaches for treating pruritus with CAM techniques. We focus on pruritus associated with atopic dermatitis, herpes zoster, chronic urticaria, burns, and postoperative contexts where the evidence for CAM approaches is promising.