Disease-specific alterations in central fear network engagement during acquisition and extinction of conditioned interoceptive fear in inflammatory bowel disease.

Interoceptive fear, which is shaped by associative threat learning and memory processes, plays a central role in abnormal interoception and psychiatric comorbidity in conditions of the gut-brain axis. Although animal and human studies support that acute inflammation induces brain alterations in the central fear network, mechanistic knowledge in patients with chronic inflammatory conditions remains sparse. We implemented a translational fear conditioning paradigm to elucidate central fear network reactivity in patients with quiescent inflammatory bowel disease (IBD), compared to patients with irritable bowel syndrome (IBS) and healthy controls (HC). Using functional magnetic resonance imaging, conditioned differential neural responses within regions of the fear network were analyzed during acquisition and extinction learning. In contrast to HC and IBS, IBD patients demonstrated distinctly altered engagement of key regions of the central fear network, including amygdala and hippocampus, during differential interoceptive fear learning, with more pronounced responses to conditioned safety relative to pain-predictive cues. Aberrant hippocampal responses correlated with chronic stress exclusively in IBD. During extinction, differential engagement was observed in IBD compared to IBS patients within amygdala, ventral anterior insula, and thalamus. No group differences were found in changes of cue valence as a behavioral measure of fear acquisition and extinction. Together, the disease-specific alterations in neural responses during interoceptive fear conditioning in quiescent IBD suggest persisting effects of recurring intestinal inflammation on central fear network reactivity. Given the crucial role of interoceptive fear in abnormal interoception, these findings point towards inflammation-related brain alterations as one trajectory to bodily symptom chronicity and psychiatric comorbidity. Patients with inflammatory conditions of the gut-brain axis may benefit from tailored treatment approaches targeting maladaptive interoceptive fear.

Amplified gut feelings under inflammation and depressed mood: A randomized fMRI trial on interoceptive pain in healthy volunteers.

BACKGROUND: Inflammation and depressed mood constitute clinically relevant vulnerability factors for enhanced interoceptive sensitivity and chronic visceral pain, but their putative interaction remains untested in human mechanistic studies. We tested interaction effects of acute systemic inflammation and sad mood on the expectation and experience of visceral pain by combining experimental endotoxemia with a mood induction paradigm. METHODS: The double-blind, placebo-controlled, balanced crossover fMRI-trial in N = 39 healthy male and female volunteers involved 2 study days with either intravenous administration of low-dose lipopolysaccharide (LPS, 0.4 ng/kg body weight; inflammation condition) or saline (placebo condition). On each study, day two scanning sessions were conducted in an experimentally induced negative (i.e., sad) and in a neutral mood state, accomplished in balanced order. As a model of visceral pain, rectal distensions were implemented, which were initially calibrated to be moderately painful. In all sessions, an identical series of visceral pain stimuli was accomplished, signaled by predictive visual conditioning cues to assess pain anticipation. We assessed neural activation during the expectation and experience of visceral pain, along with unpleasantness ratings in a condition combining an inflammatory state with sad mood and in control conditions. All statistical analyses were accomplished using sex as covariate. RESULTS: LPS administration led to an acute systemic inflammatory response (inflammation X time interaction effects for TNF-α, IL-6, and sickness symptoms, all p <.001). The mood paradigm effectively induced distinct mood states (mood X time interaction, p <.001), with greater sadness in the negative mood conditions (both p <.001) but no difference between LPS and saline conditions. Significant main and interaction effects of inflammation and negative mood were observed for pain unpleasantness (all p <.05). During cued pain anticipation, a significant inflammation X mood interaction emerged for activation of the bilateral caudate nucleus and right hippocampus (all pFWE < 0.05). Main effects of both inflammation and mood were observed in multiple regions, including insula, midcingulate cortex, prefrontal gyri, and hippocampus for inflammation, and midcingulate, caudate, and thalamus for mood (all pFWE < 0.05). CONCLUSIONS: Results support an interplay of inflammation and sad mood on striatal and hippocampal circuitry engaged during visceral pain anticipation as well as on pain experience. This may reflect a nocebo mechanism, which may contribute to altered perception and interpretation of bodily signals. At the interface of affective neuroscience and the gut-brain axis, concurrent inflammation and negative mood may be vulnerability factors for chronic visceral pain.

Distinct Alterations in Central Pain Processing of Visceral and Somatic Pain in Quiescent Ulcerative Colitis Compared to Irritable Bowel Syndrome and Health.

BACKGROUND AND AIMS: Despite relevance to pain chronicity, disease burden, and treatment, mechanisms of pain perception for different types of acute pain remain incompletely understood in patients with inflammatory bowel disease [IBD]. Building on experimental research across pain modalities, we herein addressed behavioural and neural correlates of visceral versus somatic pain processing in women with quiescent ulcerative colitis [UC] compared to irritable bowel syndrome [IBS] as a patient control group and healthy women [HC]. METHODS: Thresholds for visceral and somatic pain were assessed with rectal distensions and cutaneous thermal pain, respectively. Using functional magnetic resonance imaging, neural and behavioural responses to individually calibrated and intensity-matched painful stimuli from both modalities were compared. RESULTS: Pain thresholds were comparable across groups, but visceral thresholds correlated with gastrointestinal symptom severity and chronic stress burden exclusively within UC. Upon experience of visceral and somatic pain, both control groups demonstrated enhanced visceral pain-induced neural activation and greater perceived pain intensity, whereas UC patients failed to differentiate between pain modalities at both behavioural and neural levels. CONCLUSIONS: When confronted with acute pain from multiple bodily sites, UC patients' responses are distinctly altered. Their failure to prioritise pain arising from the viscera may reflect a lack of adaptive behavioural flexibility, possibly resulting from long-lasting central effects of repeated intestinal inflammatory insults persisting during remission. The role of psychological factors, particularly chronic stress, in visceral sensitivity and disease-specific alterations in the response to acute pain call for dedicated mechanistic research as a basis for tailoring interventions for intestinal and extraintestinal pain symptoms in IBD.

Inflammation shapes neural processing of interoceptive fear predictors during extinction learning in healthy humans.

Inflammation could impact on the formation and persistence of interoceptive fear and hypervigilance, with relevance to psychiatric disorders and chronic pain. To systematically analyze effects of inflammation on fear learning and extinction, we performed two complementary randomized, double-blind, placebo-controlled functional magnetic resonance imaging (fMRI) studies combining experimental endotoxemia as a translational model of acute systemic inflammation with a two-day multiple-threat fear conditioning paradigm involving interoceptive and exteroceptive unconditioned stimuli (US). Healthy volunteers (N = 95) were randomized to receive intravenous injections of either endotoxin (lipopolysaccharide, LPS; 0.4 ng/kg) or placebo prior to fear acquisition (study 1) or extinction training (study2). Treatment effects on behavioral and neural responses to conditioned stimuli (CS) predicting interoceptive or exteroceptive threat were assessed during fear learning and extinction phases, along with US valence ratings. Despite robust inflammatory and emotional responses triggered by LPS, no direct effects of inflammation on US ratings or on the formation or extinction of conditioned fear, as assessed with CS valence ratings, were observed. However, in the group treated with LPS prior to acquisition (i.e., study 1), we found enhanced neural responses to the interoceptive but not the exteroceptive CS in key regions of the central fear circuitry during extinction learning. After extinction, this group further showed enhanced negative valence ratings selectively for the interoceptive US during unexpected US re-exposure when compared to the placebo group. Together, inflammation during fear acquisition may promote the establishment of a more robust neural signature of the interoceptive fear memory trace, which may contribute to altered interoceptive pain perception. The fear extinction circuitry engaged during interoceptive fear memory processing may be particularly vulnerable to inflammation, with transdiagnostic implications for gut-brain mechanisms underlying disturbed interoception in psychiatric conditions and chronic visceral pain.

Positive Treatment Expectations Shape Perceived Medication Efficacy in a Translational Placebo Paradigm for the Gut-Brain Axis.

Placebo research has established the pivotal role of treatment expectations in shaping symptom experience and patient-reported treatment outcomes. Perceived treatment efficacy constitutes a relevant yet understudied aspect, especially in the context of the gut-brain axis with visceral pain as key symptom. Using a clinically relevant experimental model of visceral pain, we elucidated effects of pre-treatment expectations on post-treatment perceived treatment efficacy as an indicator of treatment satisfaction in a translational placebo intervention. We implemented positive suggestions regarding intravenous treatment with a spasmolytic drug (in reality saline), herein applied in combination with two series of individually calibrated rectal distensions in healthy volunteers. The first series used distension pressures inducing pain (pain phase). In the second series, pressures were surreptitiously reduced, modeling pain relief (pain relief phase). Using visual analog scales (VAS), expected and perceived treatment efficacy were assessed, along with perceived pain intensity. Manipulation checks supported that the induction of positive pre-treatment expectations and the modeling of pain relief were successful. Generalized Linear Models (GLM) were implemented to assess the role of inter-individual variability in positive pre-treatment expectations in perceived treatment efficacy and pain perception. GLM indicated no association between pre-treatment expectations and perceived treatment efficacy or perceived pain for the pain phase. For the relief phase, pre-treatment expectations (p = 0.024) as well as efficacy ratings assessed after the preceding pain phase (p < 0.001) were significantly associated with treatment efficacy assessed after the relief phase, together explaining 54% of the variance in perceived treatment efficacy. The association between pre-treatment expectations and perceived pain approached significance (p = 0.057) in the relief phase. Our data from an experimental translational placebo intervention in visceral pain support that reported post-treatment medication efficacy is shaped by pre-treatment expectations. The observation that individuals with higher positive expectations reported less pain and higher treatment satisfaction after pain relief may provide first evidence that perceived symptom improvement may facilitate treatment satisfaction. The immediate experience of symptoms within a given psychosocial treatment context may dynamically change perceptions about treatment, with implications for treatment satisfaction, compliance and adherence of patients with conditions of the gut-brain axis.

Altered Brain Structure in Chronic Visceral Pain: Specific Differences in Gray Matter Volume and Associations With Visceral Symptoms and Chronic Stress.

Structural brain alterations in chronic pain conditions remain incompletely understood, especially in chronic visceral pain. Patients with chronic-inflammatory or functional bowel disorders experience recurring abdominal pain in concert with other gastrointestinal symptoms, such as altered bowel habits, which are often exacerbated by stress. Despite growing interest in the gut-brain axis and its underlying neural mechanisms in health and disease, abnormal brain morphology and possible associations with visceral symptom severity and chronic stress remain unclear. We accomplished parallelized whole-brain voxel-based morphometry analyses in two patient cohorts with chronic visceral pain, i.e., ulcerative colitis in remission and irritable bowel syndrome, and healthy individuals. In addition to analyzing changes in gray matter volume (GMV) in each patient cohort vs. age-matched healthy controls using analysis of covariance (ANCOVA), multiple regression analyses were conducted to assess correlations between GMV and symptom severity and chronic stress, respectively. ANCOVA revealed reduced GMV in frontal cortex and anterior insula in ulcerative colitis compared to healthy controls, suggesting alterations in the central autonomic and salience networks, which could however not be confirmed in supplemental analyses which rigorously accounted for group differences in the distribution of sex. In irritable bowel syndrome, more widespread differences from healthy controls were observed, comprising both decreased and increased GMV within the sensorimotor, central executive and default mode networks. Associations between visceral symptoms and GMV within frontal regions were altered in both patient groups, supporting a role of the central executive network across visceral pain conditions. Correlations with chronic stress, on the other hand, were only found for irritable bowel syndrome, encompassing numerous brain regions and networks. Together, these findings complement and expand existing brain imaging evidence in chronic visceral pain, supporting partly distinct alterations in brain morphology in patients with chronic-inflammatory and functional bowel disorders despite considerable overlap in symptoms and comorbidities. First evidence pointing to correlations with chronic stress in irritable bowel syndrome inspires future translational studies to elucidate the mechanisms underlying the interconnections of stress, visceral pain and neural mechanisms of the gut-brain axis.

When gut feelings teach the brain to fear pain: Context-dependent activation of the central fear network in a novel interoceptive conditioning paradigm.

The relevance of contextual factors in shaping neural mechanisms underlying visceral pain-related fear learning remains elusive. However, benign interoceptive sensations, which shape patients' clinical reality, may context-dependently become conditioned predictors of impending visceral pain. In a novel context-dependent interoceptive conditioning paradigm, we elucidated the putative role of the central fear network in the acquisition and extinction of pain-related fear induced by interoceptive cues and pain-predictive contexts. In this fMRI study involving rectal distensions as a clinically-relevant model of visceroception, N = 27 healthy men and women underwent differential conditioning. During acquisition training, visceral sensations of low intensity as conditioned stimuli (CS) predicted visceral pain as unconditioned stimulus (US) in one context (Con+), or safety from pain in another context (Con-). During extinction training, interoceptive CS remained unpaired in both contexts, which were operationalized as images of different rooms presented in the MRI scanner. Successful contextual conditioning was supported by increased negative valence of Con+ compared to Con- after acquisition training, which resolved after extinction training. Although interoceptive CS were perceived as comparatively pleasant, they induced significantly greater neural activation of the amygdala, ventromedial PFC, and hippocampus when presented in Con+, while contexts alone did not elicit differential responses. During extinction training, a shift from CS to context differentiation was observed, with enhanced responses in the amygdala, ventromedial, and ventrolateral PFC to Con+ relative to Con-, whereas no CS-induced differential activation emerged. Context-dependent interoceptive conditioning can turn benign interoceptive cues into predictors of visceral pain that recruit key regions of the fear network. This first evidence expands knowledge about learning and memory mechanisms underlying interoceptive hypervigilance and maladaptive avoidance behavior, with implications for disorders of the gut-brain axis.

Associative learning and extinction of conditioned threat predictors across sensory modalities.

The formation and persistence of negative pain-related expectations by classical conditioning remain incompletely understood. We elucidated behavioural and neural correlates involved in the acquisition and extinction of negative expectations towards different threats across sensory modalities. In two complementary functional magnetic resonance imaging studies in healthy humans, differential conditioning paradigms combined interoceptive visceral pain with somatic pain (study 1) and aversive tone (study 2) as exteroceptive threats. Conditioned responses to interoceptive threat predictors were enhanced in both studies, consistently involving the insula and cingulate cortex. Interoceptive threats had a greater impact on extinction efficacy, resulting in disruption of ongoing extinction (study 1), and selective resurgence of interoceptive CS-US associations after complete extinction (study 2). In the face of multiple threats, we preferentially learn, store, and remember interoceptive danger signals. As key mediators of nocebo effects, conditioned responses may be particularly relevant to clinical conditions involving disturbed interoception and chronic visceral pain.

Polarity-specific modulation of pain processing by transcranial direct current stimulation - a blinded longitudinal fMRI study.

BACKGROUND: To enrich the hitherto insufficient understanding regarding the mechanisms of action of transcranial direct current stimulation (tDCS) in pain disorders, we investigated its modulating effects on cerebral pain processing using functional magnetic resonance imaging (fMRI). METHODS: Thirteen right-handed healthy participants received 20 min of 1.5 mA tDCS applied over the primary motor cortex thrice and under three different stimulation pattern (1.anodal-tDCS, 2.cathodal-tDCS, and 3.sham-tDCS) in a blinded cross-over design. After tDCS neural response to electric trigeminal-nociceptive stimulation was investigated using a block designed fMRI. RESULTS: Pain stimulation showed a distinct activation pattern within well-established brain regions associated with pain processing. Following anodal tDCS increased activation was detected in the thalamus, basal ganglia, amygdala, cingulate, precentral, postcentral, and dorsolateral prefrontal cortex, while cathodal t-DCS showed decreased response in these areas (pFWE < 0.05). Interestingly the observed effect was reversed in both control conditions (visual- and motor-stimulation). Behavioral data remained unchanged irrespective of the tDCS stimulation mode. CONCLUSIONS: This study demonstrates polarity-specific modulation of cerebral pain processing, in reconfirmation of previous electrophysiological data. Anodal tDCS leads to an activation of the central pain-network while cathodal tDCS does not. Results contribute to a network-based understanding of tDCS's impact on cerebral pain-processing.

From Anticipation to the Experience of Pain: The Importance of Visceral Versus Somatic Pain Modality in Neural and Behavioral Responses to Pain-Predictive Cues.

OBJECTIVE: The aim of this study was to compare behavioral and neural anticipatory responses to cues predicting either somatic or visceral pain in an associative learning paradigm. METHODS: Healthy women (N = 22) underwent functional magnetic resonance imaging. During an acquisition phase, two different visual cues repeatedly signalled either experimental visceral or somatic pain. In a subsequent extinction phase, identical cues were presented without pain. Before and after each phase, cue valence and contingency awareness were assessed on visual analog scales. RESULTS: Visceral compared to somatic pain-predictive cues were rated as more unpleasant after acquisition (visceral, 32.18 ± 13.03 mm; somatic, -18.36 ± 10.36 mm; p = .021) with similarly accurate cue-pain contingencies. After extinction, cue valence returned to baseline for both modalities (visceral, 1.55 ± 9.81 mm; somatic, -18.45 ± 7.12; p = .41). During acquisition, analyses of cue-induced neural responses revealed joint neural activation engaging areas associated with attention processing and cognitive control. Enhanced deactivation of posterior insula to visceral cues was observed, which correlated with enhanced responses within the salience network (anterior cingulate cortex, anterior insula) during visceral compared to somatic pain stimulation. During extinction, both pain modalities induced anticipatory neural activation in the extinction and salience network (all pFWE values < .05). CONCLUSIONS: Conditioned emotional responses to pain-predictive cues are modality specific and enhanced for the visceral modality, suggesting that pain anticipation is shaped by the salience of painful stimuli. Common but also modality-specific neural mechanisms are involved during cue-pain learning, whereas extinction of cued responses seems unaffected by modality. Future research should examine potential implications for the pathophysiology of chronic pain conditions, especially chronic visceral pain.

Cerebral gray matter changes in persistent postural perceptual dizziness.

BACKGROUND: Persistent postural perceptual dizziness (PPPD) is the most common vestibular syndrome in middle-aged patients. Multisensory maladjustment involving alterations of sensory response pattern including vestibular, visual and motion stimuli is thought to be a key pathophysiological correlate of this disorder. OBJECTIVE: We aimed to identify regional gray matter changes in PPPD patients that might be involved in the underlying pathophysiology of this disorder. METHODS: 42 PPPD patients and healthy age and gender matched controls were investigated using magnetic resonance imaging-based voxel-based morphometry. All patients fulfilled the current diagnostic criteria for PPPD, established by the Bárány-Society based on previous criteria for chronic subjective dizziness and phobic postural vertigo. RESULTS: PPPD patients showed gray matter volume decrease in the temporal cortex, cingulate cortex, precentral gyrus, hippocampus, dorsolateral prefrontal cortex, caudate nucleus and the cerebellum. A negative correlation of disease duration and gray matter volume was observed in the visual cortex, supplementary motor area and somatosensory processing structures. CONCLUSIONS: In patients with PPPD areas involved in multisensory vestibular processing show gray matter volume decrease. These brain regions resemble those previously described for other vestibular disorders. Longer duration of disease leads to a more pronounced gray matter alteration, which might represent maladaptive mechanisms within the course of disease.

Greater fear of visceral pain contributes to differences between visceral and somatic pain in healthy women.

This functional magnetic resonance imaging study addressed similarities and differences in behavioral and neural responses to experimental visceral compared with somatic pain stimuli and explored the contribution of fear of pain to differences between pain modalities. In N = 22 healthy women, we assessed blood oxygen level-dependent responses to rectal distensions and cutaneous heat stimuli matched for perceived pain intensity. Fear of pain and pain unpleasantness were assessed before and after scanning. Visceral pain was more fear evoking and more unpleasant, and trial-by-trial intensity ratings failed to habituate across trials (all interactions modality × time: P < 0.01). Differences in fear of pain and pain intensity independently contributed to greater visceral pain unpleasantness (combined regression model: R(2) = 0.59). We observed joint neural activations in somatosensory cortex and frontoparietal attention network (conjunction analysis: all pFWE <0.05), but distensions induced greater activation in somatosensory cortex, dorsal and ventral anterior insula, dorsal anterior and midcingulate cortices, and brainstem, whereas cutaneous heat pain led to enhanced activation in posterior insula and hippocampus (all pFWE <0.05). Fear of visceral pain correlated with prefrontal activation, but did not consistently contribute to neural differences between modalities. These findings in healthy women support marked differences between phasic pain induced by rectal distensions vs cutaneous heat, likely reflecting the higher salience of visceral pain. More studies with clinically relevant pain models are needed to discern the role of fear in normal interindividual differences in the response to different types of pain and as a putative risk factor in the transition from acute to chronic pain.

Short Latency Gray Matter Changes in Voxel-Based Morphometry following High Frequent Visual Stimulation.

Magnetic resonance imaging studies using voxel-based morphometry (VBM) detected structural changes in the human brain within periods of months or weeks. The underlying molecular mechanisms of VBM findings remain unresolved. We showed that simple visual stimulation by an alternating checkerboard leads to instant, short-lasting alterations of the primary and secondary visual cortex detected by VBM. The rapidness of occurrence (i.e., within 10 minutes) rather excludes most of the proposed physiological mechanism such as neural or glial cell genesis/degeneration or synapse turnover. We therefore favour cerebral fluid shifts to be the underlying correlate of the here observed VBM gray matter changes. Fast onset gray matter changes might be one important explanation for the inconsistency of VBM study results that often raise concern in regard to the validity of presented data. This study shows that changes detectable by VBM may occur within a few minutes after physiological stimulation and must be considered in future VBM experiments to avoid misinterpretation of results.

Placebo analgesia in patients with functional and organic abdominal pain: a fMRI study in IBS, UC and healthy volunteers.

OBJECTIVE: Understanding the neural circuitry of placebo analgesia in the context of visceral pain is increasingly important given evidence of clinical benefit of placebo treatment in IBS. This functional MRI study addressed placebo analgesia in IBS, UC and healthy control (HC) volunteers. DESIGN: Painful rectal distensions were delivered in N=17 patients with IBS , N=15 patients with UC in remission, and sex-matched and age-matched HCs in an adaptation phase followed by intravenous application of saline combined with either positive instructions of pain relief (placebo) or neutral instructions (control). Neural activation during cued-pain anticipation and pain was analysed along with ratings of expected and perceived pain and measures of negative affectivity and salivary cortisol concentrations. Correlational analyses between placebo analgesia responses and negative affect were accomplished. RESULTS: HC and UC revealed significant pain inhibition during placebo analgesia, as evidenced by reduced neural activation in pain-related brain areas. In contrast, patients with IBS failed to effectively engage neural downregulation of pain, as evidenced by the absence of placebo-induced changes in distension-induced brain activation, resulting in a significant group difference in the cingulate cortex compared with HC. Depression scores correlated with weaker placebo analgesia, whereas state and trait anxiety were not associated. CONCLUSIONS: Patients with IBS failed to effectively engage neural downregulation of rectal distension-induced pain during placebo analgesia, indicating a specific deficit in cognitive pain inhibition, which may in part be mediated by depression.

Cortical plasticity in episodic and chronic cluster headache.

Cluster headache (CH) is characterized by recurrent episodes of excruciatingly painful, unilateral headache attacks typically accompanied by trigeminal autonomic symptoms. Due to its rhythm with alternating episodes of pain and no-pain, it is an excellent model to investigate whether structural brain changes detected by magnetic resonance based voxel-based-morphometry (VBM) reflect the cause of the disease, may be a consequence of the underlying disease other than pain, or may simply be caused by the sensation of pain itself. We investigated 91 patients with CH in different stages of their disease using VBM and compared them to 78 age- and gender-matched healthy controls. We detected distinct regional gray matter (GM) changes in different brain regions including the temporal lobe, the hippocampus, the insular cortex and the cerebellum. The extent, location and direction of observed GM alterations depended on the state of disease and appeared dynamic in relation to pain state (i.e., pain vs. no-pain). No hypothalamic changes were detected in CH patients compared to healthy controls. The GM changes observed in this study are highly dynamic and thereby reflect the cortical plasticity of the brain in regard to pain. This observed dynamic may provide an explanation of the diverse results of previous VBM studies in pain. Regarding CH the results suggest that the disease is more likely to be caused by a network dysfunction rather than by a single malfunctioning structure.

Acupuncture-related modulation of pain-associated brain networks during electrical pain stimulation: a functional magnetic resonance imaging study.

OBJECTIVE: Findings of existing functional MRI (fMRI) studies on the neural mechanisms that mediate effects of acupuncture analgesia are inconsistent. This study analyzes the effects of manual acupuncture on pain ratings and brain activation in response to experimental, electrical pain stimuli. DESIGN: Fourteen healthy volunteers were examined by using a 1.5-T MRI scanner. The intensity of pain stimuli was adjusted to individual pain ratings on a numeric rating scale. Baseline fMRI was performed during electrical pain stimulation in a blocked design. For the second session, manual acupuncture with repeated stimulation was performed on contralateral acupoints-large intestine 4, liver 3, and stomach 36-before imaging. After imaging, subjective pain ratings and ratings of the de qi sensation were assessed. RESULTS: Compared with baseline, volunteers showed modulated brain activity under pain conditions in the cingulate gyrus, insula, primary somatosensory cortex, and prefrontal areas after the acupuncture session. In accordance with the literature, anterior insular and prefrontal activity seemed to be correlated with acupuncture treatment. CONCLUSION: This study supports the existence of analgesic acupuncture effects that outlast the needling period. Pain-associated brain areas were modulated in direct response to a preceding acupuncture treatment.

Structural correlates of motor adaptation deficits in patients with acute focal lesions of the cerebellum.

Studies of cerebellar patients employing modern lesion-symptom mapping techniques have provided valuable insights into the contribution of the cerebellum to motor adaptation. In patients with chronic focal lesions of the cerebellum, the process of adapting reaching movements to force field (FF) and visuomotor rotation (VM) perturbations relies on different anatomical structures located primarily within the territory of the superior hand area. By contrast, results within the territory of the inferior hand area are less consistent. Compensatory mechanisms may have masked the contribution of the inferior hand area. To test this hypothesis, reaching adaptation to FF and VM perturbations was investigated in 24 patients with acute and subacute lesions of the cerebellum. High-resolution magnetic resonance images were acquired to perform voxel-based lesion-symptom mapping (VLSM). VLSM confirmed that distinct and only partially overlapping areas located primarily within the territory of the superior hand area were crucial for adaptation to FF and VM. More specifically, current results add to previous findings that lobule V is of particular importance in FF adaptation, whereas lobule VI plays a more important role in VM adaptation. No clear evidence for a contribution of the inferior hand area to either task was found. Reach adaptation appears to depend primarily on the superior hand area within the cerebellum.

Central vestibular system modulation in vestibular migraine.

BACKGROUND: Vestibular migraine affects 1% of the general population, and 30%-50% of all migraine patients describe occasionally associated vertigo or dizziness. We aimed to identify brain regions altered in vestibular migraine in order to evaluate the connection between migraine and the vestibular system. METHODS: Seventeen patients with definite vestibular migraine were compared to 17 controls using magnetic resonance imaging-based voxel-based morphometry. RESULTS: We found grey matter (GM) volume reduction in the superior, inferior and middle (MT/V5) temporal gyrus as well as in the mid. cingulate, dorsolateral prefontal, insula, parietal and occipital cortex. A negative correlation of disease duration and GM volume was observed in areas associated with pain and vestibular processing. Moreover, there was a negative correlation between headache severity and prefrontal cortex volume. CONCLUSION: Alterations identified in vestibular migraine resemble those previously described for migraine, but also extend to areas involved in multisensory vestibular control and central vestibular compensation possibly representing the pathoanatomic connection between migraine and the vestibular system.