Nina Theysohn

Gray matter volume reduction reflects chronic pain in trigeminal neuralgia.

Trigeminal neuralgia (TN) is supposedly caused by an ectatic blood vessel affecting the trigeminal nerve at the root entry zone of the brain stem. Recent evidence suggests an additional central component within trigeminal pain-processing in the pathophysiology of TN. Therefore, we aimed to identify specific brain regions possibly associated with the development or maintenance of TN using magnetic resonance imaging (MRI) voxel-based morphometry (VBM). Sixty patients with classical TN were compared to 49 healthy controls. Eighteen patients had TN with concomitant constant facial pain, a condition previously described as a predictor of worse treatment outcome. We found gray matter (GM) volume reduction in TN patients compared to healthy controls in the primary somatosensory and orbitofrontal cortices, as well as the in the secondary somatosensory cortex, thalamus, insula, anterior cingulate cortex (ACC), cerebellum, and dorsolateral prefrontal cortex. GM volume decrease within the ACC, parahippocampus, and temporal lobe correlated with increasing disease duration in TN. There were no differences comparing patients with and without concomitant constant facial pain. No GM increase was found comparing patient subgroups with each other and with healthy controls. The observed changes probably reflect the impact of multiple, daily attacks of trigeminal pain in these patients similar to what was previously described in other chronic pain conditions and may be interpreted as adaptation mechanism to chronic pain in regard to neuronal plasticity. The ACC, parahippocampus and temporal lobe volume reduction in parallel with disease duration may point to a pivotal role of these structures in chronic pain.

Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: An fMRI study in healthy placebo responders and nonresponders

Summary In this placebo analgesia study, the expectation of pain relief reduced perceived painfulness of visceral stimuli, which was associated with activity changes in thalamus, and prefrontal and somatosensory cortices. Abstract This functional magnetic resonance imaging study analysed the behavioural and neural responses during expectation‐mediated placebo analgesia in a rectal pain model in healthy subjects. In N = 36 healthy subjects, the blood oxygen level–dependent (BOLD) response during cued anticipation and painful rectal stimulation was measured. Using a within‐subject design, placebo analgesia was induced by changing expectations regarding the probability of receiving an analgesic drug to 0%, 50%, and 100%. Placebo responders were identified by median split based on pain reduction (0% to 100% conditions), and changes in neural activation correlating with pain reduction in the 0% and 100% conditions were assessed in a regions‐of‐interest analysis. Expectation of pain relief resulted in overall reductions in pain and urge to defecate, and this response was significantly more pronounced in responders. Within responders, pain reduction correlated with reduced activation of dorsolateral and ventrolateral prefrontal cortices, somatosensory cortex, and thalamus during cued anticipation (paired t tests on the contrast 0% > 100%); during painful stimulation, pain reduction correlated with reduced activation of the thalamus. Compared with nonresponders, responders demonstrated greater placebo‐induced decreases in activation of dorsolateral prefrontal cortex during anticipation and in somatosensory cortex, posterior cingulate cortex, and thalamus during pain. In conclusion, the expectation of pain relief can substantially change perceived painfulness of visceral stimuli, which is associated with activity changes in the thalamus, prefrontal, and somatosensory cortices. Placebo analgesia constitutes a paradigm to elucidate psychological components of the pain response relevant to the pathophysiology and treatment of chronic abdominal pain.

Fear Conditioning in an Abdominal Pain Model: Neural Responses during Associative Learning and Extinction in Healthy Subjects

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement. In N = 21 healthy humans, visual conditioned stimuli (CS+) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS−) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness. Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS+. During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS− was observed. In the reinstatement phase, a tendency for parahippocampal activation was found. Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain.

Neural mechanisms mediating positive and negative treatment expectations in visceral pain: a functional magnetic resonance imaging study on placebo and nocebo effects in healthy volunteers.

Summary The experience and neural processing of visceral pain can be increased or decreased using nocebo or placebo suggestions. Abstract To elucidate placebo and nocebo effects in visceral pain, we conducted a functional magnetic resonance imaging (fMRI) study to analyze effects of positive and negative treatment expectations in a rectal pain model. In 36 healthy volunteers, painful rectal distensions were delivered after intravenous application of an inert substance combined with either positive instructions of pain relief (placebo group) or negative instructions of pain increase (nocebo group), each compared to neutral instructions. Neural activation during cued‐pain anticipation and pain was analyzed along with expected and perceived pain intensity. Expected and perceived pain intensity were significantly increased in the nocebo group and significantly decreased in the placebo group. In the placebo group, positive expectations significantly reduced activation of the somatosensory cortex during anticipation and of the insula, somatosensory cortex, and amygdala during pain delivery when compared to neutral expectations. Within the nocebo group, negative expectations led to significantly increased insula activation during painful stimulation. Direct group contrasts during expectation modulation revealed significantly increased distension‐induced activation within the somatosensory cortex in the nocebo group. In conclusion, the experience and neural processing of visceral pain can be increased or decreased by drug‐specific expectations. This first brain imaging study on nocebo effects in visceral pain has implications for the pathophysiology and treatment of patients with chronic abdominal complaints such as irritable bowel syndrome.

Brain changes associated with postural training in patients with cerebellar degeneration: a voxel-based morphometry study.

Recent research indicates that physiotherapy can improve motor performance of patients with cerebellar degeneration. Given the known contributions of the cerebellum to motor learning, it remains unclear whether such observable changes in performance are mediated by the cerebellum or cerebral brain areas involved in motor control and learning. The current study addressed this question by assessing the increase in gray matter volume due to sensorimotor training in cerebellar patients using voxel-based morphometry. Nineteen human subjects with pure cerebellar degeneration and matched healthy controls were trained for 2 weeks on a balance task. Postural and clinical assessments along with structural magnetic resonance imaging were performed pretraining and post-training. The main findings were as follows. First, training enhanced balance performance in cerebellar patients. Second, in contrast to controls patients revealed significantly more post-training gray matter volume in the dorsal premotor cortex. Third, training-related increase in gray matter volume was observed within the cerebellum and was more pronounced in controls than in patients. However, statistically cerebellar changes were at the trend level and thus require additional, independent confirmation. We conclude that sensorimotor training of patients with cerebellar neurodegeneration induces gray matter changes primarily within nonaffected neocortical regions of the cerebellar-cortical loop. Residual function of the cerebellum appears to be exploited suggesting either a recovery from degeneration or intact processes of cerebellar plasticity in the remaining healthy tissue.

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.

Visceral sensitivity correlates with decreased regional gray matter volume in healthy volunteers: A voxel-based morphometry study

Summary Increased visceral sensitivity correlates with decreased gray matter volumes in pain‐relevant brain regions in healthy volunteers. ABSTRACT Regional changes in brain structure have been reported in patients with altered visceral sensitivity and chronic abdominal pain, such as in irritable bowel syndrome. It remains unknown whether structural brain changes are associated with visceral sensitivity. Therefore, we present the first study in healthy individuals to address whether interindividual variations in gray matter volume (GMV) in pain‐relevant regions correlate with visceral sensitivity. In 92 healthy young adults (52 female), we assessed rectal sensory and pain thresholds and performed voxel‐based morphometry (VBM) to compute linear regression models with visceral sensory and pain thresholds, respectively, as independent variable and GMV in a priori‐defined regions of interest (ROIs) as dependent variable. All results were familywise error (FWE) corrected at a level of PFWE < .05 and covaried for age. The mean (±SEM) rectal thresholds were 14.78 ± 0.46 mm Hg for first sensation and 33.97 ± 1.13 mm Hg for pain, without evidence of sex differences. Lower rectal sensory threshold (ie, increased sensitivity) correlated significantly with reduced GMV in the thalamus, insula, posterior cingulate cortex, ventrolateral and orbitofrontal prefrontal cortices, amygdala, and basal ganglia (all PFWE < .05). Lower rectal pain threshold was associated with reduced GMV in the right thalamus (PFWE = .051). These are the first data supporting that increased visceral sensitivity correlates with decreased gray matter volume in pain‐relevant brain regions. These findings support that alterations in brain morphology not only occur in clinical pain conditions but also occur according to normal interindividual variations in visceral sensitivity.

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.

7 Tesla MPRAGE imaging of the intracranial arterial vasculature: nonenhanced versus contrast-enhanced.

PURPOSE To intraindividually compare the delineation of intracranial arterial vasculature in nonenhanced versus contrast-enhanced magnetization prepared rapid gradient echo (MPRAGE) imaging at 7 Tesla (T). MATERIALS AND METHODS Sixteen subjects were examined on a 7 T whole-body magnetic resonance system (Magnetom 7T) equipped with a 32-channel transmit/receive head coil. MPRAGE imaging was performed pre- and postcontrast after the application of 0.1 mmol/kg bodyweight gadobutrol. For qualitative analysis, the delineation of the intracranial arteries, overall image quality, and image impairment were assessed in the nonenhanced and contrast-enhanced datasets using a 5-point scale (5 = excellent to 1 = nondiagnostic). Additionally, contrast ratios (CR) of the middle cerebral artery in correlation to surrounding gray matter in nonenhanced and postcontrast images were obtained. For statistical analysis a Wilcoxon signed-rank test was applied. RESULTS Nonenhanced MPRAGE imaging offered an excellent delineation of the central vessel segments of the anterior circulation (mean anterior circulation 4.6) and a moderate- to high-quality assessment of the vessels of the posterior circulation (mean posterior circulation 3.9). Vessel delineation was improved in all assessed segments in the contrast-enhanced datasets, except for the cavernous segment of the internal carotid artery. Quantitative analysis revealed a mild, nonsignificant increase in CR mean values of the M1 segment (CRnonenhanced 0.67; CRcontrast-enhanced 0.69). CONCLUSION Our results demonstrate the high diagnostic value of nonenhanced 7 T MPRAGE imaging for the assessment of the intracranial arterial vasculature, with improved assessment of the peripheral segments because of the application of a contrast agent.

Direct visualization of cerebellar nuclei in patients with focal cerebellar lesions and its application for lesion-symptom mapping

As yet, human cerebellar lesion studies have not taken advantage of direct magnetic resonance imaging (MRI) of the cerebellar nuclei in individual patients. In the present study, susceptibility weighted imaging (SWI) was used to visualize lesions of the dentate nuclei in patients with chronic focal lesions. Fifteen patients with cerebellar lesions either due to stroke or tumor surgery underwent SWI imaging using a 1.5T MRI scanner. Dentate nuclei were seen as hypointensities in all patients. Three of the patients underwent additional SWI imaging at 3T and 7T. Compared to 1.5T, corrugation of the dentate wall was seen with greater precision and the dorsal, iron-poorer part was seen more fully. Lesion-symptom mapping was performed based on the 1.5T MR images. Patients were divided into two groups with and without upper limb ataxia. A region-of-interest-(ROI)-driven normalization technique was used which had initially been developed by Diedrichsen et al. (2011) for functional MRI (fMRI) of the dentate nuclei. Compared to conventional normalization of the cerebellum, overlap of dentate lesions improved and lead to increased sensitivity of lesion-symptom maps. Subtraction analysis revealed that the more dorsal and rostral parts of the dentate nuclei were related to upper limb ataxia. Findings were in good accordance with the dentate hand area shown in recent fMRI studies. These data provide evidence that direct identification of dentate lesions together with the ROI-driven normalization technique allows for improved lesion-symptom mapping at the level of the cerebellar nuclei already at conventional 1.5T MRI field strength.