The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age- and gender-matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus/response-functions for pinprick and dynamic mechanical allodynia, and pain summation (wind-up ratio). QST parameters were region specific and age dependent. Pain thresholds were significantly lower in women than men. Detection thresholds were generally independent of gender. Reference data were normalized to the specific group means and variances (region, age, gender) by calculating z-scores. Due to confidence limits close to the respective limits of the possible data range, heat hypoalgesia, cold hypoalgesia, and mechanical hyperesthesia can hardly be diagnosed. Nevertheless, these parameters can be used for group comparisons. Sensitivity is enhanced by side-to-side comparisons by a factor ranging from 1.1 to 2.5. Relative comparisons across body regions do not offer advantages over absolute reference values. Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes.

Our aim was identify brain areas involved in the premonitory phase of migraine using functional neuroimaging. To this end, we performed positron emission tomography scans with H2(15)O to measure cerebral blood flow as a marker of neuronal activity. We conducted positron emission tomography scans at baseline, in the premonitory phase without pain and during migraine headache in eight patients. We used glyceryl trinitrate (nitroglycerin) to trigger premonitory symptoms and migraine headache in patients with episodic migraine without aura who habitually experienced premonitory symptoms during spontaneous attacks. The main outcome was comparing the first premonitory scans in all patients to baseline scans in all patients. We found activations in the posterolateral hypothalamus, midbrain tegmental area, periaqueductal grey, dorsal pons and various cortical areas including occipital, temporal and prefrontal cortex. Brain activations, in particular of the hypothalamus, seen in the premonitory phase of glyceryl trinitrate-triggered migraine attacks can explain many of the premonitory symptoms and may provide some insight into why migraine is commonly activated by a change in homeostasis.

The runner's high describes a euphoric state resulting from long-distance running. The cerebral neurochemical correlates of exercise-induced mood changes have been barely investigated so far. We aimed to unravel the opioidergic mechanisms of the runner's high in the human brain and to identify the relationship to perceived euphoria. We performed a positron emission tomography "ligand activation" study with the nonselective opioidergic ligand 6-O-(2-[(18)F]fluoroethyl)-6-O-desmethyldiprenorphine ([(18)F]FDPN). Ten athletes were scanned at 2 separate occasions in random order, at rest and after 2 h of endurance running (21.5 +/- 4.7 km). Binding kinetics of [(18)F]FDPN were quantified by basis pursuit denoising (DEPICT software). Statistical parametric mapping (SPM2) was used for voxelwise analyses to determine relative changes in ligand binding after running and correlations of opioid binding with euphoria ratings. Reductions in opioid receptor availability were identified preferentially in prefrontal and limbic/paralimbic brain structures. The level of euphoria was significantly increased after running and was inversely correlated with opioid binding in prefrontal/orbitofrontal cortices, the anterior cingulate cortex, bilateral insula, parainsular cortex, and temporoparietal regions. These findings support the "opioid theory" of the runner's high and suggest region-specific effects in frontolimbic brain areas that are involved in the processing of affective states and mood.

Neuroimaging studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have delineated a human pain network in vivo. Despite the recognition of cerebral structures engaged in pain transmission, the cerebral mechanisms involved in pain modulation are still not well understood. Here, we investigated healthy volunteers using fMRI during experimental heat pain and distraction induced by a visual incongruent color-word Stroop task. A factorial design permitted categorical and covariation analysis of four conditions, namely innocuous and noxious heat; with and without distraction. Pain without distraction evoked an activation pattern similar to that observed in previous neuroimaging pain studies. Distraction was associated with a significant reduction of the visual analogue scale (VAS) ratings for pain intensity and unpleasantness and a reduction of pain-related activation in multiple brain areas, particularly in the so-called 'medial pain system'. Distraction significantly increased the activation of the cingulo-frontal cortex including the orbitofrontal and perigenual anterior cingulate cortex (ACC), as well as the periaquaeductal gray (PAG) and the posterior thalamus. Covariation analysis revealed functional interaction between these structures during pain stimulation and distraction, but not during pain stimulation per se. According to our results, the cingulo-frontal cortex may exert top-down influences on the PAG and posterior thalamus to gate pain modulation during distraction.

Objective.-To assess the relationship between the phenotype of the "visual snow" syndrome, comorbid migraine, and typical migraine aura on a clinical basis and using functional brain imaging.Background.-Patients with "visual snow" suffer from continuous TV-static-like tiny flickering dots in the entire visual field. Most patients describe a syndrome with additional visual symptoms of the following categories: palinopsia ("afterimages" and "trailing"), entopic phenomena arising from the optic apparatus itself (floaters, blue field entoptic phenomenon, photopsia, self-light of the eye), photophobia, nyctalopia (impaired night vision), as well as the non-visual symptom tinnitus. The high prevalence of migraine and typical migraine aura in this population has led to the assumption that "visual snow" is caused by persistent migraine aura. Due to the lack of objective measures, alternative diagnoses are malingering or a psychogenic disorder.Methods.-(1) The prevalence of additional visual symptoms, tinnitus, and comorbid migraine as well as typical migraine aura was assessed in a prospective semi-structured telephone interview of patients with "visual snow." Correlations were calculated using standard statistics with P < .05 being considered statistically significant. (2) Areas with increased brain metabolism in a group of "visual snow" patients in comparison to healthy controls were identified using [ 18 F]-2-fluoro-2-deoxy-Dglucose positron emission tomography and statistical parametric mapping (SPM8 with whole brain analysis; statistical significance was defined by P < .001 uncorrected for multiple comparisons).Results.-(1) Of 120 patients with "visual snow," 70 patients also had migraine and 37 had typical migraine aura. Having comorbid migraine was associated with an increased likelihood of having palinopsia (odds ratio [OR] 2.8; P = .04 for "afterimages" and OR 2.6; P = .01 for "trailing"), spontaneous photopsia (OR 2.9; P = .004), photophobia (OR 3.2; P = .005), nyctalopia (OR 2.7; P = .01), and tinnitus (OR 2.9; P = .006). Typical migraine aura was associated with an increased likelihood of spontaneous photopsia (OR 2.4; P = .04). (2) After adjusting for typical migraine aura, comparison of 17 "visual snow" patients with 17 age and gender matched controls showed brain hypermetabolism in the right lingual gyrus (Montreal Neurological Institute coordinates 16-78-5; k E = 101; ZE = 3.41; P < .001) and the left cerebellar anterior lobe adjacent to the left lingual gyrus (Montreal Neurological Institute coordinates -12-62-9; kE = 152; ZE = 3.28; P = .001).Conclusions.-Comorbid migraine aggravates the clinical phenotype of the "visual snow" syndrome by worsening some of the additional visual symptoms and tinnitus. This might bias studies on "visual snow" by migraineurs offering study participation more likely than non-migraineurs due to a more severe clinical presentation. The independence of entoptic phenomena from comorbid migraine indicates "visual snow" is the main determinant. The hypermetabolic lingual gyrus c...

Background:‘No evidence of disease activity’ (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression (‘NEDA-3’), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity. Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression.Objective:To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 (‘NEDA-4’)Methods:We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%–1.2%).Results:At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001). Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001). NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01–4.41; p < 0.0001).Conclusion:NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies.

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mortality, the modified ICH score had a sensitivity of 98.4% (95% CI ϭ 86.3 to 99.8%), a specificity of 59.1% (95% CI ϭ 42.2 to 74%), a positive predictive value of 69.3% (95% CI ϭ 54.6 to 80.9%), and a negative predictive value of 97.5% (95% CI ϭ 80 to 99.7%). A good outcome (mRS Ͻ2) was noted in 100%, 83.3%, 21.1%, 5.3%, and 0% for patients with 1, 2, 3, 4, and 5 points, respectively. Using a cutoff value of 2 points for good outcome (as in the original publication 4 ), the modified ICH score had a sensitivity of 77.3% (95% CI ϭ 56.6 to 89.9%), a specificity of 95% (95% CI ϭ 83.5 to 98.6%), a positive predictive value of 88.4% (95% CI ϭ 75.5 to 94.9%), and a negative predictive value of 89.5% (95% CI ϭ 68.6 to 97.1%).Discussion. Because in this series all patients had hemorrhages Ͻ30 mL, ICH scores only reflected patient age, stroke severity, and the presence of intraventricular blood; the other components could not be evaluated. ICH scores are accurate for predicting mortality in patients with pontine hemorrhages (figure). In our patients, the original and modified ICH scores had similar sensitivities, specificities, and positive and negative predictive value for mortality. The modified ICH score has the advantage of being a good instrument for predicting the outcome among survivors of the bleeding episode. We found similar figures to those reported, validating these findings and providing evidence that these scores are helpful for the evaluation of patients with infratentorial bleeding. 3,4