Till Sprenger

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values.

Abstract 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.

Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain--an fMRI analysis.

&NA; 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.

Specific hypothalamic activation during a spontaneous cluster headache attack

Cluster headache, the most severe pain condition among the primary headache syndromes, is characterized by unilateral excruciating head pain and autonomic dysfunction.1 Functional neuroimaging has recently improved the pathophysiologic understanding of the different primary headache syndromes. Thereby, brainstem activation was found in migraine,2,3⇓ and hypothalamic overactivity was observed in nitrate-induced cluster headache4 and in short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT).5 Results of voxel-based morphometry support the role of the posterior hypothalamus in the pathogenesis of cluster headache because an increased gray matter density has been shown in this structure.6 However, the cluster headache attacks investigated so far were triggered with nitroglycerin (NTG). Although clinical and experimental data show NTG-provoked and spontaneous cluster attacks to be comparable and NTG does not alter regional cerebral blood flow (rCBF) significantly,4 the vasoactive properties of nitrates have to be considered, and data from spontaneous cluster attacks are desirable to confirm the mentioned results. We present a case of a spontaneous cluster attack during an ongoing H215O-PET study. A man (aged 30 years, right-handed, no medication) with a 2-year history of chronic cluster headache …

Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks

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.

Hypothalamic Deep Brain Stimulation in Positron Emission Tomography

Recently, functional imaging data have underscored the crucial role the hypothalamus plays in cluster headache, one of the most severe forms of primary headache. This prompted the application of hypothalamic deep brain stimulation. Yet, it is not apparent how stimulation of an area that is thought to act as a pace-maker for acute headache attacks is able to prevent these attacks from occurring. We addressed this issue by examining 10 operated chronic cluster headache patients, using H215O-positron emission tomography and alternately switching the hypothalamic stimulator on and off. The stimulation induced activation in the ipsilateral hypothalamic gray (the site of the stimulator tip), the ipsilateral thalamus, somatosensory cortex and praecuneus, the anterior cingulate cortex, and the ipsilateral trigeminal nucleus and ganglion. We additionally observed deactivation in the middle temporal gyrus, posterior cingulate cortex, and contralateral anterior insula. Both activation and deactivation are situated in cerebral structures belonging to neuronal circuits usually activated in pain transmission and notably in acute cluster headache attacks. Our data argue against an unspecific antinociceptive effect or pure inhibition of hypothalamic activity. Instead, the data suggest a hitherto unrecognized functional modulation of the pain processing network as the mode of action of hypothalamic deep brain stimulation in cluster headache.

Altered cerebral response to noxious heat stimulation in patients with somatoform pain disorder.

&NA; Idiopathic chronic pain conditions with a mismatch between anatomical abnormalities and symptoms can be categorized as somatoform pain disorder according to the DSM‐IV criteria. A dysfunction of pain processing circuits has been suggested as one underlying pathophysiological factor. There is accumulating evidence for a crucial role of affect regulating brain structures such as the medial frontal cortex in this context. We investigated the cerebral processing of noxious heat stimuli as objective marker for pain sensation in 12 right handed women with somatoform pain disorder fulfilling DSM‐IV criteria and 13 age‐matched healthy volunteers using functional MRI. The average ratings for experimentally induced pain were not significantly different between controls and patients concerning pain intensity and pain unpleasantness. Comparing patients with controls a pain related hypoactive state of the ventromedial prefrontal/orbitofrontal cortex (BA 10/11) and a hyperactive state of the parahippocampal gyrus, amygdala and anterior insula were found in the patient group. Our findings of an altered cerebral processing of experimentally induced pain in patients with somatoform pain disorder support the hypothesis of dysfunctional pain processing, especially in affect regulating regions.

Patients with pain disorder show gray-matter loss in pain-processing structures: a voxel-based morphometric study.

Objective: To investigate whether the functional changes in pain disorder might be reflected by structural brain changes. Pain disorder assessed with the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria is characterized by persistent and distressing chronic pain at one or more body sites which cannot be fully explained by a physiological process or somatic disorder. Psychological factors are thought to play a major role. Recent neuroimaging studies evidenced altered pain processing in patients suffering from this disorder. Methods: Fourteen right-handed women fulfilling the DSM-IV criteria for pain disorder and 25 healthy age-matched women were investigated with magnetic resonance imaging. In the voxel-based morphometry analysis, we compared both groups for changes of gray-matter density. We included age and Beck Depression Inventory scores as nuisance variables to minimize possible confounding effects of age or depressive comorbidity. Results: In the patient group, we found significant gray-matter decreases in the prefrontal, cingulate, and insular cortex. These regions are known to be critically involved in the modulation of subjective pain experiences. Conclusions: In the context of similar results in patients with other functional pain syndromes, such as fibromyalgia and chronic back pain, we suggest that structural changes in fronto-limbic brain circuits represent not only an objective marker of these pain syndromes but also constitute a critical pathophysiological element. These findings represent a further proof of the important role of central changes in pain disorder. DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; ICD-10 = International Statistical Classification of Diseases and Related Health Problems, 10th Revision; VBM = voxel-based morphometry; fMRI = functional magnetic resonance imaging; GM = gray matter; WM = white matter; CSF = cerebrospinal fluid; BDI = Beck Depression Inventory; MNI = standardized reference space defined by the Montreal Neurological Institute; SOMS = screening for somatoform symptoms; PPS = Pain Perception Scale; SCID = Structured Clinical Interview for DSM-IV disorders.

SUNCT: bilateral hypothalamic activation during headache attacks and resolving of symptoms after trigeminal decompression.

Short‐lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a primary head‐pain syndrome, which is often refractory to any medical treatment. Concerning the pathophysiology of SUNCT, hypothalamic involvement ipsilaterally to the pain has been suggested based on the clinical features and one functional imaging case report. Here we now report a new case with SUNCT and the concomitant cerebral activation pattern (fMRI) during the pain attacks. In addition to an activation of several brain structures known to be generally involved in pain processing, bilateral hypothalamic activation occurred during the pain attacks, arguing for a central origin of the headache. Interestingly, this patient became completely pain free after surgical decompression of the ipsilateral trigeminal nerve. We hypothesize that in this case with a central predisposition for trigeminal autonomic cephalgias, a peripheral trigger with ectopic excitation might have contributed to the clinical picture of SUNCT.

Opioidergic activation in the medial pain system after heat pain

Abstract Opioids modulate the affective component of pain and in vivo data indicate that opioids induce activation changes in the rostral ACC, insula and other brain areas. Hence, opioidergic release is to be expected in these brain regions following experimental pain stimulation. We examined healthy volunteers during heat pain and control subjects during rest using [18F]fluorodiprenorphine‐PET. Pain stimulation led to significant reduction of diprenorphine binding in limbic and paralimbic brain areas including the rostral ACC and insula. The finding of altered opioidergic receptor availability in the rostral ACC after experimental nociceptive pain is novel and provides direct evidence for the involvement of this region in endogenous opioidergic inhibition of pain.

Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing–remitting multiple sclerosis

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.