Florian T. Nickel

Mechanisms of neuropathic pain.

Neuropathic pain is a disease of global burden. Its symptoms include spontaneous and stimulus-evoked painful sensations. Several maladaptive mechanisms underlying these symptoms have been elucidated in recent years: peripheral sensitization of nociception, abnormal excitability of afferent neurons, central sensitization comprising pronociceptive facilitation, disinhibition of nociception and central reorganization processes, and sympathetically maintained pain. This review aims to illustrate these pathophysiological principles, focussing on molecular and neurophysiological findings. Finally therapeutic options based on these findings are discussed.

Brain activity during sympathetic response in anticipation and experience of pain

Pain is a multidimensional phenomenon with sensory, affective, and autonomic components. Here, we used parametric functional magnetic resonance imaging (fMRI) to correlate regional brain activity with autonomic responses to (i) painful stimuli and to (ii) anticipation of pain. The autonomic parameters used for correlation were (i) skin blood flow (SBF) and (ii) skin conductance response (SCR). During (i) experience of pain and (ii) anticipation of pain, activity in the insular cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), posterior parietal cortex (PPC), secondary somatosensory cortex (S2), thalamus, and midbrain correlated with sympathetic outflow. A conjunction analysis revealed a common central sympathetic network for (i) pain experience and (ii) pain anticipation with similar correlations between brain activity and sympathetic parameters in the anterior insula, prefrontal cortex, thalamus, midbrain, and temporoparietal junction. Therefore, we here describe shared central neural networks involved in the central autonomic processing of the experience and anticipation of pain. Hum Brain Mapp, 2013.

Neuropathische Schmerzsyndrome und Neuroplastizität in der funktionellen Bildgebung

Neuropathic pain syndromes are characterised by the occurrence of spontaneous ongoing and stimulus-induced pain. Stimulus-induced pain (hyperalgesia and allodynia) may result from sensitisation processes in the peripheral (primary hyperalgesia) or central (secondary hyperalgesia) nervous system. The underlying pathophysiological mechanisms at the nociceptor itself and at spinal synapses have become better understood. However, the cerebral processing of hyperalgesia and allodynia is still controversially discussed. In recent years, neuroimaging methods (functional magnetic resonance imaging, fMRI; magnetoencephalography, MEG; positron emission tomography, PET) have provided new insights into the aberrant cerebral processing of neuropathic pain. The present paper reviews different cerebral mechanisms contributing to chronicity processes in neuropathic pain syndromes. These mechanisms include reorganisation of cortical somatotopic maps in sensory or motor areas (highly relevant for phantom limb pain and CRPS), increased activity in primary nociceptive areas, recruitment of new cortical areas usually not activated by nociceptive stimuli and aberrant activity in brain areas normally involved in descending inhibitory pain networks. Moreover, there is evidence from PET studies for changes of excitatory and inhibitory transmitter systems. Finally, advanced methods of structural brain imaging (voxel-based morphometry, VBM) show significant structural changes suggesting that chronic pain syndromes may be associated with neurodegeneration.

Brain correlates of short‐term habituation to repetitive electrical noxious stimulation

Habituation to repetitive noxious stimuli is a well‐known phenomenon. We investigated brain correlates of habituation to pain in a transdermal electrical pain model using functional magnetic resonance imaging (fMRI).

Neuropathic pain and neuroplasticity in functional imaging studies

Neuropathic pain syndromes are characterised by the occurrence of spontaneous ongoing and stimulus-induced pain. Stimulus-induced pain (hyperalgesia and allodynia) may result from sensitisation processes in the peripheral (primary hyperalgesia) or central (secondary hyperalgesia) nervous system. The underlying pathophysiological mechanisms at the nociceptor itself and at spinal synapses have become better understood. However, the cerebral processing of hyperalgesia and allodynia is still controversially discussed. In recent years, neuroimaging methods (functional magnetic resonance imaging, fMRI; magnetoencephalography, MEG; positron emission tomography, PET) have provided new insights into the aberrant cerebral processing of neuropathic pain. The present paper reviews different cerebral mechanisms contributing to chronicity processes in neuropathic pain syndromes. These mechanisms include reorganisation of cortical somatotopic maps in sensory or motor areas (highly relevant for phantom limb pain and CRPS), increased activity in primary nociceptive areas, recruitment of new cortical areas usually not activated by nociceptive stimuli and aberrant activity in brain areas normally involved in descending inhibitory pain networks. Moreover, there is evidence from PET studies for changes of excitatory and inhibitory transmitter systems. Finally, advanced methods of structural brain imaging (voxel-based morphometry, VBM) show significant structural changes suggesting that chronic pain syndromes may be associated with neurodegeneration.

Inhibition of hyperalgesia by conditioning electrical stimulation in a human pain model.

&NA; Sensory gain (ie, hyperalgesia) and sensory loss (ie, hypoalgesia) are key features of neuropathic pain syndromes. Previously, we showed that conditioning electrical stimuli may provoke either sensory gain or decline in healthy subjects, depending on the stimulation frequencies applied. In the present study we sought to determine whether sensory decline induced by 20‐Hz electrical stimulation preferentially of peptidergic C‐nociceptors induces antihyperalgesic effects in a transdermal electrical pain model. Twelve healthy volunteers underwent 0.5‐Hz noxious electrical stimulation of the right volar forearm for 35 minutes, leading to secondary mechanical hyperalgesia. In 5 sessions the 0.5‐Hz stimulus was applied either alone (Stim1) or with concurrent noxious 20‐Hz stimulation at different sites (Stim2: ipsilateral 5 cm distance; Stim3: ipsilateral 10 cm distance; Stim4: contralateral arm; Stim5: contralateral dorsal foot). Close concurrent 20‐Hz stimulation (Stim2) inhibited the development of hyperalgesia, as measured using the mechanical pain threshold, while remote and contralateral 20‐Hz stimulation had no impact on mechanical pain threshold. However, after ipsilateral (stim2, stim3) and contralateral (stim4) forearm stimulation the area of hyperalgesia around the 0.5‐Hz stimulation site was significantly reduced. Thus, antihyperalgesia was induced in a homotopic and in a heterotopic ipsisegmental manner. Underlying mechanisms may include neuroplastic changes of pro‐ and antinociceptive systems at the spinal or supraspinal level. We conclude that 20‐Hz noxious electrical stimulation may represent a neurostimulatory paradigm with antihyperalgesic properties. These findings may thus be of relevance for the future therapy of neuropathic pain syndromes as well. Sensory decline induced by 20‐Hz electrical stimulation of peptidergic C‐nociceptors induces antihyperalgesic effects in a transdermal electrical pain model.

C9ORF72-ALS: P62- and ubiquitin-aggregation pathology in skeletal muscle

A pathological GGGGCC-hexanucleotide-repeat-expansion in the C9ORF72-gene has been described to underlie several neurodegenerative diseases. It has been found to be the most frequent genetic cause of sporadic and familial amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). Several pathogenic mechanisms have been suggested, including haploinsufficiency, abnormal sequestering of RNA-binding proteins by nuclear GGGGCC-repeat RNA-foci, and pathological dipeptiderepeat proteins derived from non–ATG-initiated translation from the expanded GGGGCC-repeat of the C9ORF72-gene. We report a 59-year-old German man with the rare co-occurrence of C9ORF72-ALS and systemic sarcoidosis. In January 2010, he presented initially with a 2-month history of myalgias and progressive muscle weakness affecting the distal legs. A brother died at age 59 due to bulbar ALS, and his mother, who suffered from progressive dementia, died at age 62. Key findings of his initial neurological work-up included atrophic paresis of distal legs, generalized fasciculations, attenuated ankle reflexes, slightly elevated serum creatine kinase levels, electromyographic evidence of acute and chronic denervation in tibialis anterior and gastrocnemius muscles, and prolonged central motor conduction times to the lower extremities. A familial ALS-FTD-syndrome was suspected. Because of rapid clinical deterioration and a diagnosis of cutaneous sarcoidosis in May 2010, he was reevaluated. In June 2010, a diagnosis of systemic sarcoidosis was made on the basis of mediastinal lymphadenopathy, bronchoalveolar lavage fluid lymphocytosis, and a diagnostic biopsy of the gastrocnemius muscle. In addition to typical sarcoid granulomata, the muscle biopsy showed mild neurogenic changes (Fig. 1A). Because a contribution of muscular or neuronal sarcoidosis to the development of atrophic muscle weakness could not be ruled out, immunosuppressive therapy was initiated, but it was stopped in February 2012 when a second biopsy showed marked neurogenic changes but no evidence of active sarcoidosis (Fig. 1B). At the same time, genetic analysis revealed a pathological hexanucleotide-repeat expansion of more than 600 repeats in C9ORF72. In July 2012, the patient died of respiratory failure. We investigated both muscle biopsies with regard to putative C9ORF72-, p62-, ubiquitin-, and TDP43-pathology. Immunoblot analysis of total muscle protein extracts from both biopsies showed a reduction of the long 54-kDa C9ORF72-isoform (Fig. 1E), which is in keeping with the hypothesis that C9ORF72-pathogenesis is due to haploinsufficiency. Indirect immunofluorescence analysis showed several muscle fibers with p62and ubiquitin-positive cytoplasmic aggregates (Fig. 1C,D), whereas TDP-43 staining did not show any overt pathology. These findings were also mirrored in immunoblots, which revealed increased levels of p62 and ubiquitinated proteins in both muscle biopsies compared with normal muscle controls and a case of muscle sarcoidosis with neurogenic changes (Fig. 1E). These findings indicate that the muscular cytoplasmic inclusions mirror the pathognomonic p62-positive, TDP43-negative neuronal cytoplasmic inclusions which have been found in the cerebral cortex, basal ganglia, hippocampus, and cerebellum of C9ORF72-ALS patients. With regard to the diagnosis and pathogenesis of the disorder, analysis of haploinsufficiency and protein aggregation pathology in skeletal muscle tissue from additional patients with pathological hexanucleotide-repeat-expansion of the C9ORF72-gene is warranted.

Hypertrichosis in alopecia universalis and complex regional pain syndrome

This 46-year-old woman developed complex regional pain syndrome (CRPS) I in the right hand after distortion of the wrist. Ten …

Neuromodulation of Electrically Induced Hyperalgesia in the Trigeminocervical System

Trigeminal and cervical afferents converge on neurons of the trigeminocervical complex and may significantly alter the function of these neurons. This interaction may have implications for the pathophysiology and treatment of primary headache disorders. Therefore, the aim of this work was to study pain modulatory mechanisms within the trigeminocervical complex.

Effects of Different Anesthetics on Pain Processing in an Experimental Human Pain Model

After surgical procedures, anesthesia itself may affect pain perception. Particularly, there is increasing evidence that opioids not only have analgesic effects but also provoke pronociceptive changes, that is, opioid‐induced hyperalgesia. We investigated the effect of different anesthetic regimens on pain processing in volunteers using a transdermal electrical pain model. In this model, stimulation of epidermal nerve fibers representing mainly peptidergic C‐nociceptors leads to secondary hyperalgesia and habituation to the stimulus.