Melanie Lenz

Bilateral somatosensory cortex disinhibition in complex regional pain syndrome type I

Objective: In a previous study, we found bilateral disinhibition in the motor cortex of patients with complex regional pain syndrome (CRPS). This finding suggests a complex dysfunction of central motor-sensory circuits. The aim of our present study was to assess possible bilateral excitability changes in the somatosensory system of patients with CRPS. Methods: We measured paired-pulse suppression of somatosensory evoked potentials in 21 patients with unilateral CRPS I involving the hand. Eleven patients with upper limb pain of non-neuropathic origin and 21 healthy subjects served as controls. Innocuous paired-pulse stimulation of the median nerve was either performed at the affected and the unaffected hand, or at the dominant hand of healthy controls, respectively. Results: We found a significant reduction of paired-pulse suppression in both sides of patients with CRPS, compared with control patients and healthy control subjects. Conclusion: These findings resemble our findings in the motor system and strongly support the hypothesis of a bilateral complex impairment of central motor-sensory circuits in CRPS I.

Local cytokine changes in complex regional pain syndrome type I (CRPS I) resolve after 6 months.

Summary Local cytokine changes were analyzed in CRPS I patients. TNF‐&agr;, MIP‐1&bgr;, and IL‐1RA were changed bilaterally but returned to the level of non‐CRPS patients after 6 months. Abstract There is evidence that inflammatory processes are involved in at least the early phase of complex regional pain syndrome (CRPS). We compared a panel of pro‐ and antiinflammatory cytokines in skin blister fluids and serum from patients with CRPS and patients with upper‐limb pain of other origin (non‐CRPS) in the early stage (< 1 year) and after 6 months of pain treatment. Blister fluid was collected from the affected and contralateral nonaffected side. We used a multiplex‐10 bead array cytokine assay and Luminex technology to measure protein concentrations of the cytokines interleukin‐1 receptor antagonist (IL‐1RA), IL‐2, IL‐6, IL‐8, IL‐10, IL‐12p40, and tumor necrosis factor‐alpha (TNF‐&agr;) and the chemokines eotaxin, monocyte chemotactic protein‐1 (MCP‐1), and macrophage inflammatory protein‐1&bgr; (MIP‐1&bgr;). We found bilaterally increased proinflammatory TNF‐&agr; and MIP‐1&bgr; and decreased antiinflammatory IL‐1RA protein levels in CRPS patients compared to non‐CRPS patients. Neither group showed side differences. After 6 months under analgesic treatment, protein levels of all measured cytokines in CRPS patients, except for IL‐6, significantly changed bilaterally to the level of non‐CRPS patients. These changes were not related to treatment outcome. In serum, only IL‐8, TNF‐&agr;, eotaxin, MCP‐1, and MIP‐1&bgr; were detectable without intergroup differences. Blister fluid of CRPS patients showed a bilateral proinflammatory cytokine profile. This profile seems to be relevant only at the early stage of CRPS. Almost all measured cytokine levels were comparable to those of non‐CRPS patients after 6 months of analgesic treatment and were not related to treatment outcome.

Increased Excitability of Somatosensory Cortex in Aged Humans is Associated with Impaired Tactile Acuity

Aging affects all levels of neural processing, including changes of intracortical inhibition and cortical excitability. Paired-pulse stimulation, the application of two stimuli in close succession, is a useful tool to investigate cortical excitability in humans. The paired-pulse behavior is characterized by the second response being significantly suppressed at short stimulus onset asynchronies. While in rat somatosensory cortex, intracortical inhibition has been demonstrated to decline with increasing age, data from human motor cortex of elderly subjects are controversial and there are no data for the human somatosensory cortex (SI). Moreover, behavioral implications of age-related changes of cortical excitability remain elusive. We therefore assessed SI excitability by combining paired-pulse median nerve stimulation with recording somatosensory evoked potentials in 138 healthy subjects aged 17–86 years. We found that paired-pulse suppression was characterized by substantial interindividual variability, but declined significantly with age, confirming reduced intracortical inhibition in elderly subjects. To link the age-related increase of cortical excitability to perceptual changes, we measured tactile two-point discrimination in a subsample of 26 aged participants who showed either low or high paired-pulse suppression. We found that tactile performance was particularly impaired in subjects showing markedly enhanced cortical excitability. Our data demonstrate that paired-pulse suppression of human SI is significantly reduced in older adults, and that age-related enhancement of cortical excitability correlates with degradation of tactile perception. These findings indicate that cortical excitability constitutes an important mechanism that links age-related neurophysiological changes to behavioral alterations in humans.

Sports and brain morphology – A voxel-based morphometry study with endurance athletes and martial artists

Physical exercises and motor skill learning have been shown to induce changes in regional brain morphology, this has been demonstrated for various activities and tasks. Also individuals with special skills show differences in regional brain morphology. This has been indicated for professional musicians, London taxi drivers, as well as for athletes like dancers, golfers and judokas. However little is known about whether sports with different metabolic profiles (aerobic vs. anaerobic) are associated with different patterns of altered brain morphology. In this cross-sectional study we investigated two groups of high-performance athletes, one group performing sports that are thought to be mainly aerobic, and one group performing sports known to have intermittent phases of anaerobic metabolism. Using high-resolution structural imaging and voxel-based morphometry (VBM), we investigated a group of 26 male athletes consisting of 13 martial artists and 13 endurance athletes as well as a group of non-exercising men (n=13). VBM analyses revealed higher gray matter (GM) volumes in the supplementary motor area/dorsal premotor cortex (BA 6) in both athlete groups as compared to the control group. In addition, endurance athletes showed significantly higher GM volume in the medial temporal lobe (MTL), specifically in the hippocampus and parahippocampal gyrus, which was not seen in the martial arts group. Our data suggest that high-performance sports are associated with changes in regional brain morphology in areas implicated in motor planning and motor learning. In addition high-level endurance sports seem to affect MTL structures, areas that have previously been shown to be modulated by aerobic exercise.

Complex Regional Pain Syndrome Type I Affects Brain Structure in Prefrontal and Motor Cortex

The complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder that mostly occurs after injuries to the upper limb. A number of studies indicated altered brain function in CRPS, whereas possible influences on brain structure remain poorly investigated. We acquired structural magnetic resonance imaging data from CRPS type I patients and applied voxel-by-voxel statistics to compare white and gray matter brain segments of CRPS patients with matched controls. Patients and controls were statistically compared in two different ways: First, we applied a 2-sample ttest to compare whole brain white and gray matter structure between patients and controls. Second, we aimed to assess structural alterations specifically of the primary somatosensory (S1) and motor cortex (M1) contralateral to the CRPS affected side. To this end, MRI scans of patients with left-sided CRPS (and matched controls) were horizontally flipped before preprocessing and region-of-interest-based group comparison. The unpaired ttest of the “non-flipped” data revealed that CRPS patients presented increased gray matter density in the dorsomedial prefrontal cortex. The same test applied to the “flipped” data showed further increases in gray matter density, not in the S1, but in the M1 contralateral to the CRPS-affected limb which were inversely related to decreased white matter density of the internal capsule within the ipsilateral brain hemisphere. The gray-white matter interaction between motor cortex and internal capsule suggests compensatory mechanisms within the central motor system possibly due to motor dysfunction. Altered gray matter structure in dorsomedial prefrontal cortex may occur in response to emotional processes such as pain-related suffering or elevated analgesic top-down control.

Visual paired-pulse stimulation reveals enhanced visual cortex excitability in migraineurs.

Migraine is a common ictal disorder with an interindividual heterogeneous characteristic, whose underlying mechanisms remain elusive. On the one hand migraine is associated with abnormal cortical hyperexcitability. On the other hand, studies reported lower amplitudes of visual‐evoked potentials (VEPs) and concluded that low preactivation levels imply decreased excitability. Here we measured visual cortex excitability and paired‐pulse suppression in subjects suffering from migraine without aura and in a group of aged‐ and gender‐matched healthy subjects to address the relation between activation levels and excitability. To that aim, we analysed amplitudes of VEPs and paired‐pulse suppression evoked by a paired‐pulse stimulation paradigm using stimulus onset asynchronies (SOAs) between 80 and 133 ms. We found that in migraineurs in the interictal state the amplitudes of the first VEP were reduced as compared with healthy subjects by approximately 20%. In the case of paired‐pulse suppression comparable to healthy controls, the second response amplitude should be reduced as well, which was not the case. Instead, the ratio between the first and second VEP was higher than in healthy controls and did not depend on SOA in the range tested, which demonstrates reduced paired‐pulse suppression and therefore implicates increased cortical excitability. Our data show that in migraineurs VEPs were reduced presumably due to reduced activation levels. However, paired‐pulse suppression using short SOAs in the range of 100 ms or less was even higher than in normal subjects. Thus, our data show that signatures of both hyper‐ and hypoexcitability can be found depending on stimulation condition.

Resting BOLD fluctuations in the primary somatosensory cortex correlate with tactile acuity

Sensory perception, including 2-point discrimination (2 ptD), is tightly linked to cortical processing of tactile stimuli in primary somatosensory cortices. While the role of cortical activity in response to a tactile stimulus has been widely investigated, the role of baseline cortical activity is largely unknown. Using resting state fMRI we investigated the relationship between local BOLD fluctuations in the primary somatosensory cortex (the representational field of the hand) and 2 ptD of the corresponding index finger (right and left). Cortical activity was measured using fractional amplitudes of the low frequency BOLD fluctuations (fALFF) and synchronicity using regional homogeneity (ReHo) of the S1 hand region during rest. 2 ptD correlated with higher ReHo values in the representational areas of the contralateral S1 cortex (left hand: p = .028; right hand: p = .049). 2 ptD additionally correlated with higher fALFF in the representational area of the left hand (p = .007) and showed a trend for a significant correlation in the representational area of the right hand (p = .051). Thus, higher BOLD amplitudes and synchronicity at rest, as measures of cortical activity and synchronicity, respectively, are related to better tactile discrimination abilities of the contralateral hand. Our findings extend the relationship seen between spontaneous BOLD fluctuations and sensory perception.

Multichannel SEP-recording after paired median nerve stimulation suggests origin of paired-pulse inhibition rostral of the brainstem

Paired-pulse techniques are a common tool to investigate the excitability of the cerebral cortex. Whereas in the motor system short interval intracortical inhibition assessed by paired-pulse transcranial magnetic stimulation clearly could be demonstrated to be generated within the motor cortex, the mechanism of paired-pulse inhibition measured over the somatosensory cortex after paired-pulse median nerve stimulation is less clear. The aim of this study was to further investigate the level of somatosensory processing where this paired-pulse inhibition is generated. We applied single and paired electrical stimulation of the median nerve with an interstimulus interval of 30ms. Somatosensory evoked potentials were recorded over the brachial plexus, the cranial cervical medulla and the primary somatosensory cortex. We analyzed peak-to-peak amplitudes evoked by the second stimulus of paired-pulse stimulation after digital subtraction of a single pulse (A2s), and referred it to the first response before linear subtraction (A1). Paired-pulse inhibition was expressed as a ratio (A2s/A1) of the amplitudes of the second (A2s) and the first (A1) peaks. We found a significant reduction of A2s as compared to A1 over S1, but no significant difference between A1 and A2s over brachial plexus and cranial medulla. In addition, the cortical amplitude ratio A2s/A1 was significantly reduced compared to the amplitude ratios over cranial medulla and brachial plexus. These results suggest that the underlying inhibitory mechanisms are generated rostral to the brainstem nuclei, probably due to the activity of thalamic or intracortical inhibitory interneurons.

Influence of parameter settings on paired-pulse-suppression in somatosensory evoked potentials: A systematic analysis

OBJECTIVE Paired-pulse somatosensory evoked potentials (SEPs) are a common tool to investigate excitability in the human somatosensory cortex. Comparing literature about paired-pulse SEP, there is no standard set of stimulation parameters, while little is known about the influence of stimulation parameters on paired-pulse suppression. METHODS We analyzed changes of paired-pulse ratios by varying repetition rates from 1 to 9Hz, and using stimulus intensities of 250% of the sensory threshold and 100%, 120%, and 140% of the motor threshold, which are most frequently used in studies using paired-pulse SEPs. RESULTS We found a significant effect of repetition rate on paired-pulse suppression with increasing paired-pulse ratios from 1 to 9Hz, which is mainly caused by a change of single pulse amplitudes. We found no difference in paired-pulse suppression at the tested stimulation intensities. CONCLUSIONS The extent of paired-pulse ratios across different studies should be interpreted with caution due to the high dependence on repetition rate, while the results at the commonly used stimulus intensities are comparable. SIGNIFICANCE For an optimized parameter setting with sufficient paired-pulse suppression, we suggest a stimulation rate of 1 or 3Hz and a stimulation intensity of 250% of sensory threshold or slightly above motor threshold.

Local GABA Concentration Predicts Perceptual Improvements After Repetitive Sensory Stimulation in Humans

Learning mechanisms are based on synaptic plasticity processes. Numerous studies on synaptic plasticity suggest that the regulation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays a central role maintaining the delicate balance of inhibition and excitation. However, in humans, a link between learning outcome and GABA levels has not been shown so far. Using magnetic resonance spectroscopy of GABA prior to and after repetitive tactile stimulation, we show here that baseline GABA+ levels predict changes in perceptual outcome. Although no net changes in GABA+ are observed, the GABA+ concentration prior to intervention explains almost 60% of the variance in learning outcome. Our data suggest that behavioral effects can be predicted by baseline GABA+ levels, which provide new insights into the role of inhibitory mechanisms during perceptual learning.