P. Stude

Immobilization Impairs Tactile Perception and Shrinks Somatosensory Cortical Maps

Use is a major factor driving plasticity of cortical processing and cortical maps. As demonstrated of blind Braille readers and musicians, long-lasting and exceptional usage of the fingers results in the development of outstanding sensorimotor skills and in expansions of the cortical finger representations. However, how periods of disuse affect cortical representations and perception in humans remains elusive. Here, we report that a few weeks of hand and arm immobilization by cast wearing significantly reduced hand use and impaired tactile acuity, associated with reduced activation of the respective finger representations in the somatosensory cortex (SI), measured by functional magnetic resonance imaging. Hemodynamic responses in the SI correlated positively with hand-use frequency and negatively with discrimination thresholds, indicating that reduced activation was most prominent in subjects with severe perceptual impairment. We found, strikingly, compensatory effects on the contralateral, healthy hand consisting of improved perceptual performance compared to healthy controls. Two to three weeks after cast removal, perceptual and cortical changes recovered, whereas tactile acuity on the healthy side remained superior to that on the formerly immobilized side. These findings suggest that brief periods of reduced use of a limb have overt consequences and thus constitute a significant driving force of brain organization equivalent to enhanced use.

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.

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.

Temporal summation of trigeminal pain in human anterior cingulate cortex

Temporal summation of nociceptive inputs in trigeminal networks can induce central sensitization and maintain chronic pain. We combined functional magnetic resonance imaging and electrically evoked pain-related potentials (PREP) in healthy human subjects to identify brain regions involved in temporal summation of nociceptive inputs. We stimulated the skin innervated by the ophthalmic division of the trigeminal nerve with trains of three, seven and eleven similar nociceptive pulses, while recording evoked hemodynamic or electrical brain responses. We found that PREP amplitudes and pain ratings increased in parallel with increasing train length. Strikingly, only hemodynamic responses in the posterior part of the anterior cingulate cortex (pACC) scaled with individual pain ratings on a verbal rating scale (VRS) and electrically evoked responses (i.e., PREP amplitudes for the three train lengths). These findings indicate that pACC codes temporal summation of trigeminal nociception and in this regard may be important for the development of central sensitization observed in chronic head and facial pain.

Intact 2D-form recognition despite impaired tactile spatial acuity in complex regional pain syndrome type I

Summary Despite impaired tactile spatial acuity, CRPS‐I patients demonstrate intact form recognition performance as long as the spacing of the dot patterns are above the spatial resolution performance of the patients. ABSTRACT Tactile acuity measured by 2‐point discrimination performance is impaired in patients with complex regional pain syndrome type I (CRPS‐I). This is mirrored by pain‐associated shrinkage of the cortical representation of the affected limb. We investigated whether, also, more complex tactile performance assessed by a dynamic 2D‐form perception task is disturbed in CRPS‐I patients. Therefore, we developed a Braille‐like recognition task (BT) for geometrical dot pattern identification by dynamic touch. We studied 47 healthy volunteers (Study I) and compared them to 16 CRPS‐I patients (Study II). Besides recognition time and error quote of the BT, we assessed static 2‐point discrimination thresholds (TPDT). In healthy subjects, the performance in the BT correlated significantly with age and TPDT. In CRPS patients, TPDT was significantly increased on the affected side compared to sex‐ and age‐matched controls from study I (2.98 ± 0.84 mm vs 2.05 ± 0.82 mm, P < 0.01). The performance in the BT was not impaired in CRPS‐I patients (compared to sex‐ and age‐matched controls from study I) and was not correlated to the TPDT. The intact 2D‐form recognition ability in CRPS‐I patients might be explained by intact dynamic tactile and proprioceptive functions, which appear to be uncompromised by the impaired static tactile perception, provided that the spacing of the dot pattern is above the individual tactile acuity. These intact 2D‐form perception capacities may also be related to higher sensory integration functions like the visual system and intact semantic understanding, which may be spared by the cortical reorganization phenomena in CRPS‐I.

Behavioural and neurophysiological markers reveal differential sensitivity to homeostatic interactions between centrally and peripherally applied passive stimulation

Repetitive transcranial magnetic stimulation (rTMS) is an effective tool for inducing functional plastic changes in the brain. rTMS can also potentiate the effects of other interventions such as tactile coactivation, a form of repetitive stimulation, when both are applied simultaneously. In this study, we investigated the interaction of these techniques in affecting tactile acuity and cortical excitability, measured with somatosensory evoked potentials after paired median nerve stimulation. We first applied a session of 5‐Hz rTMS, followed by a session of tactile repetitive stimulation, consisting of intermittent high‐frequency tactile stimulation (iHFS) to a group of 15 healthy volunteers (“rTMS + iHFS” group). In a second group (“rTMS w/o iHFS”), rTMS was applied without iHFS, with a third assessment performed after a similar wait period. In the rTMS w/o iHFS group, the 5‐Hz rTMS induced an increase in cortical excitability that continued to build for at least 25 min after stimulation, with the effect on excitability after the wait period being inversely correlated to the baseline state. In the rTMS + iHFS group, the second intervention prevented the continued increase in excitability after rTMS. In contrast to the effect on cortical excitability, rTMS produced an improvement in tactile acuity that remained stable until the last assessment, independent of the presence or absence of iHFS. Our results show that these methods can interact homeostatically when used consecutively, and suggest that different measures of cortical plasticity are differentially susceptible to homeostatic interactions.

Quantification of acute neck pain following whiplash injury by computer-aided pressure algesimetry

Until now the clinical investigation of cervical pain due to whiplash injury is mainly based on finger palpation. The present study introduces a PC-interactive pressure algesimetry to standardize cervical pain measurement. Pressure pain scores of the splenius and trapezius muscles of 23 patients with an acute cervical syndrome after whiplash injury were compared to those of 24 healthy subjects. The pressure painfulness of neck and shoulder muscles was significantly increased in whiplash patients. The splenii muscles showed an equally increased muscle pain whereas the trapezii muscles showed a left-sided preponderance of painfulness, possibly due to the seat belt position in this group of motor vehicle drivers. The computer-interactive pressure algesimetry enables a standardized and rater-independent quantification of the cervical syndrome with neck and shoulder pain caused by whiplash injury.

A single dose of lorazepam reduces paired-pulse suppression of median nerve evoked somatosensory evoked potentials

Paired‐pulse behaviour in the somatosensory cortex is an approach to obtain insights into cortical processing modes and to obtain markers of changes of cortical excitability attributable to learning or pathological states. Numerous studies have demonstrated suppression of the response to the stimulus that follows a first one after a short interval, but the underlying mechanisms remain elusive, although there is agreement that GABAergic mechanisms seem to play a crucial role. We therefore aimed to explore the influence of the GABAA agonist lorazepam on paired‐pulse somatosensory evoked potentials (SEPs). We recorded and analysed SEPs after paired median nerve stimulation in healthy individuals before and after they had received a single dose of 2.5 mg of lorazepam as compared with a control group receiving placebo. Paired‐pulse suppression was expressed as a ratio of the amplitudes of the second and the first peaks. We found that, after lorazepam application, paired‐pulse suppression of the cortical N20 component remained unchanged, but suppression of the N20–P25 complex was significantly reduced, indicative of GABAergic involvement in intracortical processing. Our data suggest that lorazepam most likely enhances inhibition within the cortical network of interneurons responsible for creating paired‐pulse suppression, leading to reduced inhibitory drive with a subsequently reduced amount of suppression. The results provide further evidence that GABAA‐mediated mechanisms are involved in the generation of median nerve evoked paired‐pulse suppression.