Morphological Differentiation of Corneal Inflammatory Cells: Proposal of Pragmatic Protocol.

PURPOSE: Corneal confocal microscopy is a noninvasive imaging technique to analyze corneal nerve fibers and corneal inflammatory cells (CICs). The amount of CICs is a potential biomarker of disease activity in chronic autoinflammatory diseases. To date, there are no standardized criteria for the morphological characterization of CICs. The aim was to establish a protocol for a standardized morphological classification of CICs based on a literature search and to test this protocol for applicability and reliability. METHODS: A systematic review of the literature about definitions of CICs was conducted. Existing morphological descriptions were translated into a structured algorithm and applied by raters. Subsequently, the protocol was optimized by reducing and defining the criteria of the cell types. The optimized algorithm was applied by 4 raters. The interrater reliability was calculated using Fleiss kappa (K). RESULTS: A systematic review of the literature revealed no uniform morphological criteria for the differentiation of the individual cell types in CICs. Our first protocol achieved only a low level of agreement between 3 raters (K = 0.09; 1062 rated cells). Our revised protocol was able to achieve a higher interrater reliability with 3 (K = 0.64; 471 rated cells) and 4 (K = 0.61; 628 rated cells) raters. CONCLUSIONS: The indirect use of criteria from the literature leads to a high error rate. By clearly defining the individual cell types and standardizing the protocol, reproducible results were obtained, allowing the introduction of this protocol for the future evaluation of CICs in the corneal confocal microscopy.

Early Use of Erenumab vs Nonspecific Oral Migraine Preventives: The APPRAISE Randomized Clinical Trial.

Importance: Patients with migraine often cycle through multiple nonspecific preventive medications due to poor tolerability and/or inadequate efficacy leading to low adherence and increased disease burden. Objective: To compare the efficacy, tolerability, patient adherence, and patient satisfaction between erenumab and nonspecific oral migraine preventive medications (OMPMs) in patients with episodic migraine (EM) who had previously failed 1 or 2 preventive treatments. Design, Setting, and Participants: The 12-month prospective, interventional, global, multicenter, active-controlled, randomized clinical trial comparing sustained benefit of 2 treatment paradigms (erenumab qm vs oral prophylactics) in adult episodic migraine patients (APPRAISE) trial was a 12-month open-label, multicenter, active-controlled, phase 4 randomized clinical trial conducted from May 15, 2019, to October 1, 2021. This pragmatic trial was conducted at 84 centers across 17 countries. Overall, participants 18 years or older with a 12-month or longer history of migraine, and 4 or more but fewer than 15 monthly migraine days (MMDs) were included. Interventions: Patients were randomized (2:1) to receive erenumab or OMPMs. Dose adjustment was permitted (label dependent). Main Outcomes and Measures: The primary end point was the proportion of patients completing 1 year of the initially assigned treatment and achieving a reduction of 50% or greater from baseline in MMDs at month 12. Secondary end points included the cumulative mean change from baseline in MMDs during the treatment period and the proportion of responders according to the Patients' Global Impression of Change (PGIC) scale at month 12 for patients taking the initially assigned treatment. Results: A total of 866 patients were screened, of whom 245 failed the screening and 621 completed the screening and baseline period. Of the 621 randomized patients (mean [SD] age, 41.3 [11.2] years; 545 female [87.8%]; 413 [66.5%] in the erenumab group; 208 [33.5%] in the OMPM group), 523 (84.2%) completed the treatment phase, and 98 (15.8%) discontinued the study. At month 12, significantly more patients assigned to erenumab vs OMPM achieved the primary end point (232 of 413 [56.2%] vs 35 of 208 [16.8%]; odds ratio [OR], 6.48; 95% CI, 4.28-9.82; P <.001). Compared with OMPMs, treatment with erenumab showed higher responder rate (314 of 413 [76.0%] vs 39 of 208 [18.8%]; OR, 13.75; 95% CI, 9.08-20.83; P <.001) on the PGIC scale (≥5 at month 12). Significant reduction in cumulative average MMDs was reported with erenumab treatment vs OMPM treatment (-4.32 vs -2.65; treatment difference [SE]: -1.67 [0.35] days; P < .001). Substantially fewer patients in the erenumab arm compared with the OMPM arm switched medication (9 of 413 [2.2%] vs 72 of 208 [34.6%]) and discontinued treatment due to adverse events (12 of 408 [2.9%] vs 48 of 206 [23.3%]). No new safety signals were identified. Conclusions and Relevance: Results of this randomized clinical trial demonstrated that earlier use of erenumab in patients with EM who failed 1 or 2 previous preventive treatments provided greater and sustained efficacy, safety, and adherence than continuous OMPM. Trial Registration: ClinicalTrials.gov Identifier: NCT03927144.

Real-world evidence data on the monoclonal antibody erenumab in migraine prevention: perspectives of treating physicians in Germany.

BACKGROUND: Erenumab, the first-in-class fully human monoclonal antibody targeting the calcitonin gene-related peptide receptor, was shown to be efficacious and safe for the prophylactic treatment of migraine in adults in randomized clinical trials. Large-scale, real-world evidence in multi-centre settings is still needed to confirm these results. Erenumab patient profiles outside clinical trials and physicians' treatment patterns, as well as data from patients treated in Germany, a severely impacted population, are not published yet. METHODS: TELESCOPE was a multi-centre survey gathering real-world data from 45 German headache centres between July 2019 and December 2019. The project consisted of two parts. In the first part, treating physicians shared their experiences on current erenumab treatment with regard to patient profiles, treatment patterns and treatment responses. In the second part, a retrospective chart review was conducted of 542 migraine patients treated with erenumab for at least three months. Treatment responses focused on various aspects of patients' quality of life. RESULTS: The analysis of 542 patients' charts revealed that three-month treatment with erenumab significantly reduced monthly headaches, migraine and acute medication days. Furthermore, headache intensity and frequency were reduced in over 75 % and accompanying aura in 35 % of patients. The clinical global impression scale revealed a general improvement in 91 % of patients. According to the treating physicians' professional judgement, 83 % of patients responded to erenumab and 80 % were satisfied with the treatment. Physicians evaluated restricted quality of life, the number of monthly migraine days and previous, prophylactic treatments as the main components of the current patient profile for monoclonal antibody recipients. Based on the assessment of physicians, erenumab reduced migraine symptoms in 65 % and increased quality of life in more than 75 % of their patients. CONCLUSIONS: TELESCOPE confirms positive treatment responses with erenumab shown in clinical trials in a real-world multi-centre setting. The results show consistently positive experiences of physicians utilizing erenumab in clinical practice and underline that therapy with this monoclonal antibody is effective in migraine patients, particular in those, who have failed several prophylactic therapies.

[Joint position error in patients with headache : Systematic review of the literature and experimental data for patients with chronic migraine]. / Zervikaler "joint position error" bei Kopfschmerzen : Systematische Literaturübersicht und empirische Daten bei chronischer Migräne.

BACKGROUND: Chronic migraine (CM) is a primary headache type associated with a severe reduction in the quality of life. The association of sensorimotor dysfunction in the neck, measured with the joint position error test (JPE), and CM is largely unknown, even though up to 60% of migraine patients report neck pain accompanying the migraine. METHODS: This manuscript reports a systematic review of the literature on JPE in patients with headache as well as data on an observational study. To determine the JPE of migraine patients, 37 subjects with CM were tested and compared with a control group (CG; n = 22). In an additional analysis, CM patients were divided into two subgroups based on the medical treatment approach. The measurements were taken in the three movement dimensions with five repetitions in each direction using a laser pointer fixed to the head. RESULTS: The mean JPE in the sagittal plane was 3.7° (SD ± 1.4°) and 3.1° (SD ± 1.1°) for CM (n = 37) and CG, respectively. In the transverse plane it was measured as 3.7° (SD ± 1.5°) for CM and 3.2° (SD ± 1°) for the CG, while it was 3.6° (SD ± 1.2°; CM) and 3.3° (SD ± 1.1°; CG) in the frontal plane. The between group difference was not significant for all movement planes. When groups according to the treatment regimen, both groups showed similar migraine and neck pain features but the JPE was significantly larger in the CM + BTh group compared to the CM without BTh group and the CG. In the sagittal plane, the JPE was 4.21° (SD ± 1.8°) for the CM + BTh compared to 2.99° (SD ± 1.2°) in CM without BTh and 3.21° (SD ± 1.2°) in the CG (p = 0.0053). The difference between CM + BTh and CM without BTh was 1.52° (p = 0.016) after propensity score matching in the sagittal plane. CONCLUSIONS: Only patients in the CM + BTh group showed a statistically increased JPE. The influence of neck pain does not explain the between group difference. A possible factor is the degree of chronification. This study indicates that the JPE might discriminate a subgroup of migraine patients.

Increased thalamic glutamate/glutamine levels in migraineurs.

BACKGROUND: Increased cortical excitability has been hypothesized to play a critical role in various neurological disorders, such as restless legs syndrome, epilepsy and migraine. Particularly for migraine, local hyperexcitability has been reported. Levels of regional excitatory and inhibitory neurotransmitters are related to cortical excitability and hence may play a role in the origin of the disease. Consequently, a mismatch of the excitatory-inhibitory neurotransmitter network might contribute to local hyperexcitability and the onset of migraine attacks. In this study we sought to assess local levels of glutamate / glutamine (GLX) and gamma-aminobutyric acid (GABA) in the occipital cortex and right thalamus of migraineurs and healthy subjects. METHODS: We measured interictally local biochemical concentrations in the occipital lobe and the right thalamus in patients with migraine (without aura) and healthy controls (HCs) using proton magnetic resonance spectroscopy at 3 T. GLX levels were acquired using PRESS and GABA levels using the GABA-sensitive editing sequence MEGA-PRESS. Regional GLX and GABA levels were compared between groups. RESULTS: Statistical analyses revealed significantly increased GLX levels in both the primary occipital cortex and thalamus. However, we found no group differences in GABA levels for these two regions. Correlation analyses within the migraine group revealed no significant correlations between pain intensity and levels of GLX or GABA in either of the two brain regions. CONCLUSIONS: Further research is needed to investigate the role of GABA/GLX ratios in greater depth and to measure changes in neurotransmitter levels over time, i.e. during migraine attacks and interictally.

Sphenopalatine ganglion stimulation for cluster headache, results from a large, open-label European registry.

BACKGROUND: Cluster headache (CH) is a disabling primary headache disorder characterized by severe periorbital pain. A subset of patients does not respond to established pharmacological therapy. This study examines outcomes of a cohort of mainly chronic CH patients treated with sphenopalatine ganglion (SPG) stimulation. METHODS: Patients were followed in an open-label prospective study for 12 months. Ninety-seven CH patients (88 chronic, 9 episodic) underwent trans-oral insertion of a microstimulator targeting the SPG. Patients recorded stimulation effect prospectively for individual attacks. Frequency, use of preventive and acute medications, headache impact (HIT-6) and quality of life measures (SF-36v2) were monitored at clinic visits. Per protocol, frequency responders experienced ≥ 50% reduction in attack frequency and acute responders treated ≥ 50% of attacks. HIT-6 responders experienced an improvement ≥ 2.3 units and SF-36 responders ≥ 4 units vs. baseline. RESULTS: Eighty-five patients (78 chronic, 7 episodic) remained implanted and were evaluated for effectiveness at 12 months. In total, 68% of all patients were responders, 55% of chronic patients were frequency responders and 32% of all patients were acute responders. 67% of patients using acute treatments were able to reduce the use of these by 52% and 74% of chronic patients were able to stop, reduce or remain off all preventive medications. 59% of all patients were HIT-6 responders, 67% were SF-36 responders. CONCLUSIONS: This open-label registry corroborates that SPG stimulation is an effective therapy for CH patients providing therapeutic benefits and improvements in use of medication as well as headache impact and quality of life.

Improved surgical procedure using intraoperative navigation for the implantation of the SPG microstimulator in patients with chronic cluster headache.

INTRODUCTION: The ATI SPG microstimulator is designed to be fixed on the posterior maxilla, with the integrated lead extending into the pterygopalatine fossa to electrically stimulate the sphenopalatine ganglion (SPG) as a treatment for cluster headache. Preoperative surgical planning to ensure the placement of the microstimulator in close proximity (within 5 mm) to the SPG is critical for treatment efficacy. The aim of this study was to improve the surgical procedure by navigating the initial dissection prior to implantation using a passive optical navigation system and to match the post-operative CBCT images with the preoperative treatment plan to verify the accuracy of the intraoperative placement of the microstimulator. METHODS: Custom methods and software were used that result in a 3D rotatable digitally reconstructed fluoroscopic image illustrating the patient-specific placement with the ATI SPG microstimulator. Those software tools were preoperatively integrated with the planning software of the navigation system to be used intraoperatively for navigated placement. Intraoperatively, the SPG microstimulator was implanted by completing the initial dissection with CT navigation, while the final position of the stimulator was verified by 3D CBCT. Those reconstructed images were then immediately matched with the preoperative CT scans with the digitally inserted SPG microstimulator. This method allowed for visual comparison of both CT scans and verified correct positioning of the SPG microstimulator. RESULTS: Twenty-four surgeries were performed using this new method of CT navigated assistance during SPG microstimulator implantation. Those results were compared to results of 21 patients previously implanted without the assistance of CT navigation. Using CT navigation during the initial dissection, an average distance reduction of 1.2 mm between the target point and electrode tip of the SPG microstimulator was achieved. Using the navigation software for navigated implantation and matching the preoperative planned scans with those performed post-operatively, the average distance was 2.17 mm with navigation, compared to 3.37 mm in the 28 surgeries without navigation. CONCLUSION: Results from this new procedure showed a significant reduction (p = 0.009) in the average distance from the SPG microstimulator to the desired target point. Therefore, a distinct improvement could be achieved in positioning of the SPG microstimulator through the use of intraoperative navigation during the initial dissection and by post-operative matching of pre- and post-operatively performed CBCT scans.

Case report of an alleviation of pain symptoms in hypnic headache via greater occipital nerve block.

Background Hypnic headache is a rare primary headache disorder with a few hundred described cases so far. Due to the fact that this headache disease is rare, there are no placebo-controlled oral medication studies. After all reported oral medication failed to control pain symptoms of a hypnic headache disease, we were able to reduce pain intensity and frequency via two greater occipital nerve (GON) blocks. Case We report on a 74-year-old patient diagnosed with hypnic headache in our headache outpatient department two years ago. Over a course of nine months none of the recommended oral drugs had an effect in pain alleviation and we decided to try an occipital nerve injection therapy. Two GON-blocks then led to a stable and significant pain reduction over the course of six months during monthly follow-ups. Conclusion GON block can be a successful therapeutic approach for the treatment of hypnic headache when oral medication fails.

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.

Local anesthetic sympathectomy restores fMRI cortical maps in CRPS I after upper extremity stellate blockade: a prospective case study.

BACKGROUND: Patients with complex regional pain syndrome type I (CRPS I) show a cortical reorganization with contralateral shrinkage of cortical maps in S1. The relevance of pain and disuse for the development and the maintenance of this shrinkage is unclear. OBJECTIVE: Aim of the study was to assess whether short-term pain relief induces changes in the cortical representation of the affected hand in patients with CRPS type I. STUDY DESIGN: Case series analysis of prospectively collected data. METHODS: We enrolled a case series of 5 consecutive patients with CRPS type I (disease duration 3 - 36 months) of the non-dominant upper-limb and previously diagnosed sympathetically maintained pain (SMP) by reduction of the pain intensity of more than > 30% after prior diagnostic sympathetic block. We performed fMRI for analysis of the cortical representation of the affected hand immediately before as well as one hour after isolated sympathetic block of the stellate ganglion on the affected side. STATISTICS: Wilcoxon-Test, paired t-test, P < 0.05. RESULTS: Pain decrease after isolated sympathetic block (pain intensity on the numerical rating scale (0 - 10) before block: 6.8 ± 1.9, afterwards: 3.8 ± 1.3) was accompanied by an increase in the blood oxygenation level dependent (BOLD) response of cortical representational maps only of the affected hand which had been reduced before the block, despite the fact that clinical and neurophysiological assessment revealed no changes in the sensorimotor function. LIMITATIONS: The interpretation of the present results is partly limited due to the small number of included patients and the missing control group with placebo injection. CONCLUSIONS: The association between recovery of the cortical representation and pain relief supports the hypothesis that pain could be a relevant factor for changes of somatosensory cortical maps in CRPS, and that these are rapidly reversible.

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

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-α) and the chemokines eotaxin, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1ß (MIP-1ß). We found bilaterally increased proinflammatory TNF-α and MIP-1ß 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-α, eotaxin, MCP-1, and MIP-1ß 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.

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

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.

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.

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.

Habituation of the auditory startle response in cervical dystonia and Parkinson's disease.

The auditory startle response (ASR) is a brainstem reflex elicited by an unexpected acoustic stimulus. In focal dystonia (FD), the excitability of brainstem neurons is abnormally enhanced. To identify a possible impact of this pathology on the processing of acoustic stimuli, we studied the habituation of the ASR in patients (n = 11) with FD and compared the findings to those of patients with Parkinson's disease (PD; n = 11) and controls (n = 11). Latencies in FD patients did not differ from those of controls but were delayed in PD patients compared to controls (p < 0.0001). Habituation was normal at the orbicularis oculi muscles but reduced at the sternocleidomastoid muscles in FD (p = 0.005). Habituation in PD was comparable to controls. Normal latencies and sequence activation indicate intact neural pathways mediating the ASR in FD. Impaired habituation of the ASR points towards a reduced inhibition of acoustic stimuli in FD.

Saccade induced cortical activation in patients with post-stroke visual field defects.

Substantial disability in patients with hemianopia results from reduced visual perception. Several studies have shown that these patients have impaired saccades but may improve search strategies with appropriate training of saccades. We used fMRI to study the representation of saccades in patients with post-stroke hemianopia to the left. Brain activation during visually guided saccades was measured in 10 patients with a pure occipital cortical lesion causing homonymous hemianopia and in 10 healthy control subjects. Differences in activation between rest and saccades and between controls and patients were assessed with statistical parametric mapping (SPM'99). In normal subjects, significant activation was found in the frontal and parietal eye fields bilaterally and in the supplementary eye field. These areas were also activated in patients, however, to a lesser degree. In contrast, an area of increased activation in patients was found in the posterior parietal cortex of the (non-affected) left hemisphere. Visual field defects after striate lesions are associated with changes in the frontoparietal network underlying the cortical control of saccades.

Activity of attention related structures in multiple sclerosis patients.

AIMS: It was investigated whether the cortical activity during tasks requiring focused or divided attention is reduced in multiple sclerosis patients with prominent deficits (MS(+D)) and increased in patients without impairment (MS(-D)) in these specific attention functions. METHODS: Six MS(+D) patients with attention deficits, six unimpaired MS(-D) patients, and age-, gender-, and education-matched healthy control subjects were examined with functional magnetic resonance imaging (fMRI). The experimental paradigm consisted of visual tasks requiring focused or divided attention. RESULTS: Performance accuracy and reaction times were impaired in MS(+D) patients. This subgroup showed reduced activation within superior and inferior frontal gyrus during focused attention. Under conditions of divided attention decreased activity was found within middle and inferior frontal gyrus, inferior parietal structures, and occipital areas. No compensatory activity was observed. MS(-D) patients did neither differ in behavioral data nor in cortical activity in attention related structures from control subjects. CONCLUSIONS: The study found evidence for the neural correlate of attentional deficits in MS patients. In patients with specific attention deficits, reduced cortical activity in prefrontal and parietal areas, which are associated with attention and executive control, reflects the patients' reduced performance on a behavioral level. Our findings also suggest impaired top-down attentional control on sensory structures in these patients. In patients without verifiable attention deficits a normal functioning of structures relevant for executive attention was observed. Compensatory activity in these structures as a marker of reorganization in less pronounced stages of the disease was not found.