Arne Knutzen

Manual activity shapes structure and function in contralateral human motor hand area

From longitudinal voxel-based morphometry (VBM) studies we know that relatively short periods of training can increase regional grey matter volume in trained cortical areas. In 14 right-handed patients with writers cramp, we employed VBM to test whether suppression (i.e., immobilization) or enhancement (i.e., training) of manual activity lead to opposing changes in grey matter in the contralateral primary motor hand area (M1(HAND)). We additionally used transcranial magnetic stimulation (TMS) to evaluate concurrent changes in regional excitability. Patients were recruited from a clinical trial which was designed to improve handwriting-associated dystonia. Initially the dystonic hand was immobilized for 4 weeks with the intention to reverse faulty plasticity. After immobilization, patients accomplished a motor re-training for 8 weeks. T1-weighted MRIs of the whole brain and single-pulse TMS measurements of the resting motor threshold (RMT) were performed every 4 weeks. Immobilization of the right hand resulted in a relative grey matter decrease in the contralateral left M1(HAND) along with a decrease in corticomotor excitability as indexed by an increase in RMT. Subsequent training reversed the effects of immobilization, causing an increase in regional grey matter density and excitability of left M1(HAND). The relative changes in grey matter correlated with the relative shifts in RMT. This prospective within-subject VBM study in task-specific hand dystonia shows that the grey matter density of M1(HAND) is dynamically shaped by the level of manual activity. This bi-directional structural plasticity is functionally relevant as local grey matter changes are mirrored by changes in regional excitability.

How to assess motor impairment in writer's cramp

Writers cramp is a task‐specific hand dystonia affecting handwriting. Clinical scores such as the Arm Dystonia Disability Scale (ADDS) or Writers Cramp Rating Scale (WCRS) as well as kinematic analysis of handwriting movements have been used to assess functional impairment in affected patients. In 21 patients with writers cramp and healthy controls, we analyzed the kinematics of writing and cyclic drawing movements. We rated the severity of dystonia using the ADDS and WCRS and correlated the clinical scores with movement kinematics. Mean stroke frequency was significantly reduced in dystonic patients. Drawing movements showed more frequently a decrease in stroke frequency than handwriting movements. During circle drawing, mean vertical peak velocity was more variable in patients relative to controls, indicating an impaired ability to reproduce the same kinematic pattern over time. An increase in vertical writing pressure was only observed during handwriting but not during circle drawing and may reflect a compensatory effort to stabilize the pencil. Kinematic measures and individual ADDS and WCRS scores did not correlate with each other. The lack of correlation is not surprising as ADDS, WCRS, and kinematic analysis probe different aspects of motor impairment. The ADDS characterizes how dystonia affects a set of fine manual tasks, whereas the WCRS scores the manifestation of dystonia during handwriting. Therefore, the clinical scores and kinematic analysis of handwriting provide complementary insights into motor impairment. Future studies need to address which combination of clinical scores and kinematic measures are most appropriate to quantify impairment in writers cramp.

Motor re‐training does not need to be task specific to improve writer's cramp

Previous studies showed a beneficial effect of motor re‐training in task‐specific hand dystonia. Here we examined whether re‐training needs to specifically focus on the task affected by dystonia. 21 patients with writers cramp were randomly assigned to two types of re‐training: One group of patients trained drawing and writing movements using a pen attached to the bottom of a finger splint. The second group used therapeutic putty to train finger movements without exercises of drawing and writing movements. Training lasted for 8 weeks. Before re‐training, affected hand and forearm were immobilized for 4 weeks to facilitate the responsiveness to re‐training. Dystonia was assessed during handwriting using the Writers Cramp Rating Scale. Although no clinical improvement was observed immediately after immobilization, 8 weeks of re‐training improved task‐specific dystonia relative to baseline (P = 0.005). Both training modalities were equally effective. More severely affected patients benefited most. There was no correlation between disease duration and the individual treatment response. Re‐training also improved hand function as indexed by the Arm Dystonia Disability Scale (P = 0.008). Kinematic handwriting analysis showed that re‐training lowered vertical force level and enhanced the fluency of handwriting. We conclude that re‐training does not need to specifically focus on the task affected by dystonia to be clinically effective.

Increased volume and impaired function: the role of the basal ganglia in writer's cramp.

The pathophysiology of writers cramp, a task‐specific dystonia, remains unclear. The objective of this study was to investigate the basal ganglia circuit and the cerebellum during a complex motor sequence learning task carried out with the nonaffected hand in writers cramp patients.

Associative Stimulation of the Supraorbital Nerve Fails to Induce Timing-Specific Plasticity in the Human Blink Reflex

Background Associative high-frequency electrical stimulation (HFS) of the supraorbital nerve in five healthy individuals induced long-term potentiation (LTP)-like or depression (LTD)-like changes in the human blink reflex circuit according to the rules of spike timing-dependent plasticity (Mao and Evinger, 2001). HFS given at the onset of the R2 component of the blink reflex (HFSLTP) produced a lasting facilitation of the R2, whereas HFS given shortly before R2 (HFSLTD) caused a lasting suppression of the R2. In patients with benign essential blepharospasm (BEB), a focal dystonia affecting the orbicularis oculi muscles, HFSLTP induced excessive LTP-like associative plasticity relative to healthy controls, which was normalized after botulinum toxin (BTX) injections (Quartarone et al, 2006). Methodology/Principal Findings We used HFS conditioning of the supraorbital nerve to study homeostatic metaplasticity of the blink reflex circuit in healthy subjects and dystonic patients. On separate days, we tested the conditioning effects on the R2 response and paired-pulse R2 inhibition after (i) HFSLTP, (ii) HFSLTP followed by HFSLTP, and (iii) HFSLTP followed by HFSLTD. Controls also received (iv) HFSLTD alone and (v) a non-intervention protocol. In BEB patients, HFSLTP followed by HFSLTD was given before and after BTX treatment. We were not able to replicate the bidirectional timing-dependent effects of HFSLTP and HFSLTD alone. All HFS protocols produced a non-specific reduction of the R2 response and a relative decrease in paired-pulse inhibition. These R2 changes also occurred in controls when no HFS was applied. There was also no trace of a homeostatic response pattern in BEB patients before or after BTX treatment. Conclusion/Significance Our data challenge the efficacy of associative HFS to produce bidirectional plasticity in the human blink reflex circuit. The non-specific decrease of the R2 response might indicate habituation of the blink reflex following repeated electrical supraorbital stimulation. The increase of inhibition after paired pulse stimulation might reflect homeostatic behaviour to prevent further down regulation of the R2 response to preserve the protection of this adverse-effects reflex.

Slow pre-movement cortical potentials do not reflect individual response to therapy in writer’s cramp

OBJECTIVE To investigate whether movement-related cortical potentials (MRCP) provide a physiological correlate that indicates the response to treatment in patients with writers cramp. METHODS In 21 patients with writers cramp, who underwent 4 weeks of limb immobilization followed by re-training for 8 weeks, we recorded MRCPs preceding a self-initiated brisk finger abduction movement. MRCP measurements of pre-movement activity were performed at baseline, after the end of immobilization and four and 8 weeks of re-training. We examined 12 controls, who received no intervention, twice 4 weeks apart. RESULTS Patients benefited from the therapeutical intervention (Zeuner et al., 2008). They showed no abnormalities of the MRCPs at baseline. In controls, MRCPs did not significantly change after 4 weeks. In patients, immobilization and re-training had no effect on MRCPs. There was no correlation between the severity of dystonic symptoms or the individual treatment response and MRCPs. CONCLUSION MRCPs are stable measures for interventional studies. However, they do not reflect clinical severity of dystonic symptoms or improvement after therapeutic interventions. SIGNIFICANCE This is the first study to investigate MRCPs in a large cohort of patients with writers cramp compared to a control group at different time points. These potentials do not reflect the motor control disorder in patients with writers cramp.

Botulinum neurotoxin treatment improves force regulation in writer's cramp

Writers cramp patients show poor force regulation during handwriting, but also in other experimental tasks requiring fine motor control. Botulinum neurotoxin (BoNT) treatment is clinically effective in a substantial portion of writers cramp patients, but the full mechanism of action remains enigmatic. BoNT possibly influences α- and γ-motoneurons through chemodenervation not only of extra-, but also intrafusal muscle fibres and might thus influence muscle spindle afferents. Hence, BoNT weakens injected muscles, but may also modulate sensory aspects of force control. Ten patients and 18 controls pressed their index finger on a force sensor tracking two visual targets: The first target consisted of five plateaus with successively higher force levels and alternated with ascending ramps. In the second target condition the same successive plateaus were to be reached by abrupt jumps. The generated force displayed as a time dependant curve. Root mean square of the difference between target and produced force level was calculated for each plateau/ramp/jump. Patients were treated with BoNT at week 4 and measured at baseline, weeks 2, 4, 6 and 8. Disturbed force regulation in patients for the plateaus and the second jump at baseline resolved after BoNT treatment, and the root mean square of force deviation decreased for the ramps. Fine force control was within the 95% confidence interval of the control group after treatment. In conclusion, force regulation was disturbed in patients and improved after BoNT treatment. This is not compatible with a simple muscle weakening and might thus reflect improved sensorimotor integration.

Altered brain activation in a reversal learning task unmasks adaptive changes in cognitive control in writer's cramp

Previous receptor binding studies suggest dopamine function is altered in the basal ganglia circuitry in task-specific dystonia, a condition characterized by contraction of agonist and antagonist muscles while performing specific tasks. Dopamine plays a role in reward-based learning. Using fMRI, this study compared 31 right-handed writers cramp patients to 35 controls in reward-based learning of a probabilistic reversal-learning task. All subjects chose between two stimuli and indicated their response with their left or right index finger. One stimulus response was rewarded 80%, the other 20%. After contingencies reversal, the second stimulus response was rewarded in 80%. We further linked the DRD2/ANKK1-TaqIa polymorphism, which is associated with 30% reduction of the striatal dopamine receptor density with reward-based learning and assumed impaired reversal learning in A + subjects. Feedback learning in patients was normal. Blood-oxygen level dependent (BOLD) signal in controls increased with negative feedback in the insula, rostral cingulate cortex, middle frontal gyrus and parietal cortex (pFWE < 0.05). In comparison to controls, patients showed greater increase in BOLD activity following negative feedback in the dorsal anterior cingulate cortex (BA32). The genetic status was not correlated with the BOLD activity. The Brodmann area 32 (BA32) is part of the dorsal anterior cingulate cortex (dACC) that plays an important role in coordinating and integrating information to guide behavior and in reward-based learning. The dACC is connected with the basal ganglia-thalamo-loop modulated by dopaminergic signaling. This finding suggests disturbed integration of reinforcement history in decision making and implicate that the reward system might contribute to the pathogenesis in writers cramp.

Dynamic causal modeling revealed dysfunctional effective connectivity in both, the cortico-basal-ganglia and the cerebello-cortical motor network in writers' cramp

Writers cramp (WC) is a focal task-specific dystonia characterized by sustained or intermittent muscle contractions while writing, particularly with the dominant hand. Since structural lesions rarely cause WC, it has been assumed that the disease might be caused by a functional maladaptation within the sensory-motor system. Therefore, our objective was to examine the differences between patients suffering from WC and a healthy control (HC) group with regard to the effective connectivity that describes causal influences one brain region exerts over another within the motor network. The effective connectivity within a network including contralateral motor cortex (M1), supplementary motor area (SMA), globus pallidus (GP), putamen (PU) and ipsilateral cerebellum (CB) was investigated using dynamic causal modeling (DCM) for fMRI. Eight connectivity models of functional motor systems were compared. Fifteen WC patients and 18 age-matched HC performed a sequential, five-element finger-tapping task with the non-dominant and non-affected left hand within a 3 T MRI-scanner as quickly and accurately as possible. The task was conducted in a fixed block design repeated 15 times and included 30 s of tapping followed by 30 s of rest. DCM identified the same model in WC and HC as superior for reflecting basal ganglia and cerebellar motor circuits of healthy subjects. The M1-PU, as well as M1-CB connectivity, was more strongly influenced by tapping in WC, but the intracortical M1-SMA connection was more facilitating in controls. Inhibiting influences originating from GP to M1 were stronger in controls compared to WC patients whereby facilitating influences the PU exerts over CB and CB exerts over M1 were not as strong. Although the same model structure explains the given data best, DCM confirms previous research demonstrating a malfunction in effective connectivity intracortically (M1-SMA) and in the cortico-basal ganglia circuitry in WC. In addition, DCM analysis demonstrates abnormal reciprocal excitatory connectivity in the cortico-cerebellar circuitry. These results highlight the dysfunctional cerebello-cortical as well as basalganglio-cortical interaction in WC.

Functional impact of different muscle localization techniques for Botulinum neurotoxin A injections in clinical routine management of post-stroke spasticity

ABSTRACT Background: Treatment options for spasticity include intramuscular botulinum neurotoxin A (BoNT-A) injections. Both ultrasound (US) or electromyographic (EMG) guided BoNT-A injections are employed to isolate muscles. To date, most studies have included patients naïve to BoNT-A or following a prolonged wash out phase. Objective: To determine the impact of US/EMG guided BoNT-A injections on function in outpatients with spasticity receiving an established re-injection regime. Methods: Thirty patients post-stroke were investigated in a single-blinded, randomized controlled trial using a cross-over design for the EMG and US and a parallel design for the control group. The Modified Ashworth (MAS), Disability Assessment (DAS), Quality of Life (EQ-5D), self-rating scale and Barthel Index were assessed pre- and post-BoNT-A injections of upper limb muscles by a to the injection technique blinded person. Results: MAS improved in arm, finger and upper limb 4 weeks after BoNT-A treatment. The improvement showed no significant differences between the three injection techniques. Barthel Index, DAS and EQ-5D remained unchanged in all groups. Conclusions: This pilot study questions the impact of the instrumental guided injection techniques on everyday functionality in a routine clinical setting with established re-injection intervals. Larger trials are warranted with patients who are under long-term treatment on a regular basis.