Integrating plant physiology into simulation of fire behavior and effects.

Wildfires are a global crisis, but current fire models fail to capture vegetation response to changing climate. With drought and elevated temperature increasing the importance of vegetation dynamics to fire behavior, and the advent of next generation models capable of capturing increasingly complex physical processes, we provide a renewed focus on representation of woody vegetation in fire models. Currently, the most advanced representations of fire behavior and biophysical fire effects are found in distinct classes of fine-scale models and do not capture variation in live fuel (i.e. living plant) properties. We demonstrate that plant water and carbon dynamics, which influence combustion and heat transfer into the plant and often dictate plant survival, provide the mechanistic linkage between fire behavior and effects. Our conceptual framework linking remotely sensed estimates of plant water and carbon to fine-scale models of fire behavior and effects could be a critical first step toward improving the fidelity of the coarse scale models that are now relied upon for global fire forecasting. This process-based approach will be essential to capturing the influence of physiological responses to drought and warming on live fuel conditions, strengthening the science needed to guide fire managers in an uncertain future.

Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction.

BACKGROUND: Protein synthesis is a tightly controlled process, involving a host of translation-initiation factors and microRNA-associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental-delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability. OBJECTIVE: We sought to characterize the role of EIF4A2 variants in dystonic conditions. METHODS: We undertook an unbiased search for likely deleterious variants in mutation-constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient-derived fibroblasts. RESULTS: We report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence- to adulthood-onset dystonia with tremor. In patient-derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4-Not, the complex that interacts with eIF4A2 to mediate microRNA-dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4-Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia-affected pedigrees. CONCLUSIONS: Our findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia-tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later-onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset.

Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites, which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1× log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (P = 0.003)-being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.

Multimodal assessment of autonomic dysfunction in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with predominant progressive degeneration of motor neurons and motor deficits, but non-motor symptoms (NMS) such as cognitive and behavioural deficits are frequent and underestimated in current diagnostic pathways. Autonomic dysfunction has occasionally been described, although its frequency and relevance are unclear. The aim of this study was to investigate the role of the autonomic nervous system in ALS using a multimodal approach. METHODS: Thirty-seven ALS patients and 40 healthy sex- and age-matched controls were included. NMS were studied with the NMS assessment scale for Parkinson's disease and an autonomic subscale was calculated. Cardioautonomic innervation at rest and whilst standing was assessed by different parameters of heart rate variability. Morphological changes (cross-sectional area) of the vagus and median nerves for control were measured with high-resolution ultrasound. RESULTS: Non-motor symptoms in general were more frequent in ALS patients and correlated inversely with the ALS Functional Rating Scale whereas the autonomic subscore of the NMS assessment scale for Parkinson's disease did not differ between the two groups and was not related to functional impairment. Cardioautonomic assessment solely revealed an increased heart rate at rest in ALS patients, whereas the other heart rate variability parameters did not differ from controls. Structural sonographic investigation of the vagus and median nerves was similar in both groups. CONCLUSIONS: Using a multimodal approach evidence was found for a rather mild cardio-sympathetic overactivity in ALS patients. Overall, autonomic dysfunction seems to be subtle and is not related to the functional state of ALS patients.

[Hallucinations in Patients with Idiopathic Parkinson's Disease]. / Halluzinationen bei Patienten mit idiopathischem Parkinson-Syndrom.

Patients with idiopathic Parkinson's disease develop symptoms of the hallucination-psychosis spectrum in more than 20%. Most common are visual hallucinations. The pathogenesis of hallucinations mainly depends on disease duration, the distribution and extent of alpha-synuclein pathology, and modulating effects of the dopaminergic therapy. When managing PD hallucinations both anti-delirogenic actions and medication management are important. However, decrease in dopaminergic medication may lead to critical worsening of akinesia. If appropriate neuroleptic medication - essentially quetiapin or clozapin - can be considered. Instead, anti-dopaminergic neuroleptics should not be used owing to their pro-akinetic side-effects. Here, we provide therapy recommendations to manage PD hallucinations based on an up-to-date targeted review of the literature and expert-based empirical evidence.

Scoring Algorithm-Based Genomic Testing in Dystonia: A Prospective Validation Study.

BACKGROUND: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications. OBJECTIVES: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity). METHODS: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses. RESULTS: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81. CONCLUSIONS: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Sonographic evaluation of the vagus nerves: Protocol, reference values, and side-to-side differences.

INTRODUCTION: Reported sonographic reference values for the vagus nerves (VNs) vary greatly. We aimed to generate reference values in a large cohort and examine intrarater, interrater, and across-ultrasound systems agreement. METHODS: The VNs of 60 healthy subjects were examined by 2 sonographers and with 2 ultrasound systems. Cross-sectional areas (CSAs) of each VN were assessed at the level of the carotid sinus [proximal measurement level (ML)] and thyroid gland (distal ML). RESULTS: Mean VN CSA was significantly larger on the right side (proximal ML: 2.7 ± 0.6 mm2 vs. 2.1 ± 0.5 mm2 ; distal ML: 2.6 ± 0.6 mm2 vs. 1.9 ± 0.4 mm2 ). VN CSA decreased with increasing age. There were good intrarater, interrater, and across-ultrasound systems agreements. DISCUSSION: The right VN CSA is significantly larger than the left. These side- and age-specific reference values for the VN may be useful for future studies. Muscle Nerve 57: 766-771, 2018.

Differential Regulation of Human Paired Associative Stimulation-Induced and Theta-Burst Stimulation-Induced Plasticity by L-type and T-type Ca2+ Channels.

Activity-dependent changes of postsynaptic Ca2+-concentration are influenced by a variety of different Ca2+-channels and play an important role in synaptic plasticity. Paired associative stimulation (PAS) and theta-burst stimulation (TBS) are noninvasive magnetic stimulation protocols used in human subjects to induce lasting corticospinal excitability changes that have been likened to synaptic long-term potentiation and long-term depression. To better characterize the Ca2+-related physiological mechanisms underlying PAS- and TBS-induced plasticity, we examined the impact of different Ca2+-sources. PAS-induced facilitation of corticospinal excitability was blocked by NMDA-receptor blocker dextromethorphan (DXM) and L-type voltage gated Ca2+ channels (VGCC) blocker nimodipine (NDP), but turned into depression by T-type VGCC blocker ethosuximide (ESM). Although, surprisingly, static corticospinal excitability was increased by the combination of DXM and NDP, PAS-induced facilitation was blocked. TBS-induced facilitation of corticospinal excitability, which has previously been shown to be turned into depression by L-type VGCC blocker NDP (Wankerl K, Weise D, Gentner R, Rumpf J, Classen J. 2010. L-type voltage-gated Ca2+ channels: a single molecular switch for long-term potentiation/long-term depression-like plasticity and activity-dependent metaplasticity in humans. J Neurosci. 30(18):6197-6204.), was blocked, but not reverted, by T-type VGCC blocker ESM. The different patterns of Ca2+-channel modulation of PAS- and TBS-induced plasticity may point to an important role of backpropagating action potentials in PAS-induced plasticity, similar as in spike-timing dependent synaptic plasticity, and to a requirement of dendritic Ca2+-dependent spikes in TBS-induced plasticity.

Differential spatial representation of precision and power grasps in the human motor system.

Power and precision grasps are two interrelated, kinematically distinct types of finger movements. We examined whether these types of motor actions may be spatially differently represented in the human central nervous system. In healthy participants representations of finger movements were mapped by delivering single pulse TMS to multiple scalp regions covering the left primary motor cortex (M1). Finger joint motions were recorded from the right hand using a data glove. Principal component analysis was used to extract local subspaces representing the TMS-evoked movement data from each scalp region. Voluntary power and precision grasps were reconstructed with these subspaces. The spatial properties of these reconstructions were analyzed for each grasp type using a general linear model. We found overlapping, yet distinct spatial representations for precision and power grasps with precision grasps represented slightly posterior compared to a more uniform distribution for power grasps. Differential spatial encoding of both grasp types may point towards a representation of power grasps within a phylogenetically older M1 area at the crown of the precentral gyrus and of precision grasps in a newer area in the depth of the central sulcus. Results also support the idea of separate synergistic movement representations in the human motor system.

Evaluation Of freehand high-resolution 3-dimensional ultrasound of the median nerve.

INTRODUCTION: In this study we evaluated freehand 3D ultrasound (3DUS) of the median nerve in comparison to 2D ultrasound (2DUS) and assessed the influence of tilting the transversal plane on cross-sectional area (CSA) measurement. METHODS: Two examiners investigated the median nerves of 22 healthy subjects over a distance of 20 cm using 3DUS. Image quality and CSA were assessed at random points within the virtual 3D volume and compared with 2DUS. RESULTS: Image quality within the virtual 3D volume was good/sufficient/poor in 53.0%/40.2%/6.8% (examiner 1) and 21.6%/69.6%/8.8% (examiner 2), respectively. CSA measurements with 3DUS were smaller than with 2DUS (-12% and -17%; Wilcoxon test, P < 0.001). Interrater agreement for 3DUS and intermethod agreement between 2DUS and 3DUS were moderate. Stepwise tilting of the transversal plane increased CSA significantly. CONCLUSION: Freehand 3DUS of the median nerve over 20 cm is feasible and may help overcome some of the limitations and pitfalls of 2DUS. Muscle Nerve 55: 206-212, 2017.

Dissociating Parieto-Frontal Networks for Phonological and Semantic Word Decisions: A Condition-and-Perturb TMS Study.

Left posterior inferior frontal gyrus (pIFG) and supramarginal gyrus (SMG) are key regions for phonological decisions, whereas angular gyrus (ANG) and anterior IFG (aIFG) are associated with semantics. However, it is less clear whether the functional contribution of one area changes in the presence of a dysfunctional area within the network. Using repetitive transcranial magnetic stimulation (rTMS), we first tested whether perturbing one area would disrupt behavior. Second, we applied a condition-and-perturb approach, combining parietal offline rTMS with frontal online rTMS to investigate how the functional contribution of a frontal region changes in the presence of a dysfunctional parietal region. We found that rTMS over SMG or pIFG delayed phonological decisions, but this was not enhanced by combining supramarginal rTMS with pIFG rTMS. In contrast, semantic decisions were only impaired when angular rTMS was combined with aIFG rTMS. We infer that offline rTMS caused a dysfunction of ANG which increased the functional relevance of aIFG for semantic decisions and sensitized this network to the disruptive effects of aIFG rTMS. The results provide causal evidence that ANG and aIFG contribute to semantics and that the functional significance of one area within this network depends on the functional integrity of the other.

Positional Relations of the Cervical Vagus Nerve Revisited.

OBJECTIVES: The cervical part of the vagus nerve (CVN) has become an important target for stimulation therapy to treat epilepsy and psychiatric conditions. For this purpose, the CVN is visualized in the carotid sheath, assuming it to be localized dorsomedially between the carotid artery (CA) and the internal jugular vein (JV). The aim of our morphological study was therefore to revisit the CVN relationships to the CA and JV, hypothesizing it to have common variations to this classical textbook anatomy. MATERIALS AND METHODS: Positional relations of the CVN, CA and JV were investigated in the carotid sheath of 35 cadavers at the C3 to C6 level. Positional relations of the CVN, CA and JV were documented on the basis of a 3 × 3 chart. RESULTS: Eighteen different arrangements of the CVN, CA and JV were observed. The typical topographic relationship of the CVN dorsomedially between the CA and JV was only found in 42% of all cases. The CVN was located dorsally or (dorso-)laterally to the CA in 80% and dorsally or (dorso-)medially of the JV in 96% of all cases. CONCLUSIONS: Classical textbook anatomy of the CVN is only present in a minority of cases. Positional variations in contrast to textbook anatomy are considerably more frequent than previously described, which might be a hypothetical morphological explanation for the lack of efficacy or side effects of CVN stimulation. Furthermore, the position of the CVN relative to the internal jugular vein is more consistent than to the CA.

Early [(18)F]florbetaben and [(11)C]PiB PET images are a surrogate biomarker of neuronal injury in Alzheimer's disease.

PURPOSE: [(18)F]FDG is a commonly used neuronal injury biomarker for early and differential diagnosis of dementia. Typically, the blood supply to the brain is closely coupled to glucose consumption. Early uptake of the Aß tracer [(11)C]PiB on PET images is mainly determined by cerebral blood flow and shows a high correlation with [(18)F]FDG uptake. Uptake data for (18)F-labelled Aß PET tracers are, however, scarce. We investigated the value of early PET images using the novel Aß tracer [(18)F]FBB in the diagnosis of Alzhimers disease (AD). METHODS: This retrospective analysis included 22 patients with MCI or dementia who underwent dual time-point PET imaging with either [(11)C]PiB (11 patients) or [(18)F]FBB (11 patients) in routine clinical practice. Images were acquired 1 - 9 min after administration of both tracers and 40 - 70 min and 90 - 110 min after administration of [(11)C]PiB and [(18)F]FBB, respectively. The patients also underwent [(18)F]FDG brain PET imaging. PET data were analysed visually and semiquantitatively. Associations between early Aß tracer uptake and dementia as well as brain atrophy were investigated. RESULTS: Regional visual scores of early Aß tracer and [(18)F]FDG PET images were significantly correlated (Spearman's ρ = 0.780, P < 0.001). Global brain visual analysis revealed identical results between early Aß tracer and [(18)F]FDG PET images. In a VOI-based analysis, the early Aß tracer data correlated significantly with the [(18)F]FDG data (r = 0.779, P < 0.001), but there were no differences between [(18)F]FBB and [(11)C]PiB. Cortical SUVRs in regions typically affected in AD on early Aß tracer and [(18)F]FDG PET images were correlated with MMSE scores (ρ = 0.458, P = 0.032, and ρ = 0.456, P = 0.033, respectively). A voxel-wise group-based search for areas with relatively higher tracer uptake on early Aß tracer PET images compared with [(18)F]FDG PET images revealed a small cluster in the midbrain/pons; no significant clusters were found for the opposite comparison. CONCLUSION: Early [(18)F]FBB and [(11)C]PiB PET brain images are similar to [(18)F]FDG PET images in AD patients, and these tracers could potentially be used as biomarkers in place of [(18)F]FDG. Thus, Aß tracer PET imaging has the potential to provide biomarker information on AD pathology and neuronal injury. The potential of this approach for supporting the diagnosis of AD needs to be confirmed in prospective studies in larger cohorts.

Light pigmentation phenotype is correlated with increased substantia nigra echogenicity.

OBJECTIVE: This study was undertaken to address the question of whether pigmentation may be mechanistically linked with Parkinson's disease. METHODS: In a cross-sectional, observational study, 116 healthy subjects received transcranial sonography of the substantia nigra. Pigmentation phenotype was assessed using the Fitzpatrick skin phototype classification, and five additional phenotypic pigmentation traits as well as a photographic method (Melanin index) in a subgroup of 46 subjects. RESULTS: Lighter skin phototype was associated with larger echogenic substantia nigra area and increased prevalence of abnormally enlarged echogenic substantia nigra area. The strongest association of substantia nigra echogenicity and phenotypic pigmentation traits was found for hair color and facial tanning. INTERPRETATION: Findings suggest an increasing prevalence of structural abnormality of substantia nigra with decreasing darkness of skin and thus may provide additional evidence in favor of a pathogenic link of pigmentation and Parkinson's disease.

Effect of low-density polyethylene on smoke emissions from burning of simulated debris piles.

UNLABELLED: Low-density polyethylene (LDPE) plastic is used to keep piled debris from silvicultural activities--activities associated with development and care of forests--dry to enable efficient disposal by burning. The effects of inclusion of LDPE in this manner on smoke emissions are not well known. In a combustion laboratory experiment, 2-kg mixtures of LDPE and manzanita (Arctostaphylos sp.) wood containing 0, 0.25, and 2.5% LDPE by mass were burned. Gaseous and particulate emissions were sampled in real time during the entire flaming, mixed combustion phase--when the flaming and smoldering phases are present at the same time--and during a portion of the smoldering phase. Analysis of variance was used to test significance of modified combustion efficiency (MCE)--the ratio of concentrations of fire-integrated excess CO2 to CO2 plus CO--and LDPE content on measured individual compounds. MCE ranged between 0.983 and 0.993, indicating that combustion was primarily flaming; MCE was seldom significant as a covariate. Of the 195 compounds identified in the smoke emissions, only the emission factor (EF) of 3M-octane showed an increase with increasing LDPE content. Inclusion of LDPE had an effect on EFs of pyrene and fluoranthene, but no statistical evidence of a linear trend was found. Particulate emission factors showed a marginally significant linear relationship with MCE (0.05 < P-value < 0.10). Based on the results of the current and previous studies and literature reviews, the inclusion of small mass proportions of LDPE in piled silvicultural debris does not appear to change the emissions produced when low-moisture-content wood is burned. In general, combustion of wet piles results in lower MCEs and consequently higher levels of emissions. IMPLICATIONS: Current air quality regulations permit the use of burning to dispose of silvicultural piles; however, inclusion of low-density polyethyelene (LDPE) plastic in silvicultural piles can result in a designation of the pile as waste. Waste burning is not permitted in many areas, and there is also concern that inclusion of LDPE leads to toxic air emissions.

Microcircuit mechanisms involved in paired associative stimulation-induced depression of corticospinal excitability.

Synaptic weight changes induced by temporal correlations between the spikes of pre- and postsynaptic neurons are referred to as spike-timing-dependent plasticity (STDP). Transcranial magnetic stimulation (TMS) induces long-lasting effects on corticospinal excitability, if it is repetitively paired with stimulation of afferents from a corresponding contralateral hand region at short intervals (paired associative stimulation, PAS). PAS-induced plasticity has been linked with synaptic STDP. We aimed to investigate which elements of the cortical microcircuitry sustain and govern PAS-induced depression of corticospinal excitability in the target muscle representation (and enhancement of excitability in its functional surround). We show that the time window during which the interaction between both stimulus-induced cortical events leads to immediate post-interventional depression is short (<4.5 ms). The depressant PAS effects at the target representation were completely blocked by applying a subthreshold magnetic pulse 3 ms before the principal TMS pulse, even when the strength of the latter was adjusted to generate a motor-evoked potential of similar amplitude to that with the unconditioned magnetic pulse. Epidural recordings from the cervical cord of a patient showed that under this condition late TMS-evoked I-waves remain suppressed. When the intensity of the TMS component during PAS was lowered - sufficient to allow activation of inhibitory neurons, but insufficient to activate corticospinal neurons - excitability of short-latency intracortical inhibition remained unchanged. PAS-induced facilitation in the functional surround followed the same pattern as the centre-depressant effects. These findings may suggest that excitability-depressant PAS-induced effects are due to weakening of excitatory synapses between upper cortical layer principal neurons, but not those located on the corticospinal neuron, or inhibitory synapses. Inhibitory interneurons involved in short-latency intracortical inhibition are gate-keepers to producing centre-depressant/surround-facilitatory PAS effects. Based on these and earlier findings we propose a model specifying the composition and laminar location of the involved microcircuit of PAS-induced plasticity that may enhance its utility as a model of STDP in humans.

Sonographic abnormality of the substantia nigra in melanoma patients.

BACKGROUND: Evidence derived from large epidemiological studies suggests an association between Parkinson's disease (PD) and malignant melanoma. Transcranial sonography of the midbrain reveals an extended echogenic substantia nigra (SN) area in a high proportion of patients with PD. This characteristic, in the context of PD, may signal degeneration of dopaminergic nigrostriatal projection neurons. Demonstration of an increased prevalence of abnormal echogenic SN in melanoma patients could add weight to the hypothesis of an underlying common pathogenic pathway of both diseases. METHODS: This was a cross-sectional observational study. Transcranial sonography of the SN region was performed on 31 patients suffering from malignant melanoma and 29 healthy participants. In addition, patients and controls were screened for motor and non-motor symptoms of PD. RESULTS: The echogenic SN area was abnormally extended in 42% of melanoma patients versus 7% of control subjects (χ(2) = 9.811, P = .002). Mean echogenic SN area (SN[R, L]) was significantly larger in melanoma patients than in controls (patients, 0.21 ± 0.07 cm(2); controls, 0.15 ± 0.04 cm(2) [mean ± SD]; unpaired t test, P < .001). CONCLUSIONS: These findings provide additional evidence in favor of a common pathogenic pathway of PD and malignant melanoma and raise the possibility that their association is closer than previously assumed.

Excitability decreasing central motor plasticity is retained in multiple sclerosis patients.

BACKGROUND: Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS. METHODS: We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window. RESULTS: cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 ± 22% of baseline amplitude, p < 0.001) and in MS patients (69 ± 18%, p < 0.001). In contrast, post-cTBS force production performance was only impaired in controls (2.2 ± 2.8, p = 0.011), but not in MS patients (2.0 ± 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls. CONCLUSIONS: Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS.

Impairment of the rubber hand illusion in focal hand dystonia.

Patients with dystonia display a number of disturbances in the cognitive processing of movements, such as movement simulation and prediction, but whether these deficits point to a deeper rooted disturbance of perceptual bodily representations remains unknown. A useful way to investigate the sense of body ownership is the rubber hand paradigm, in which an illusion of ownership is established by synchronous stroking of the participants' real unseen hand and a visible fake hand, whereas similar asynchronous stroking does not bring about the illusion. This paradigm allows testing of both the subjective experience of feeling ownership over the rubber hand and the proprioceptive relocation of the real unseen hand towards the viewed rubber hand. Previous studies have mapped these different aspects onto two anatomically distinct neuronal substrates, with the ventral premotor cortex processing the illusory feeling of ownership and the inferior parietal lobule and cerebellum processing proprioceptive drift. We applied the rubber hand illusion task to healthy subjects and to patients affected by two different types of focal dystonia-one specifically affecting the hand (focal hand dystonia) and one not affecting the hand (torticollis and blepharospasm). Results showed that in patients with focal hand dystonia, the proprioceptive drift was selectively disrupted on the dystonic hand while the subjective experience of the illusion was retained. In the non-dystonic hand and in the other two groups (non-hand dystonia and healthy subjects), the rubber hand illusion resembled the typical pattern with synchronous stroking eliciting the illusion. These findings provide support for the contention that the mechanisms underlying the presence of the illusory feeling of ownership and the proprioceptive drift are different. Selective impairment of the limb recalibration on the dystonic hand points to underlying deficits in integrating the visual-tactile input with the proprioceptive information in order to update the current body position and may support a model linking dystonia to dysfunctions in a network comprising the inferior parietal cortex and the cerebellum.