Showing papers by "Mark Hallett published in 2014"

Sensory aspects of movement disorders.

Abstract: Summary Movement disorders, which include disorders such as Parkinson's disease, dystonia, Tourette's syndrome, restless legs syndrome, and akathisia, have traditionally been considered to be disorders of impaired motor control resulting predominantly from dysfunction of the basal ganglia This notion has been revised largely because of increasing recognition of associated behavioural, psychiatric, autonomic, and other non-motor symptoms The sensory aspects of movement disorders include intrinsic sensory abnormalities and the effects of external sensory input on the underlying motor abnormality The basal ganglia, cerebellum, thalamus, and their connections, coupled with altered sensory input, seem to play a key part in abnormal sensorimotor integration However, more investigation into the phenomenology and physiological basis of sensory abnormalities, and about the role of the basal ganglia, cerebellum, and related structures in somatosensory processing, and its effect on motor control, is needed

Effects of subconcussive head trauma on the default mode network of the brain.

Abstract: Although they are less severe than a full blown concussive episodes, subconcussive impacts happen much more frequently and current research has suggested this form of head trauma may have an accumulative effect and lead to neurological impairment later in life. To investigate the acute effects that subconcussive head trauma may have on the default mode network of the brain resting-state, functional magnetic resonance was performed. Twenty-four current collegiate rugby players were recruited and all subjects underwent initial scanning 24 h prior to a scheduled full contact game to provide a baseline. Follow-up scanning of the rugby players occurred within 24 h following that game to assess acute effects from subconcussive head trauma. Differences between pre-game and post-game scans showed both increased connectivity from the left supramarginal gyrus to bilateral orbitofrontal cortex and decreased connectivity from the retrosplenial cortex and dorsal posterior cingulate cortex. To assess whether or not a history of previous concussion may lead to a differential response following subconcussive impacts, subjects were further divided into two subgroups based upon history of previous concussion. Individuals with a prior history of concussion exhibited only decreased functional connectivity following exposure to subconcussive head trauma, while those with no history showed increased connectivity. Even acute exposure to subconcussive head trauma demonstrates the ability to alter functional connectivity and there is possible evidence of a differential response in the brain for those with and without a history of concussion.

Tricks in dystonia: ordering the complexity

Abstract: Sensory tricks are various manoeuvres that can ameliorate dystonia. Common characteristics are well known, but their variety is wide, sensory stimulation is not necessarily the critical feature, and their physiology is unknown. To enumerate the various forms of sensory tricks and describe their nature, research findings and theories that may elucidate their neurophysiologic mechanism, we reviewed the literature pertaining to sensory tricks, including variants like motor tricks, imaginary tricks, forcible tricks and reverse sensory tricks. On the basis of this information, we propose a new classification of sensory tricks to include its variants. We highlight neurophysiologic evidence suggesting that sensory tricks work by decreasing abnormal facilitation. We tie this with established dystonia pathogenesis and postulate that sensory tricks decrease abnormally increased facilitation to inhibition ratios in the dystonic brain. It appears worthwhile for patients to search for possible sensory tricks.

Role of the sensorimotor cortex in tourette syndrome using multimodal imaging

Abstract: Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics. Most patients describe uncomfortable premonitory sensations preceding the tics and a subjective experience of increased sensitivity to tactile stimuli. These reports indicate that a sensory processing disturbance is an important component of TS together with motor phenomena. Thus, we focused our investigation on the role of the sensorimotor cortex (SMC) in TS using multimodal neuroimaging techniques. We measured the gamma-aminobutyric acid (GABA)+/Creatine (Cre) ratio in the SMC using GABA (1) H magnetic resonance spectroscopy. We recorded the baseline beta activity in the SMC using magnetoencephalography and correlated GABA+/Cre ratio with baseline beta band power. Finally, we examined the resting state functional connectivity (FC) pattern of the SMC using functional magnetic resonance imaging (fMRI). GABA+/Cre ratio in the SMC did not differ between patients and controls. Correlation between the baseline beta band power and GABA+/Cre ratio was abnormal in patients. The anterior insula showed increased FC with the SMC in patients. These findings suggest that altered limbic input to the SMC and abnormal GABA-mediated beta oscillations in the SMC may underpin some of the sensorimotor processing disturbances in TS and contribute to tic generation.

Frequency-dependent neural activity in Parkinson's disease

Abstract: The brainstem and basal ganglia are important in the pathophysiology of Parkinson's disease (PD). Reliable and sensitive detection of neural activity changes in these regions should be helpful in scientific and clinical research on PD. In this study, we used resting state functional MRI and amplitude of low frequency fluctuation (ALFF) methods to examine spontaneous neural activity in 109 patients with PD. We examined activity in two frequency bands, slow-4 (between 0.027 and 0.073 Hz) and slow-5 (0.010-0.027 Hz). Patients had decreased ALFF in the striatum and increased ALFF in the midbrain, and changes were more significant in slow-4. Additionally, changes in slow-4 in both basal ganglia and midbrain correlated with the severity of the parkinsonism. The ALFF in the caudate nucleus positively correlated with the dose of levodopa, while the ALFF in the putamen negatively correlated with the disease duration in both slow-4 and slow-5 bands. In addition, the ALFF in the rostral supplementary motor area negatively correlated with bradykinesia subscale scores. Our findings show that with a large cohort of patients and distinguishing frequency bands, neural modulations in the brainstem and striatum in PD can be detected and may have clinical relevance. The physiological interpretation of these changes needs to be determined.

Efficient and reliable characterization of the corticospinal system using transcranial magnetic stimulation.

Abstract: Purpose: The purpose of this study is to develop a method to reliably characterize multiple features of the corticospinal system in a more efficient manner than typically done in transcranial magnetic stimulation studies. Methods: Forty transcranial magnetic stimulation pulses of varying intensity were given over the first dorsal interosseous motor hot spot in 10 healthy adults. The first dorsal interosseous motor-evoked potential size was recorded during rest and activation to create recruitment curves. The Boltzmann sigmoidal function was fit to the data, and parameters relating to maximal motor-evoked potential size, curve slope, and stimulus intensity leading to half-maximal motor-evoked potential size were computed from the curve fit. Results: Good to excellent test–retest reliability was found for all corticospinal parameters at rest and during activation with 40 transcranial magnetic stimulation pulses. Conclusions: Through the use of curve fitting, important features of the corticospinal system can be determined with fewer stimuli than typically used for the same information. Determining the recruitment curve provides a basis to understand the state of the corticospinal system and select subject-specific parameters for transcranial magnetic stimulation testing quickly and without unnecessary exposure to magnetic stimulation. This method can be useful in individuals who have difficulty in maintaining stillness, including children and patients with motor disorders.

Absent movement-related cortical potentials in children with primary motor stereotypies.

Abstract: The underlying pathophysiologic mechanism for complex motor stereotypies in children is unknown, with hypotheses ranging from an arousal to a motor control disorder. Movement-related cortical potentials (MRCPs), representing the activation of cerebral areas involved in the generation of movements, precede and accompany self-initiated voluntary movements. The goal of this study was to compare cerebral activity associated with stereotypies to that seen with voluntary movements in children with primary complex motor stereotypies. Electroencephalographic (EEG) activity synchronized with video recording was recorded in 10 children diagnosed with primary motor stereotypies and 7 controls. EEG activity related to stereotypies and self-paced arm movements were analyzed for presence or absence of early or late MRCP, a steep negativity beginning about 1 second before the onset of a voluntary movement. Early MRCPs preceded self-paced arm movements in 8 of 10 children with motor stereotypies and in 6 of 7 controls. Observed MRCPs did not differ between groups. No MRCP was identified before the appearance of a complex motor stereotypy. Unlike voluntary movements, stereotypies are not preceded by MRCPs. This indicates that premotor areas are likely not involved in the preparation of these complex movements and suggests that stereotypies are initiated by mechanisms different from voluntary movements. Further studies are required to determine the site of the motor control abnormality within cortico-striatal-thalamo-cortical pathways and to identify whether similar findings would be found in children with secondary stereotypies.

Temporal macrodynamics and microdynamics of the postoperative impedance at the tissue–electrode interface in deep brain stimulation patients

Abstract: Objective To study the temporal dynamics of tissue impedance after deep brain stimulation (DBS). Background DBS therapy commonly employs a constant voltage approach, and current delivery to the tissue is a function of electrode–tissue impedance. It is presumed that impedance fluctuates early postimplantation, with implications for variations in current delivery and therapeutic efficacy. We hypothesised that the largest variation will be recorded early after surgery, followed by stabilisation. Methods Review of impedance checks of implanted DBS systems at standard parameters during the first five months postimplantation. All measurement time points were binned into 1-week periods, and we used repeated measures analysis of variance with Tukey pairwise multiple comparisons correction. The analysis was repeated after normalising impedance values for each subject to that patient9s baseline value. Results There was an initial (non-significant) drop in impedance at week 1, followed by significant increase at week 3 (p=0.0002). There were no further significant differences in impedance values at subsequent time points. Analysis of normalised data showed a significant difference between the initial measurement in postoperative week 1 (normalised value 1) and week 3 (normalised value 1.73, p Conclusions We found major changes in impedance within the first month postimplantation, with no further variation. This is an important confirmation in patients of this temporal dynamics of the impedance of implanted DBS hardware, with potential therapeutic implications.

Alcohol challenge and sensitivity to change of the Essential Tremor Rating Assessment Scale.

Abstract: Background The ability of the Essential Tremor (ET) Rating Assessment Scale (TETRAS) to detect changes in tremor severity is unknown. Methods Fifteen adult ET patients received a single oral ethanol dose calculated to reach 0.05 g/dL breath alcohol content (brAC). Effects were investigated independently with accelerometry and TETRAS. Results Accelerometry data were log-transformed and a cumulative score logACC(R+L) was calculated. Correlation between logACC(R+L) and TETRAS was significant. TETRAS and accelerometry showed a significant effect of time point using repeated-measures analysis of variance. The difference between baseline and each of the following six time points as well as the correlation of TETRAS with brAC were significant. The calculated minimum detectable change of TETRAS was 8.9% and the effect size was d = 4.75 (95% confidence interval: 3.60–5.90). Conclusion We demonstrated sensitivity to change of the TETRAS performance scale after a therapeutic intervention, which further establishes its potential for use in both clinical and research settings. © 2013 International Parkinson and Movement Disorder Society

Abnormal dorsal premotor-motor inhibition in writer's cramp.

Abstract: The authors hypothesized that a deficient premotor–motor inhibitory network contributes to the unwanted involuntary movements in dystonia. The authors studied nine controls and nine patients with writer's cramp (WC). Dorsal premotor–motor cortical inhibition (dPMI) was tested by applying conditioning transcranial magnetic stimulation (TMS) to the dorsal premotor cortex and then a test pulse to the ipsilateral motor cortex at an interval of 6 ms. The authors used an H-reflex in flexor carpi radialis paired with TMS over the premotor cortex to assess for spinal cord excitability change. Finally, the authors interrupted a choice reaction time task with TMS over dorsal premotor cortex to assess performance in a nondystonic task. The results showed that WC patients exhibited dPMI at rest (88.5%, the ratio of conditioned to unconditioned test pulse), in contrast to controls, who did not show dPMI (109.6%) (P = 0.0198). This difference between patients and controls persisted during contraction (100% vs. 112%) and pen-holding (95.6% vs. 111%). The H-reflex in the arm was not modulated by the premotor cortex stimulation. The WC patients made more errors, and the error rate improved with TMS over the premotor cortex. These results suggest that abnormal premotor–motor interactions may play a role in the pathophysiology of focal dystonia. The dPMI was not modulated by task in either group, but was constantly greater in the patients. The significance of the increased inhibition is likely to be compensatory. It appears to be a robust finding and, in combination with other features, could be further explored as a biomarker. © 2014 International Parkinson and Movement Disorder Society

Sports-related concussion: ongoing debate

Abstract: Research in mild traumatic brain injury (mTBI), also known as concussion, has increased significantly within the past decade parallel to the increased attention being given from injured athletes on high school, collegiate and professional sports teams. These patients have focused the research community's efforts into further understanding the pathophysiological underpinnings of the injury as well as its both short-term and long-term effects.1 Widespread media coverage and several high-profile cases have raised the issue of possible severe and devastating long-term consequences of repetitive sports-related brain trauma that may involve the acquisition of a proteinopathy2 as well as an increased risk for developing neurodegenerative diseases associated with repetitive concussive and subconcussive blows.3 Following a concussive episode there is a destructive pathophysiological and biochemical response that initiates a chain of neurometabolic and neurochemical reactions that include activation of inflammatory response, imbalances of ion concentrations, increase in the presence of excitatory amino acids, dysregulation of neurotransmitter synthesis and release, imbalance in mitochondrial functions and energy metabolism, and production of free radicals.4 Most of these molecular changes resolve spontaneously but, since cells are highly vulnerable, a second concussive event during this period of altered cell functions may have catastrophic …

Clinico‐Pathological Correlation in Progressive Ataxia and Palatal Tremor: A Novel Tauopathy

Abstract: Palatal tremor (PT) is an uncommon movement disorder that has been subdivided into essential and symptomatic forms. A distinct subgroup of the symptomatic form presents with progressive ataxia and PT. The histopathology of progressive ataxia and PT has not been previously determined. This study consisted of a clinical review, histopathology, and electron microscopy of the brain of a man with progressive ataxia and PT. The inferior olivary hypertrophy was symmetrical and homogenous, and no focal pathologic lesions could be identified in the brainstem. Insoluble tau deposits were found in neurons, exclusively infratentorially. We present the clinical and pathological evaluation of a case of progressive ataxia and PT that provide evidence for a unique form of 4R tauopathy.

Characteristics of Bilateral Hand Function in Individuals With Unilateral Dystonia Due to Perinatal Stroke Sensory and Motor Aspects

Abstract: The authors assessed bilateral motor and sensory function in individuals with upper limb dystonia due to unilateral perinatal stroke and explored interrelationships of motor function and sensory ability. Reach kinematics and tactile sensation were measured in 7 participants with dystonia and 9 healthy volunteers. The dystonia group had poorer motor (hold time, reach time, shoulder/elbow correlation) and sensory (spatial discrimination, stereognosis) outcomes than the control group on the nondominant side. On the dominant side, only sensation (spatial discrimination, stereognosis) was poorer in the dystonia group compared with the control group. In the dystonia group, although sensory and motor outcomes were uncorrelated, dystonia severity was related to poorer stereognosis, longer hold and reach times, and decreased shoulder/elbow coordination. Findings of bilateral sensory deficits in dystonia can be explained by neural reorganization. Visual compensation for somatosensory changes in the nonstroke hemisphere may explain the lack of bilateral impairments in reaching.

Short apraxia screening test.

Abstract: Background: Limb apraxia comprises many different and common disorders, which are largely unrecognized essentially because there is no easy-to-use screening test sensitive enough to identify all types of limb praxis deficits. Method: We evaluated 70 right-handed patients with limb apraxia due to a single focal lesion of the left hemisphere and 40 normal controls, using a new apraxia screening test. The test covered 12 items including: intransitive gestures, transitive gestures elicited under verbal, visual, and tactile modalities, imitation of meaningful and meaningless postures and movements, and a multiple object test. Results: Interrater reliability was maximum for a cutoff of >2 positive items identifying apraxia on the short battery (Cohen’s kappa .918, p 3 items (Cohen’s kappa .768, p 2 was higher, indicating greater apraxia diagnosis agreement between raters at this cutoff value. Conclusions: The scree...

Post-traumatic shoulder movement disorders: A challenging differential diagnosis between organic and functional.

Abstract: Peripheral trauma may be a trigger for the development of various movement disorders though the pathophysiology remains controversial and some of these patients have a functional (psychogenic) disorder. We report 3 cases of shoulder movement disorders following trauma to the shoulder region. Physiology was done in all the patients to extend the physical examination. Two patients had history of recurrent shoulder dislocation and were diagnosed with Ehlers-Danlos syndrome. One patient had shoulder injury following repeated falls while performing as a cheerleader. In two patients there were some clinical features suggesting a functional etiology, but physiological studies in all three failed to produce objective evidence of a functional nature. Shoulder movement following trauma is uncommon. Diagnosis in such cases is challenging considering the complex pathophysiology. The movements can be associated with prolonged pain and handicap, and once established they appear resistant to treatment.

Relationship and factor structure in multisystem neurodegeneration in Parkinson's disease.

Abstract: Objectives Parkinson's disease (PD) is a multisystem neurodegenerative disease. We aimed to identify the relationship and factor structure among its different features. Materials & methods Motor, olfactory and cognitive function, and cardiac sympathetic denervation were evaluated in 125 patients with PD using the Unified Parkinson's Disease Rating Scale (UPDRS) part III score, odor stick identification test for the Japanese (OSIT-J), Mini-Mental State Examination (MMSE), and [123I] meta-iodobenzylguanidine (MIBG) cardiac scintigraphy (heart-to-mediastinum (H/M) ratio). Pearson's correlation and multiple regression analysis were used to evaluate the association among the four measures with age, gender, and disease duration as the covariates. Exploratory factor analysis was used to identify the underlying factor structure among the measures and covariates. Results Pearson's correlation and multiple regression analysis showed correlations between OSIT-J score and MIBG H/M ratio, OSIT-J and MMSE scores, UPDRS part III score and MIBG H/M ratio, UPDRS part III score and disease duration, and MMSE score and age. Factor analysis identified three factors: (i) age and MMSE score; (ii) MIBG H/M ratio and OSIT-J score; and (iii) UPDRS part III score and disease duration. Conclusions Our results suggest that aging, PD-related pathogenesis, and disease duration underlie the multisystem neurodegeneration present in PD. Moreover, age and disease duration are the major risk factors for cognitive impairment and motor symptoms, respectively. Olfactory impairment and cardiac sympathetic denervation are strongly associated in PD.

Treatment of Essential Tremor with Long-chain Alcohols: Still Experimental or Ready for Prime Time?

Abstract: Aim: To review current literature on long‐chain alcohols and their derivatives as novel pharmacotherapy for the treatment of essential tremor (ET). Background: Currently available and recommended pharmacotherapies for ET are often limited by suboptimal treatment effects, frequent adverse effects, and drug interactions. While ethanol is reported to profoundly decrease tremor severity in the majority of patients with ET, preclinical experience suggests that long‐chain alcohols such as 1‐octanol might lead to a comparable tremor reduction without ethanol’s typical side effects of sedation and intoxication. Here, we review the literature on the first clinical trials on 1‐octanol and its metabolite octanoic acid (OA) for the treatment of ET. Methods: The literature on preclinical and clinical trials on long‐chain alcohols as well as OA was reviewed and summarized, and an outlook given on next phases of development. Discussion: 1‐octanol was demonstrated to be safe and effective in a double‐blind, placebo‐controlled low‐dose trial, and open‐label data showed excellent tolerability and dose‐dependent efficacy up to 128 mg/kg. Despite 1‐octanol’s efficacy, its future viability as an effective therapy is limited by its pharmacological properties that require large volumes to be orally administered. Pharmacokinetic data indicate that OA is the active metabolite of 1‐octanol. Preclinical efficacy data for OA are positive, and human pilot data demonstrated excellent safety as well as efficacy in secondary outcome measures of tremor amplitudes. OA also has more favorable pharmacological properties for drug delivery; hence, OA may be worth developing as a pharmaceutical.

Functional or psychogenic: what's the better name?

Abstract: tional’ is that it might imply normal function rather than dysfunction and contradicts the notion that the treating physician wants and should convey to the patient about the ‘cause’ of the psychogenic disorder.” These are some of the reasons why I still prefer the term psychogenic instead of functional. Patients who present with these disorders generally perceive themselves as “dysfunctional” rather than “functional.” Furthermore, I believe that the latter term is too vague. When the term psychogenic is introduced to the patients in a sensitive and tactful way and the patients are reassured that there is no evidence of “neurological damage,” they are more willing to accept the role of psychodynamic factors, such as stress, in their condition and are more amenable to psychological and psychiatric intervention. Most patients understand that stress can cause elevation in blood pressure, palpitation, and tremors, so they can also accept that dystonia, parkinsonism, tics, and other movement disorders can be manifestations of stress or other psychological factors, even though these precipitants may not always be obvious or readily identifiable, especially during the first encounter.

Head Accelerometry May be Useful as a Test of Psychogenic Head Tremor

Abstract: Physiological studies of head tremor are challenging, and clinically relevant data to guide diagnosis in literature is sparse. Head accelerometry has been used as a quantitative assessment of botulinum toxin treatment in head tremor.1 Tremor studies rely on accelerometry to detect frequency and coherence for interpretation of test results.

Hemidystonia with one eye-of-the-tiger sign.

Abstract: Awomaninher lateteenspresentedwithdystonicposturingofher left hand for 2 years and left foot for 3months. Dystonic posturing of her hand had started when she was 8 months pregnant, and it slowly worsened to involve her left lower limb, leading to difficulty in walking (Video). She was evaluated for left hemidystonia. Fluid-attenuated inversion recovery (FLAIR)magnetic resonance images (MRIs) of the brain gave the appearance of the eyeof-the-tiger sign in the right basal ganglia similar to what would be seenwithaneuroferritinopathy,butsusceptibility-weighted imaging revealed evidence of hemosiderin indicative of an old hemorrhagic infarct (Figure). The results ofmagnetic resonanceangiography for evaluation of intracranial vessels were normal. Mutation analysis for pantothenate kinase 2 was negative. Antinuclear antibody and anti–double-stranded DNAwere negative.

Clinical Response to IncobotulinumtoxinA, after Demonstrated Loss of Clinical Response to OnabotulinumtoxinA and RimabotulininumtoxinB in a Patient with Musician's Dystonia.

Abstract: Botulinum toxin is a mainstay therapy for dystonia. Formulations available are three types of botulinumtoxinA and one type of botulinumtoxinB.(1) Antibodies can develop against the toxin, leading to treatment failure. IncobotulinumtoxinA (Xeomin; Merz Pharmaceuticals GmbH, Frankfurt, Germany) is differentiated from other types of botulinumtoxinA preparations by being free from complexing proteins, speculated to make the product less antigenic.(2).

Reply: Dystonia after severe head injuries

Abstract: In their recent publication in Movement Disorders, Albanese et al. reported the results of a consensus update on the phenomenology and classification of dystonias. They encouraged clinicians and researchers to test their innovative classification scheme in various clinical settings. Motivated by their report, we aimed to assess their classification of dystonias among patients in a vegetative or minimally conscious state after experiencing traumatic brain injury (TBI), vascular disease, or cerebral anoxia. Of the 132 consecutive patients who were admitted to our Department of Rehabilitation in a vegetative or minimally conscious state after sustaining severe brain injury, 28 patients developed dystonias. According to axis I of the new classification, we observed the following: (1) focal dystonias (i.e., cervical dystonias, blepharospasms, and oromandibular dystonias); (2) hemidystonias; and (3) generalized dystonias. Dystonias were more frequent in patients who suffered brain injury caused by cerebral anoxia (32%), compared to patients with TBI (24%) or cerebrovascular disease (10%). Generalized dystonias were prevalent in patients with cerebral anoxia, whereas focal dystonias were predominant after TBI. During the rehabilitation period, some patients showed improvements in their dystonic patterns, whereas the conditions of other patients remained stationary (static dystonia) or worsened (progressive dystonia). Some characteristics observed in our patients and data reported in the literature may contribute additional insights to the new classification. First, onset of acquired dystonias may occur with a bimodal temporal distribution. Previous studies defined early-onset acquired dystonias as events that occurred over a short time interval (weeks or months) after cerebral damage. Late-onset acquired dystonias were considered to occur after a longer interval of time ( 1 year). We followed up patients in the postacute rehabilitation phase; thus, we only evaluated early-onset acquired dystonic events. Second, the clinical course of dystonia showed three distinct temporal patterns: worsening; static; or improving. Notably, improvements in acquired dystonia were previously described in patients who suffered from movement disorders caused by traumatic injury or by stroke. In light of these observations, we suggest some updates to the new classification. In particular, we recommend that (1) “earlyor late-onset acquired dystonia” be added as a new clinical descriptor, (2) disease course descriptors be changed to “worsening, static, or improving,” and (3) “cerebral anoxia” be added as a possible cause of acquired dystonia.