Showing papers by "Mark Hallett published in 2007"

Genotype–phenotype correlation of paroxysmal nonkinesigenic dyskinesia

Abstract: Background: Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder characterized by episodic hyperkinetic movement attacks. We have recently identified mutations in the MR-1 gene causing familial PNKD. Methods: We reviewed the clinical features of 14 kindreds with familial dyskinesia that was not clearly induced by movement or during sleep. Of these 14 kindreds, 8 had MR-1 mutations and 6 did not. Results: Patients with PNKD with MR-1 mutations had their attack onset in youth (infancy and early childhood). Typical attacks consisted of a mixture of chorea and dystonia in the limbs, face, and trunk, and typical attack duration lasted from 10 minutes to 1 hour. Caffeine, alcohol, and emotional stress were prominent precipitants. Attacks had a favorable response to benzodiazepines, such as clonazepam and diazepam. Attacks in families without MR-1 mutations were more variable in their age at onset, precipitants, clinical features, and response to medications. Several were induced by persistent exercise. Conclusions: Paroxysmal nonkinesigenic dyskinesia (PNKD) should be strictly defined based on age at onset and ability to precipitate attacks with caffeine and alcohol. Patients with this clinical presentation (which is similar to the phenotype initially reported by Mount and Reback) are likely to harbor myofibrillogenesis regulator 1 ( MR-1 ) gene mutations. Other “PNKD-like” families exist, but atypical features suggests that these subjects are clinically distinct from PNKD and do not have MR-1 mutations. Some may represent paroxysmal exertional dyskinesia.

The etiopathogenesis of Parkinson disease and suggestions for future research. Part II.

Abstract: We are at a critical juncture in our knowledge of the etiology and pathogenesis of Parkinson disease (PD). It is clear that PD is not a single entity simply resulting from a dopaminergic deficit; rather it is most likely caused by a combination of genetic and environmental factors and, although there is extensive new information on the etiology and pathogenesis of PD that may advance its treatment, new syntheses of this information are needed. The first part of this two-part, state-of-the-art review by leaders in Parkinson research critically examines the field to identify where new knowledge and ideas might be helpful for treatment purposes. Topics reviewed in Part I include the definition of the disease, neuropathologic contributions, and epidemiologic, environmental, and demographic issues. ### Current Knowledge The definition of idiopathic Parkinson disease (PD) remains controversial. Classically, it includes a characteristic motor phenotype (1) and a distinctive neuropathology and substantial loss of dopaminergic neurons from the substantia nigra associated with the presence of α-synuclein-positive inclusions in the cell body (Lewy bodies) and processes (Lewy neurites) of specific neurons of the brainstem. ### Parkinson Syndrome Without Synucleinopathy Some genetically determined Parkinson syndromes resemble, sometimes closely, idiopathic PD, but differ from it neuropathologically, sometimes substantially. In particular, a number of juvenile-onset autosomal recessive cases of familial Parkinson syndrome do not have α-synuclein lesions (2), contrasting with the autosomal dominant forms of the disease which often have unusual types of lesions (3-5). The recently identified leucine-rich repeat kinase 2 ( LRRK2, Park-8 ) mutations produce variable pathologic phenotypes. Although the most common is Lewy body disease, nigral degeneration with ubiquitin inclusions or, in a few cases, even pathologic changes more typical of frontotemporal lobar degeneration or progressive supranuclear palsy have been described in patients with LRRK2 mutations (6). Two recent reports insist on the high prevalence of Lewy bodies in the LRRK2 mutations (7 …

Voxel based morphometry reveals specific gray matter changes in primary dystonia.

Abstract: The present study assessed patterns of brain tissue alterations in different types of primary dystonia using voxel-based morphometry (VBM). Nine patients with primary generalized dystonia (GD), 11 patients with primary cervical dystonia (CD), and 11 patients with primary focal hand dystonia (FHD) as well as 31 age and gender-matched controls were included. When compared with healthy controls, patients with primary dystonia (n=31) showed gray matter volume increase bilaterally in the globus pallidus internus, nucleus accumbens, prefrontal cortex, as well as unilaterally in the left inferior parietal lobe. This is the first study using VBM in patients with different types of primary dystonia, showing a common pattern of gray matter changes.

Immune Cross-Reactivity in Celiac Disease: Anti-Gliadin Antibodies Bind to Neuronal Synapsin I

Abstract: Celiac disease is an immune-mediated disorder triggered by ingestion of wheat gliadin and related proteins in genetically susceptible individuals. In addition to the characteristic enteropathy, celiac disease is associated with various extraintestinal manifestations, including neurologic complications such as neuropathy, ataxia, seizures, and neurobehavioral changes. The cause of the neurologic manifestations is unknown, but autoimmunity resulting from molecular mimicry between gliadin and nervous system proteins has been proposed to play a role. In this study, we sought to investigate the immune reactivity of the anti-gliadin Ab response toward neural proteins. We characterized the binding of affinity-purified anti-gliadin Abs from immunized animals to brain proteins by one- and two-dimensional gel electrophoresis, immunoblotting, and peptide mass mapping. The major immunoreactive protein was identified as synapsin I. Anti-gliadin Abs from patients with celiac disease also bound to the protein. Such cross-reactivity may provide clues into the pathogenic mechanism of the neurologic deficits that are associated with gluten sensitivity.

Neuroimaging of neuronal circuits involved in tic generation in patients with Tourette syndrome.

Abstract: Objective: To identify brain regions generating tics in patients with Tourette syndrome using sleep as a baseline. Methods: We used [ 15 O]H 2 O PET to study nine patients with Tourette syndrome and nine matched control subjects. For patients, conditions included tic release states and sleep stage 2; and for control subjects, rest states and sleep stage 2. Results: Our study showed robust activation of cerebellum, insula, thalamus, and putamen during tic release. Conclusion: The network of structures involved in tics includes the activated regions and motor cortex. The prominent involvement of cerebellum and insula suggest their involvement in tic initiation and execution.

Changes in spinal excitability after PAS.

Abstract: Repetitive pairing of a peripheral stimulation with a magnetic transcortical stimulation (PAS) is widely used to induce plastic changes in the human motor cortex noninvasively. Based on the contrast between PAS-induced increase of corticospinal excitability and absence of PAS-induced increase of the spinal F wave size, it has been generally accepted that PAS-induced plasticity is cortical in origin. Here, instead of F waves, we used H reflex recruitment curves to assess spinal excitability, and we demonstrate that PAS induces parallel changes in cortical and spinal excitability.

How to assess motor impairment in writer's cramp.

Abstract: Writer's cramp is a task-specific hand dystonia affecting handwriting. Clinical scores such as the Arm Dystonia Disability Scale (ADDS) or Writer's 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 writer's 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 writer's cramp.

Assessing the role of DRD5 and DYT1 in two different case-control series with primary blepharospasm.

Abstract: Primary blepharospasm is a common adult-onset focal dystonia. Polymorphisms of the genes encoding TorsinA (DYT1) and the D5 dopamine receptor (DRD5) have previously been associated with lifetime risk for focal dystonia. We describe here experiments testing common variability within these two genes in two independent cohorts of Italian and North American patients with primary blepharospasm. We have failed to identify a consistent association with disease in the two patient groups examined here; however, analysis of the Italian group reveals an association with the same risk genotype in DYT1 as previously described in an Icelandic population. We have also found global significant DYT1 haplotype differences between patients and controls in the Italian series. These data suggest that further examination is warranted of the role genetic variability at this locus plays in the risk for primary dystonia. © 2006 Movement Disorder Society

Task-related interaction between basal ganglia and cortical dopamine release.

Abstract: Dopamine (DA) is a powerful neuromodulator for a wide variety of behaviors. Considerable evidence accumulated from rodent and monkey experiments over the last two decades suggests that DA activity in the frontal cortex is reciprocally linked to that in functionally related basal ganglia (BG) structures. However, the functional importance of this in humans is still unknown. To address this issue, we measured endogenous DA release using positron emission tomography in 15 healthy subjects as they practiced the first training session of a finger sequence learning task. Significant results were observed not only in striatal areas but also in extrastriatal "motor" regions, bilaterally. Faster learning was specifically coupled to lower DA release in the sensorimotor part of the globus pallidus pars interna (GPi) contralateral to the moving hand, which was paralleled by a higher increase in DA levels in the pre-supplementary motor area (pre-SMA). This finding provides original evidence supporting a motor-learning-related interaction between DA release in left GPi and pre-SMA, a mechanism that may also apply to other anatomically and functionally interconnected BG and frontal cortical areas as a function of behavior.

The role of the human ventral premotor cortex in counting successive stimuli.

Abstract: Adult humans have the ability to count large numbers of successive stimuli exactly. What brain areas underlie this uniquely human process? To identify the candidate brain areas, we first used functional magnetic resonance imaging, and found that the upper part of the left ventral premotor cortex was preferentially activated during counting of successive sensory stimuli presented 10–22 times, while the area was not activated during small number counting up to 4. We then used transcranial magnetic stimulation to assess the necessity of this area, and found that stimulation of this area preferentially disrupted subjects’ exact large number enumeration. Stimulation to the area affected neither subjects’ number word perception nor their ability to perform a non-numerical sequential letter task. While further investigation is necessary to determine the precise role of the left ventral premotor cortex, the results suggest that the area is indispensably involved for large number counting of successive stimuli, at least for the types of tasks in this study.

Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation

Abstract: BACKGROUND: Patients with Parkinson disease (PD) often have cardiac sympathetic denervation and failure of neurocirculatory regulation by baroreflexes. Familial PD caused by mutation of the gene encoding alpha-synuclein or by alpha-synuclein gene triplication also features cardiac sympathetic denervation and baroreflex failure. METHODS: Here we report results of cardiac sympathetic neuroimaging by 6-[(18)F]fluorodopamine PET, baroreflex testing based on beat-to-beat hemodynamic responses to the Valsalva maneuver, and nigrostriatal neuroimaging using 6-[(18)F] fluorodopa PET in a proband with mutation of the gene encoding leucine-rich repeat kinase 2 (LRRK2), the most common genetic abnormality identified so far in familial PD. RESULTS: The patient had no detectable 6-[(18)F] fluorodopamine-derived radioactivity in the left ventricular myocardium, a progressive fall in blood pressure during the Valsalva maneuver and no pressure overshoot after release of the maneuver, and decreased 6-[(18)F] fluorodopa-derived radioactivity bilaterally in the putamen and substantia nigra. CONCLUSION: This patient with Parkinson disease (PD) caused by LRRK2 mutation had evidence of cardiac sympathetic denervation, baroreflex-sympathoneural and baroreflex-cardiovagal failure, and nigrostriatal dopamine deficiency, a pattern resembling that in the sporadic disease. The results fit with the concept that in LRRK2 PD, parkinsonism, cardiac sympathetic denervation, and baroreflex failure can result from a common pathogenetic process.

Essential tremor, deceptively simple....

Abstract: The diagnosis and management of essential tremor appears deceptively simple. However, isolated mild tremor may be difficult to classify, and if the patients have any additional features the diagnosis is more difficult. Management can be challenging, despite the numerous treatments available, because so many patients are not benefited adequately and some not at all. However, as we gain a better understanding of the disorder, more effective therapies with fewer adverse effects are sure to follow.

Abnormality of motor cortex excitability in peripherally induced dystonia

Abstract: It is widely accepted that peripheral trauma such as soft tissue injuries can trigger dystonia, although little is known about the underlying mechanism. Because peripheral injury only rarely appears to elicit dystonia, a predisposing vulnerability in cortical motor areas might play a role. Using single and paired-pulse pulse transcranial magnetic stimulation, we evaluated motor cortex excitability of a hand muscle in a patient with peripherally induced foot dystonia, in her brother with craniocervical dystonia, and in her unaffected sister, and compared their results to those from a group of normal subjects. In the patient with peripherally induced dystonia, we found a paradoxical intracortical facilitation at short interstimulus intervals of 3 and 5 milliseconds, at which regular intracortical inhibition (ICI) occurred in healthy subjects. These findings suggest that the foot dystonia may have been precipitated as the result of a preexisting abnormality of motor cortex excitability. Furthermore, the abnormality of ICI in her brother and sister indicates that altered motor excitability may be a hereditary predisposition. The study demonstrates that the paired-pulse technique is a useful tool to assess individual vulnerability, which can be particularly relevant when the causal association between trauma and dystonia is less evident.

Diagnosing psychogenic movement disorders—which criteria should be used in clinical practice?

Abstract: Diagnosing psychogenic movement disorders—which criteria should be used in clinical practice?

Etiological musculo-skeletal factor in focal dystonia in a musician's hand: A case study of the right hand of a guitarist

Abstract: A case study is presented in which a focal hand dystonia seems to have developed in the right hand of a classical guitarist as a result of a neuromuscular peripheral defect caused by trauma. The trauma was a near total perforation of the first web space by a splinter. Healing was uneventful without apparent functional complications. Two years later the patient noticed difficulties in extending the index in playing, for which he received various unsuccessful treatments during seven years. However, we found more severe dystonic symptoms (cocontractions) in the thumb than in the index during playing, which correlated with an undiagnosed insufficiency in the flexor pollicis brevis (FPB). This defect allowed proposing a biomechanical analysis of compensations for diminished thumb control in playing, which would explain the dysfunction in the index in playing as overcompensation for the thumb problem. If this analysis is correct, the etiology of the case can be traced back to underlying multiarticular control problems in the thumb caused by an insufficient FPB. This defect was considered irrepairable. It was concluded that even with knowledge of the underlying cause, a potentially successful treatment of the dystonia might not exist in this case. The case would demonstrate that task-specific hand dystonias can arise as overcompensations for (peripheral) neuro-musculoskeletal defects. The case is illustrated by videos of playing and functional thumb tests.

Binary EEG Control for Two-Dimensional Cursor Movement: An Online Approach

Abstract: Electroencephalography (EEG) is an appealing basis for brain-computer interface technology because EEG is non-invasive. However, because EEG signals are spatially blurred and typically have very low signal-to-noise ratios, extracting relevant information in the single-event case is challenging. The most easily accessible information is one-dimensional (for example, mu rhythm amplitude, average hemispherical power, or presence of a P300 evoked potential). Many studies have attempted to use such one-dimensional parameters as a basis for control. Robust results may be obtained when control is restricted to answering "yes" or "no" questions, such as comparison of a value to a threshold. However, possible applications of such control have been limited, and more dimensions of control are desirable. This research presents a new technique for obtaining more dimensions of control from existing technology. Yes/no answers are taken sequentially in groups of n, and in combination designate a specific choice from 2^n possible values. This is homologous to the function of bits, and consequently has been termed "binary control." To demonstrate this approach, a two-dimensional cursor control paradigm was developed in MATLAB. Users move a cursor among squares of a grid towards a target while avoiding a trap. At each move, there are up to four positions into which the cursor may be directed (up, down, left, and right). In this embodiment, control is achieved by twice comparing average alpha-and beta-frequency power of each hemisphere during continuous imagined lateralized hand movement. The first comparison narrows the four choices to two, and the second uniquely determines the cursor movement. This paradigm was shown to be compatible with the Brain-Computer Interface-to-Virtual Reality (BCI2VR) software, and preliminary tests were run on normal volunteers. These tests demonstrated the feasibility of pursuing future research with binary control. Binary control is promising because of its robust underlying principles, and because it is easily expandable and adaptable. The source of control may be any EEG feature that can signal a yes/no answer, and the quantity of possible choices doubles with the addition of each answer "bit." This might provide means for more complex control, such as of a robotic arm or virtual keyboard. The binary approach might also prove more efficient than current EEG-based control methods, possibly with less computational demand.

Intramedullary spinal tumor causing "belly dancer syndrome".

Abstract: philic capacity (60 to 100 times its weight), and second, by its increase of stool mass within the intestinal walls and by peristaltic stimulation.2 Our patients also reported an improvement in difficult defecation, presumably suggesting augmentation of SPRC. Despite the small number of patients, the differences in the etiologies of primary autonomic failure, and the lack of a control group, this pilot study calls for a large study to determine whether polycarbophil can treat constipation in patients with primary autonomic failure.

Predicting Motor Intention

Abstract: People have the perception that prior to making a voluntary movement, there is an intention to move. This subjective impression has been measured objectively using Libet’s clock and is on average about 300 ms prior to EMG onset. The EEG shows activity prior to movement, and by the voltage measurement, there is a rising negativity called the Bereitschaftspotential beginning about 1.5 s prior to EMG onset. This indicates that the brain mechanisms for generating a voluntary movement begin prior to the subjective intention, that is, unconsciously. If it were possible to detect relevant EEG signals with single events in real time, then it would be possible to identify that movement is being prepared prior to the subjective experience. Work in our laboratory has been making progress in accomplishing this aim. Such a signal could also be used to drive a brain-computer interface.

Prediction of Multiple Movement Intentions from CNV Signal for Multi-Dimensional BCI

Abstract: Patients that suffer from loss of motor control would benefit from a brain-computer interface (BCI) that would, optimally, be noninvasive, allow multiple dimensions of control, and be controlled with quick and simple means. Ideally, the control mechanism would be natural to the patient so that little training would be required; and the device would respond to these control signals in a predictable way and on a predictable time scale. It would also be important for such a device to be usable by patients capable and incapable of making physical movements. A BCI was created that used electroencephalography (EEG). Multiple dimensions of control were achieved through the movement or motor imagery of the right hand, left hand, tongue, and right foot. The movements were non-sustained to be convenient for the user. The BCI used the 1.5 seconds of the Bereitschaftspotential prior to movement or motor imagery for classification. This could allow the BCI to execute an action on a time scale anticipated by the user. To test this BCI, eight healthy participants were fitted with 29 EEG electrodes over their sensorimotor cortex and one bipolar electrooculography electrode to detect eye movement. Each participant completed six blocks of 100 trials. A trial included visual presentation of three stimuli: a cross, an arrow, and a diamond. Participants rested during the presentation of the cross. The arrow indicated the action that the participant should perform: right hand squeeze, left hand squeeze, press of the tongue against the roof of the mouth, or right foot toe curl. The diamond indicated that the participant should execute the movement during the first three blocks; and that the participant should imagine executing the movement during the last three blocks. Trials affected by motion artifacts, in particular face muscle activity, were removed. Of the remaining data, about 80% were used to train a Bayesian classification and about 20% were used to test this classification. Prediction of the four movements reached accuracies above 150% that of random classification for both real and imagined movements. This suggests a promising future for this BCI.