Mark Hallett - US grants

A major effort in the laboratory is devoted to understanding dystonia. Our fundamental view is that there is a deficiency of inhibition in central nervous system mechanisms in dystonia. Specifically, an important type of defective inhibition is surround inhibition, where muscles and movements not desired for the task need to be inhibited. Lack of inhibition leads to motor overflow and action dystonia. We are trying to identify the specific inhibitory circuit that contributes to surround inhibition. Studies are first done in normal subjects and then in patients. We have investigated a variety of inhibitory mechanisms already, and we are now engaged in understanding the premotor to motor cortex interactions in focal hand dystonia. We are also exploring the physiology of motor learning in dystonia. Motor learning seems disturbed, and seems to have a principal role in producing focal hand dystonia since long term repetitive activity is certainly an etiological factor. In one type of experiment, we are evaluating brain and spinal cord plasticity using brain and nerve stimulation paradigms. We are also conducting a case-control experimental study to evaluate long-term learning of sequential finger movements in focal hand dystonia patients. We have been studying the mechanisms underlying the somesthetic discrimination deficit in focal hand dystonia using EEG. We are showing that the recovery function of cortical somatosensory evoked potential (SEP) component in the paired-pulse paradigm is impaired and that this was well correlated with somesthetic temporal discrimination capability. This suggests that there is a deficit in inhibition in sensory processing as well as motor processing. In order to study task specificity, we are engaged in some fMRI studies with various tasks and various limb effectors. We should hopefully identify which regions of brain are specific for a task, and then to see how this would malfunction in dystonia. Our first attempt with this will be to study handwriting and patients with writers cramp. To gather further evidence for abnormalities in dystonia we are also exploring evidence for anatomical changes and for a deficiency of GABA-ergic mechanism. We are doing MRI studies with voxel based morphometry (VBM), diffusion tensor imaging (DTI), GABA magnetic resonance spectroscopy (MRS), anatomical imaging at 7 tesla, flumazenil PET studies and pathological studies of brains of patients with focal dystonias. The genetic markers in focal dystonia are largely unknown. Currently, we are evaluating patients with all forms of focal dystonia (blepharospasm, cranial dystonia, cervical dystonia, focal hand dystonia and spasmodic dysphonia) to look for a genetic marker. The study involves large families with focal dystonia and individuals without a family history. We have collaborators in the NIA for the genetics work. We are also exploring further the physiology of Parkinson disease (PD). Although fatigue is one of the most common symptom in PD, its characteristics and etiology are largely unknown because it is a subjective, complicated symptom hard to evaluate. With objective measurement, we are planning to study the clinical features and the beneficial effect of levodopa and repetitive transcranial magnetic stimulation. We are initiating a project on the pathophysiology of gait freezing. The pathophysiology of medication-related compulsive behaviors (pathological gambling and hypersexuality) in PD is poorly understood. We are doing behavioral studies on the obsessive compulsive and impulse control symptoms in PD compared to normal subjects and other patients, such as focal hand dystonia. Additionally, we are doing neuroimaging studies in PD patients with and without these symptoms to look for abnormal brain patterns of activation. We are collaborating with investigators in NIA on the clinical aspects of patients with genetic forms of PD. In particular, we have a study of patients with the LRRK2 mutation (PARK8). We will be studying patients with overt disease, but also carriers of the mutation who may become symptomatic. This will show the earliest manifestations of disease and progression of signs and symptoms.

The pathophysiology of psychogenic movement disorders (PMD) is very poorly understood. These disorders are common in the population, diagnosis is difficult and treatment typically ineffective. We are studying the mechanisms underlying these disorders using cognitive tasks, neurophysiological testing, psychiatric measures, and functional imaging. One functional imaging study is an fMRI investigation of patients with tremor, and results show abnormally reduced activation in the temporoparietal junction region. We have initiated similar studies in patients with psychogenic myoclonus. We are also looking for abnormal activations related to tasks that probe functions such as emotional expression and movement inhibition, and have shown abnormal activation in the amygdala. We have also investigated these patients for their sense of agency during fMRI studies, similar to the way we have studied normal subjects. The origin of tics is generally unknown, and we have been approaching physiology in several ways. Tourette syndrome patients report "premonitory urge" and other sensory abnormalities associated with the presence of tics. We have been studying tic genesis with functional neuroimaging and EEG, and are pursuing a series of studies looking at the physiology of the sensory urge. We are also seeing if we can detect the urge with real time fMRI. For many years, we have been collecting families with essential tremor looking for possible genetic abnormalities, and in several families found an area suggestive of genetic linkage on chromosome 6 and 11. This work is being pursued with additional sequencing in conjunction with Drs. Lev Goldfarb and David Goldman.

A number of efforts in the laboratory are devoted to understanding the physiology of volition. This includes the sense of willing to make a movement and the sense of agency, the sense of personal responsibility for the movement that has occurred. We have been trying to devise improved techniques to get quantitative measures of the timing of these subjective events. To determine which areas of the brain are activated with the sense of agency when making voluntary movement, we have used an MRI-compatible dataglove which subjects wore while making hand movements in the scanner. Subjects viewed their movements in real-time and the visual feedback they received was varied during the experiment to simulate different degrees of voluntary control. Now both MRI and EEG results have been published that show the relevant brain networks. We have determined EEG methods to predict in real time when someone is going to move and what movement they will make. We have optimized features and classification methods for the prediction. We have completed studies identifying that persons are not necessarily thinking about movement when a movement prediction can be made. We are now trying to influence the decision of when or what to move using non-invasive brain stimulation. The learning of motor skills is an important function. We have been studying how movements become automatic, that is, the stage of learning where much attention does not need to be devoted to an action. We are carrying out studies on the learning of chunks, and on the influence of reward on learning. We will use information learned in these studies to investigate patients with different movement disorders. The ability to make selective movements, particularly of individual fingers, is a critical human function. Anatomical and physiological features of the motor system make this difficult since most neurons (other than alpha motoneurons in the spinal cord and brainstem) are not muscle specific. Our hypothesis is that selective motor action must require inhibitory mechanisms, and we are seeking to understand them using TMS. We refer to this process as surround inhibition, as muscles not intended for the selective action need to be inhibited. Many inhibitory processes in the cortex, such as short intracortical inhibition and short afferent inhibition, can be analyzed at rest and with movement. Such studies seem to indicate that networks within the motor cortex itself are responsible for surround inhibition.

In the area of dystonia treatment, we continue to provide botulinum toxin injections to our patients while training physicians to perform these injections. Past studies from our group have shown that certain rehabilitation techniques, such as motor training and sensory training can be therapeutic. We have completed a new project for patients with writers cramp combining botulinum toxin and rehabilitation that might be more efficacious, and some secondary endpoints of the study suggest that this might well be the case. We have also been developing a new scale for severity of writers cramp to help in the analysis of clinical trials. Another protocol has begun of Deep Brain Stimulation (DBS) for focal hand dystonia. New treatments are needed for essential tremor. One promising agent is 1-octanol and its metabolite, 1-octanoic acid, which we continue to develop. We have characterized the pharmacokinetics and compared the efficacy of different formulations in a dose escalation and cross-over study in patients with essential tremor. We have completed a study with 1-octanoic acid, seeking the maximum tolerated dose. We are initiating studies of non-invasive brain stimulation for functional movement disorders.