Mark S. Baron

Deep Brain Stimulation for Dystonia: A Meta‐Analysis

Objective.  To use a meta‐analysis on all reported cases of deep brain stimulation (DBS) for dystonia to determine which factors significantly influence outcome. The Burke‐Fahn‐Marsden (BFM) movement scale, the most reported measure, was chosen as the primary outcome measure for this analysis.

Caregiver distress in parkinsonism

This study examined the frequency and degree of caregiver burden in persons with parkinsonism, a group of disorders with four primary symptoms that include tremor, rigidity, postural instability, and bradykinesia. We assessed associations between perceived caregiver burden and physical, cognitive, and functional impairments using well-established tools for persons with parkinsonism. The 49 individuals with parkinsonism ranged in age from 61 to 87 (mean = 75), while their caregivers (N = 49) ranged in age from 48 to 83 (mean = 70). The caregivers were predominantly either wives (82%) or daughters (6%), with other family members, friends, and/or neighbors (12%) making up the rest. The caregivers reported a relatively high ability for coping (mean scores = 4.6/6). Caregiver burden was significantly negatively associated with activities of daily living and motoric difficulties as measured on the Unified Parkinsons Disease Rating Scale (UPDRS). Likewise, caregiver burden was negatively associated with caregiver self-reported sleep and coping ability. Results did not demonstrate an association on the UPDRS among mentation, behavior, and mood. We found a significant negative correlation for mentation between the Folstein Mini-Mental Status Examination and caregiver burden measures; however, we did not find this association with the Dementia Rating Scale-2. Patients self-reported pain and caregiver burden were not associated.

Slowed Saccades and Increased Square Wave Jerks in Essential Tremor

Background Eye movements in essential tremor (ET) are poorly described and may present useful information on the underlying pathophysiology of the disorder. Methods Sixty patients with ET, including 15 de novo untreated patients, and 60 age-matched controls constitute the study population. A video-based eye tracker was used to assess binocular eye position. Oculomotor function was assessed while subjects followed random horizontally and vertically step-displaced targets. Results For all reflexive saccades, latencies were increased in ET subjects by a mean of 16.3% (p<0.01). Saccades showed reduced peak velocities with a lengthy, wavering velocity plateau, followed by slowed decelerations. For larger 30°+ saccades, peak velocities were decreased by a mean of 25.2% (p<0.01) and durations increased by 31.8% (p<0.01). The frequency of square wave jerks (SWJs) in patients was more than triple that of controls (p<0.0001). Despite frequent interruptions by SWJs, fixations were otherwise stable and indistinguishable from controls (root mean square [RMS] velocity, p = 0.324). The abnormal eye movement parameters were independent of disease duration, tremor severity, and medication therapy. Discussion In contrast to normally swift onset and efficient acceleration/deceleration movements, saccades in ET are characterized by abnormally prolonged latencies and slowed velocity profiles. Although ET subjects maintain highly stable fixations, they are interrupted by increased numbers of SWJs. This study reveals novel oculomotor deficits in ET, which are distinct from the eye movement dysfunction of other movement disorders, supporting a role for eye tracking to assist in the differential diagnoses of not only atypical, but also more common movement disorders.

Pervasive Ocular Tremor in Patients With Parkinson Disease

OBJECTIVE To further assess oculomotor control of patients with Parkinson disease (PD) during fixation and with movement. DESIGN Case-control study. SETTING A Parkinson disease research, education, and clinical center. PATIENTS One hundred twelve patients with PD, including 18 de novo untreated patients, and 60 age-matched controls. INTERVENTION Modern, precise eye tracking technology was used to assess oculomotor parameters. Oculomotor function was compared between groups during fixation and while tracking a randomly displaced target on a PC monitor. MAIN OUTCOME MEASURES Fixation stability and saccadic parameters. RESULTS All patients with PD and 2 of 60 control subjects showed oscillatory fixation instability (ocular tremor), with an average fundamental frequency of 5.7 Hz and average magnitude of 0.27°. Saccadic parameters and occurrences of square wave jerks did not differ between subjects with PD and controls. The amplitude and frequency of fixation instability did not correlate with disease duration, clinical Unified Parkinsons Disease Rating Scale scores, or dopa-equivalent dosing. No differences in oculomotor parameters were found between medicated and unmedicated patients with PD. CONCLUSIONS All patients with PD exhibited persistent ocular tremor that prevented stability during fixation. The pervasiveness and specificity of this feature suggest that modern, precise oculomotor testing could provide a valuable early physiological biomarker for diagnosing PD.

Efficacy of multidisciplinary treatment program on long-term outcomes of individuals with Parkinson's disease.

We examined the impact of multidisciplinary clinical management of the Parkinsons Disease Research, Education, and Clinical Center program on Parkinsons disease progression. Initial and follow-up scores on the Part III Motor Examination subscale of the Unified Parkinsons Disease Rating Scale (UPDRS) were examined. Overall, 37 (75.5%) of the 49 patients demonstrated stable or improved UPDRS motor scores at 1- to 3-year follow-up; in the 1-year group (n = 28), 22 patients (78.6%) improved, while 6 (21.4%) worsened. In the 2-year group (n = 15), 10 (66.7%) improved, while 5 (33.3%) worsened. In the 3-year group (n = 6), 5 (83.3%) improved, while 1 (16.7%) worsened. Multidisciplinary interventions included neurology (95.9% of patients), physiatry (93.9%), nursing (87.8%), psychology (42.9%), medication changes (59.2% increases, 18.4% decreases), rehabilitation therapies (physical, occupational, speech-language, 67.3%), functional diagnostic testing (18.4%), support group (16.3%), home exercise instruction (85.7%), and disease and wellness education (81.6%). Improved and worsened patients did not significantly differ on the individual program components. Clinical implications and study limitations are discussed.

Multi-neuronal recordings in the Basal Ganglia in normal and dystonic rats.

Classical rate-based pathway models are invaluable for conceptualizing direct/indirect basal ganglia pathways, but cannot account for many aspects of normal and abnormal motor control. To better understand the contribution of patterned basal ganglia signaling to normal and pathological motor control, we simultaneously recorded multi-neuronal and EMG activity in normal and dystonic rats. We used the jaundiced Gunn rat model of kernicterus as our experimental model of dystonia. Stainless steel head fixtures were implanted on the skulls and EMG wires were inserted into antagonistic hip muscles in nine dystonic and nine control rats. Under awake, head-restrained conditions, neuronal activity was collected from up to three microelectrodes inserted in the principal motor regions of the globus pallidus (GP), subthalamic nucleus, and entopeduncular nucleus (EP). In normal animals, most neurons discharged in regular or irregular patterns, without appreciable bursting. In contrast, in dystonic animals, neurons discharged in slow bursty or irregular, less bursty patterns. In normal rats, a subset of neurons showed brief discharge bursts coinciding with individual agonist or antagonist EMG bursts. In contrast, in dystonics, movement related discharges were characterized by more prolonged bursts which persist over multiple dystonic co-contraction epics. The pattern of movement related decreases in discharge activity however did not differ in dystonics compared to controls. In severely dystonic rats, exclusively, simultaneously recorded units often showed abnormally synchronized movement related pauses in GP and bursts in EP. In conclusion, our findings support that slow, abnormally patterned neuronal signaling is a fundamental pathophysiological feature of intrinsic basal ganglia nuclei in dystonia. Moreover, from our findings, we suggest that excessive movement related silencing of neuronal signaling in GP profoundly disinhibits EP and in turn contributes to sustained, unfocused dystonic muscle contractions.

Quantification of gait in dystonic Gunn rats.

Spontaneously jaundiced Gunn rats exposed to sulfadimethoxine develop bilirubin encephalopathy (kernicterus) with hearing loss and dystonia, closely resembling the human syndrome. We recently characterized the electromyographic activity in this animal model supporting our clinical impression of dystonia. The objective of this study was to develop a simple, non-invasive method to quantify the motor deficits in dystonic rodents. On postnatal day 16, Gunn rats were treated with 100mg/kg of sulfadimethoxine or saline. On postnatal day 31, the ventral view of the animals was videotaped while the animals walked inside a Plexiglas chamber. Individual video frames were reviewed and specific gait parameters including hindlimb spread, step length ratio variability, stance/swing ratio and walking speed were compared between dystonic and non-dystonic jaundiced and non-jaundiced littermates. Data analysis demonstrated statistically significant increases in hindlimb spread and step length ratio variability and decreases in walking speed in dystonic animals as compared to controls. This study demonstrates a valuable technique to objectively characterize dystonia in Gunn rats, which could have wide use for other experimental movement disorders as well.

Electromyographic characterization in an animal model of dystonia.

Kernicterus is known to produce damage to the auditory system and the basal ganglia in humans. Although the Gunn rat model of kernicterus has been extensively used to characterize the auditory features, this model has not been similarly utilized to systematically investigate the movement disorder. In the present study, spontaneously jaundiced (jj) 16 day old Gunn rat pups were treated with sulfadimethoxine to exacerbate bilirubin toxicity and compared to saline treated jjs and non‐jaundiced (Nj) littermates. Electromyographic (EMG) activity was recorded from antagonistic hip muscles in dystonic and in normal appearing rats. Raw EMG signals were decomposed using the Discrete Wavelet Transform based multi‐resolution analysis and signal coefficients corresponding to the dominant EMG frequency band were chosen. Gunn rats exposed to sulfadimethoxine developed a stable clinical state characterized by prolonged abnormal axial and appendicular postures. Coherence plots of the separated signals coefficients revealed 4–7 Hz co‐activation in antagonistic muscles that was significantly more prominent in jj sulfa treated dystonic compared to normal rats. The EMG findings support the presence of dystonia in sulfadimethoxine exposed jj Gunn rats and suggest that these animals can serve as a valuable model for experimental investigations of dystonia.

A Novel Stereotaxic Apparatus for Neuronal Recordings in Awake Head-restrained Rats

A novel technique for neuronal recordings in awake head-restrained animals is presented. Our setup allows (1) daily repeat microelectrode studies in rats without use of anesthesia, (2) excellent stabilization of head using an eight point fixation, (3) painless head-restraint of the animal, (4) accurate stereotaxic localization during multiple sessions of recording, (5) to considerably reduced surgical time, (6) quick repositioning during chronic recording sessions and (7) high quality stabilized neuronal recordings during periods of rest and active movements.

Experimental support that ocular tremor in Parkinson's disease does not originate from head movement

INTRODUCTION Our recent report of ocular tremor in Parkinsons disease (PD) has raised considerable controversy as to the origin of the tremor. Using an infrared based eye tracker and a magnetic head tracker, we reported that ocular tremor was recordable in PD subjects with no apparent head tremor. However, other investigators suggest that the ocular tremor may represent either transmitted appendicular tremor or subclinical head tremor inducing the vestibulo-ocular reflex (VOR). The present study aimed to further investigate the origin of ocular tremor in PD. METHODS Eye movements were recorded in 8 PD subjects both head free, and with full head restraint by means of a head holding device and a dental impression bite plate. Head movements were recorded independently using both a high sensitivity tri-axial accelerometer and a magnetic tracking system, each synchronized to the eye tracker. RESULTS Ocular tremor was observed in all 8 PD subjects and was not influenced by head free and head fixed conditions. Both magnetic tracking and accelerometer recordings supported that the ocular tremor was fully independent of head position. CONCLUSION The present study findings support our initial findings that ocular tremor is a fundamental feature of PD unrelated to head movements. Although the utility of ocular tremor for diagnostic purposes requires validation, current findings in large cohorts of PD subjects suggest its potential as a reliable clinical biomarker.