Parkinsonism originates in a discrete secondary and dystonia in a primary motor cortical-basal ganglia subcircuit.

Although manifesting contrasting phenotypes, Parkinson's disease and dystonia, the two most common movement disorders, can originate from similar pathophysiology. Previously, we demonstrated that lesioning (silencing) of a discrete dorsal region in the globus pallidus (rodent equivalent to globus pallidus externa) in rats and produced parkinsonism, while lesioning a nearby ventral hotspot-induced dystonia. Presently, we injected fluorescent-tagged multi-synaptic tracers into these pallidal hotspots (n = 36 Long Evans rats) and permitted 4 days for the viruses to travel along restricted connecting pathways and reach the motor cortex before sacrificing the animals. Viral injections in the Parkinson's hotspot fluorescent labeled a circumscribed region in the secondary motor cortex, while injections in the dystonia hotspot labeled within the primary motor cortex. Custom probability mapping and N200 staining affirmed the segregation of the cortical territories for Parkinsonism and dystonia to the secondary and primary motor cortices. Intracortical microstimulation localized territories specifically to their respective rostral and caudal microexcitable zones. Parkinsonian features are thus explained by pathological signaling within a secondary motor subcircuit normally responsible for initiation and scaling of movement, while dystonia is explained by abnormal (and excessive) basal ganglia signaling directed at primary motor corticospinal transmission.

Deep Brain Stimulation of Nucleus Basalis of Meynert improves learning in rat model of dementia.

Background: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been preliminarily investigated as a potential treatment for dementia. The degeneration of NBM cholinergic neurons is a pathological feature of many forms of dementia. Although stimulation of the NBM has been demonstrated to improve learning, the ideal parameters for NBM stimulation have not been elucidated. This study assesses the differential effects of varying stimulation patterns and duration on learning in a dementia rat model. Methods: 192-IgG-saporin (or vehicle) was injected into the NBM to produce dementia in rats. Next, all rats underwent unilateral implantation of a DBS electrode in the NBM. The experimental groups consisted of i-normal, ii-untreated demented, and iii-demented rats receiving NBM DBS. The stimulation paradigms included testing different modes (tonic and burst) and durations (1-hr, 5-hrs, and 24-hrs/day) over 10 daily sessions. Memory was assessed pre- and post-stimulation using two established learning paradigms: novel object recognition (NOR) and auditory operant chamber learning. Results: Both normal and stimulated rats demonstrated improved performance in NOR and auditory learning as compared to the unstimulated demented group. The burst stimulation groups performed better than the tonic stimulated group. Increasing the daily stimulation duration to 24-hr did not further improve cognitive performance in an auditory recognition task and degraded the results on a NOR task as compared with 5-hr. Conclusion: The present findings suggest that naturalistic NBM burst DBS may offer a potential effective therapy for treating dementia and suggests potential strategies for the reevaluation of current human NBM stimulation paradigms.

Healthy and pathological pallidal regulation of thalamic burst versus tonic mode firing: a computational simulation.

The mechanisms by which the basal ganglia influence the pallidal-receiving thalamus remain to be adequately defined. Our prior in vivo recordings in fully alert normal and dystonic rats revealed that normally fast tonic discharging entopeduncular [EP, rodent equivalent of the globus pallidus internus (GPi)] neurons are pathologically slow, highly irregular, and bursty under dystonic conditions. This, in turn, induces pallidal-receiving thalamic movement-related neurons to change from a healthy burst predominant to a pathological tonic-predominant resting firing mode. This study aims to understand the pallidal influence on thalamic firing modes using computational simulations. We inputted various combinations of healthy and pathological (dystonic) in vivo neuronal recordings to the Rubin and Terman's computational model of low threshold spiking pallidothalamic neurons. The input sets consist of representative tonic, burst, irregular tonic and irregular burst inputs collected from EP/GPi in our animal lab. Initial test combinations of EP/ GPi input to the model were identical to the neuronal population distributions observed in vivo. The thalamic neuron model outputted similar firing rate and mode as observed in corresponding in-vivo thalamus. Further influence of each individual patterns was also delineated. By simulating the firing properties of encountered neurons, the basal ganglia output is suggested to critically act as firing mode selector for thalamic motor relay neurons. By selecting and determining the timing and extent of opening of thalamic T-type calcium channels via GABAergic hyperpolarizing input, GPi neurons are in position to precisely orchestrate thalamocortical burst motor signaling.

Anticholinergic Medication Burden in Parkinson's Disease Outpatients.

BACKGROUND: Individuals with Parkinson's disease (PD) may be especially vulnerable to future cognitive decline from anticholinergic medications. OBJECTIVE: To characterize anticholinergic medication burden, determine the co-occurrence of anticholinergic and cholinesterase inhibitors, and to assess the correlations among anticholinergic burden scales in PD outpatients. METHODS: We studied 670 PD outpatients enrolled in a clinic registry between 2012 and 2020. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Drug Burden Index-Anticholinergic component (DBI-Ach). Correlations between scales were assessed with weighted kappa coefficients. RESULTS: Between 31.5 to 46.3% of PD patients were taking medications with anticholinergic properties. Among the scales applied, the ACB produced the highest prevalence of medications with anticholinergic properties (46.3%). Considering only medications with definite anticholinergic activity (scores of 2 or 3 on ACB, ADS, or ARS), the most common anticholinergic drug classes were antiparkinsonian (8.2%), antipsychotic (6.4%), and urological (3.3%) medications. Cholinesterase inhibitors and medications with anticholinergic properties were co-prescribed to 5.4% of the total cohort. The most highly correlated scales were ACB and ADS (κ= 0.71), ACB and ARS (κ= 0.67), and ADS and ARS (κ= 0.55). CONCLUSION: A high proportion of PD patients (20%) were either taking antiparkinsonian, urological, or antipsychotic anticholinergic medications or were co-prescribed anticholinergic medications and cholinesterase inhibitors. By virtue of its detection of a high prevalence of anticholinergic medication usage and its high correlation with other scales, our data support use of the ACB scale to assess anticholinergic burden in PD patients.

A comparison of computerized dynamic posturography therapy to standard balance physical therapy in individuals with Parkinson's disease: a pilot study.

Postural instability is a common impairment in idiopathic Parkinson's disease (PD). People with PD are prone to balance and walking difficulties. This study analyzed the feasibility of a prospective investigation of Computerized Dynamic Posturography (CDP) and standard Physical Therapy (PT) treatments in individuals with mild-moderate PD. Treatment took place at two sites: 1) CDP therapy at the Southeast Parkinson's Disease Research Education and Clinical Center (PADRECC) within a Veterans Affairs Medical Center and 2) standard physical therapy at a community outpatient rehabilitation center. Final analysis compared 15 patients randomly assigned for therapy to either the CDP or PT treatments. Therapy time was eight weeks (four weeks of CPD or PT followed by home therapy for four weeks). The CDP therapy included gradually intensified closed chain and mobility training. Standard PT consisted of upright, mat, and theraball exercises and gait training. The home exercise phase was identical for both groups. The pilot data demonstrated treatment was tolerated by 68 percent of the sample despite the occurrence of a progressive neurological condition and medical comorbidities. While results failed to reveal any differences between treatment groups, both groups demonstrated improvement on selected outcome measures. An expanded prospective study with methodological improvements appears warranted.

Parkinsonism and dystonia are differentially induced by modulation of different territories in the basal ganglia.

Numerous clinical and experimental observations suggest that deficient neuronal signaling in the globus pallidus externa (GPe) is integral to both Parkinson's disease (PD) and dystonia. In our previous studies in jaundiced dystonic rats, widespread silencing of neurons in GP (rodent equivalent to GPe) preceded and persisted during dystonic motor activity. We therefore hypothesized that on a background of slow and highly irregular and bursty neuronal activity in GP, cortical motor drive produces profound inhibition of GP as the basis for action-induced dystonia in Gunn rats. Presently, the neurotoxin ibotenate was injected locally into the motor territory of GP at one to four sites, over one to two tracts, in 19 normal rats. We found that highly circumscribed dorsal motor territory lesions reproducibly induced parkinsonism, while ventral lesions consistently produced dystonia. Post-lesioning, slow neuronal burst oscillations in the entopeduncular nucleus distinguished parkinsonian from dystonic rats. Next, we compared the deep brain stimulation contact sites in the GP internus used to treat patients with PD (n=21 implants in 12 successive patients) versus dystonia (n=16 implants in nine patients) and found the efficacious territory for ameliorating PD to be located chiefly dorsal to that for dystonia. The comparative distribution for treating PD versus dystonia was therefore anatomically consistent with that for inducing these features via GP lesions in rodents. Our collective findings thus suggest that dystonia and parkinsonism are differentially produced by pathological silencing of GPe neurons along distinct motor sub-circuits, resulting in disparate pathological basal ganglia output signaling.

Effects of transient focal inactivation of the basal ganglia in parkinsonian primates.

Ablative and chronic stimulation procedures targeting the internal pallidum (GPi) and the subthalamic nucleus (STN) have led to major advancements in the treatment of Parkinson's disease and other movement disorders. Although these procedures have evolved to primarily target the posterior ventrolateral sensorimotor portion of GPi and to less selectively target STN, centrally, the ideal targets within these structures remain to be fully established. In this study, we sought to identify the optimal targeting sites in GPi and STN for reversal of parkinsonian signs through a series of reversible injections of the GABA(A) agonist muscimol in these nuclei in parkinsonian primates. Akinesia and bradykinesia were strongly ameliorated by discrete inactivation within the centromedial extent of the sensorimotor territory in GPi and the lateral portion of the sensorimotor territory in STN. This suggests that akinesia and bradykinesia might, in fact, originate from abnormalities in the same, or at least overlapping, motor circuits in the parkinsonian state. Inactivation of areas outside of the motor territories did not improve parkinsonism but induced circling and behavioral abnormalities. The segregation of basal ganglia-thalamocortical circuits appears to be therefore maintained, at least to a large extent, in the parkinsonian state. These results underscore that inactivation of discrete regions in the central territory of GPi and the lateral portion of STN are sufficient to ameliorate parkinsonian motor signs and that extension of lesions into nonmotor territories may be deleterious. Surgical outcomes might therefore be optimized by placing more discrete lesions and by restricting the extent of chronic stimulation.

Movement disorders in the older patient: differential diagnosis and general management.

Movement disorders are especially prevalent in the elderly, and some are highly treatable. Because reduced agility and slowing of gait are associated with numerous movement disorders as well as with the normal aging process, the differential diagnosis of movement disorders in the elderly can be challenging. Many of these disorders share features of parkinsonism-hypokinesia, tremor, and muscular rigidity. This article reviews common and less common movement disorders in the elderly from a primary care perspective, with an emphasis on the presenting features and the differential diagnosis. It also provides general management recommendations with advice for tailoring treatment to elderly patients.

A novel tri-component scheme for classifying neuronal discharge patterns.

BACKGROUND: Neuronal discharge patterns can be described by three principle patterns, namely, regular, irregular, and bursty. NEW METHOD: Available discrimination metrics, including global ISI metrics (e.g., coefficient of variation (CV), asymmetric index), local variables (CV2, CV for a sequence of two ISIs; IR, difference of log of two adjacent ISIs; LVr, local variation with refractory period), Fano factor (FF) and Allan factor (AF), and three new burst metrics, 'burst percentage' (BP), 'burst tendency' (BT) and 'burst entropy' (BE), were extensively tested on representative simulated spike trains. Upon verifying that individual metrics could not by themselves reliably classify the diverse simulation patterns, a novel tri-component classification algorithm was developed. Inadequate metrics were rejected and the remaining selected metrics were grouped and weighted using multiple metric optimization to form three proxy metrics: 'regularity' (combining local variables), 'burstiness' (combining BP, BT and BE), and 'corruption' (combining FF and AF). RESULTS: The accuracy of the proxy metrics was verified on a large set of neuronal spike trains extracellularly recorded from multiple regions of the brain in unsedated normal and dystonic rats. Cross-validation of the tri-component classifier against meticulous subjective classification of these data demonstrated an agreement of 95.9%, with a high discriminatory power of 2.6. COMPARISON WITH EXISTING METHODS: The tri-component classifier was demonstrated to well outperform individual metrics on all aspects of pattern and corruption discrimination. CONCLUSIONS: The tri-component classifier provides a novel, reliable algorithm to differentiate highly diverse neuronal discharge patterns and discriminate natural or erroneous corruption in the signal.

Preserved dichotomy but highly irregular and burst discharge in the basal ganglia in alert dystonic rats at rest.

Despite its prevalence, the underlying pathophysiology of dystonia remains poorly understood. Using our novel tri-component classification algorithm, extracellular neuronal activity in the globus pallidus (GP), STN, and the entopeduncular nucleus (EP) was characterized in 34 normal and 25 jaundiced dystonic Gunn rats with their heads restrained while at rest. In normal rats, neurons in each nucleus were similarly characterized by two physiologically distinct types: regular tonic with moderate discharge frequencies (mean rates in GP, STN and EP ranging from 35-41 spikes/s) or irregular at slower frequencies (17-20 spikes/s), with a paucity of burst activity. In dystonic rats, these nuclei were also characterized by two distinct principal neuronal patterns. However, in marked difference, in the dystonic rats, neurons were primarily slow and highly irregular (12-15 spikes/s) or burst predominant (14-17 spikes/s), with maintained modest differences between nuclei. In GP and EP, with increasing severity of dystonia, burstiness was moderately further increased, irregularity mildly further increased, and discharge rates mildly further reduced. In contrast, these features did not appreciably change in STN with worsening dystonia. Findings of a lack of bursting in GP, STN and EP in normal rats in an alert resting state and prominent bursting in dystonic Gunn rats suggest that cortical or other external drive is normally required for bursting in these nuclei and that spontaneous bursting, as seen in dystonia and Parkinson's disease, is reflective of an underlying pathophysiological state. Moreover, the extent of burstiness appears to most closely correlate with the severity of the dystonia.

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

INTRODUCTION: Our recent report of ocular tremor in Parkinson's 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.

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 Parkinson's 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.

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.

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.

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.