Beta Burst-Driven Adaptive Deep Brain Stimulation Improves Gait Impairment and Freezing of Gait in Parkinson's Disease.

Background: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) that is often refractory to medication. Pathological prolonged beta bursts within the subthalamic nucleus (STN) are associated with both worse impairment and freezing behavior in PD, which are improved with deep brain stimulation (DBS). The goal of the current study was to investigate the feasibility, safety, and tolerability of beta burst-driven adaptive DBS (aDBS) for FOG in PD. Methods: Seven individuals with PD were implanted with the investigational Summit™ RC+S DBS system (Medtronic, PLC) with leads placed bilaterally in the STN. A PC-in-the-loop architecture was used to adjust stimulation amplitude in real-time based on the observed beta burst durations in the STN. Participants performed either a harnessed stepping-in-place task or a free walking turning and barrier course, as well as clinical motor assessments and instrumented measures of bradykinesia, OFF stimulation, on aDBS, continuous DBS (cDBS), or random intermittent DBS (iDBS). Results: Beta burst driven aDBS was successfully implemented and deemed safe and tolerable in all seven participants. Gait metrics such as overall percent time freezing and mean peak shank angular velocity improved from OFF to aDBS and showed similar efficacy as cDBS. Similar improvements were also seen for overall clinical motor impairment, including tremor, as well as quantitative metrics of bradykinesia. Conclusion: Beta burst driven adaptive DBS was feasible, safe, and tolerable in individuals with PD with gait impairment and FOG.

A novel method for calculating beta band burst durations in Parkinson's disease using a physiological baseline.

BACKGROUND: Pathologically prolonged bursts of neural activity in the 8-30 Hz frequency range in Parkinson's disease have been measured using high power event detector thresholds. NEW METHOD: This study introduces a novel method for determining beta bursts using a power baseline based on spectral activity that overlapped a simulated 1/f spectrum. We used resting state local field potentials from people with Parkinson's disease and a simulated 1/f signal to measure beta burst durations, to demonstrate how tuning parameters (i.e., bandwidth and center frequency) affect burst durations, to compare burst duration distributions with high power threshold methods, and to study the effect of increasing neurostimulation intensities on burst duration. RESULTS: The baseline method captured a broad distribution of resting state beta band burst durations. Mean beta band burst durations were significantly shorter on compared to off neurostimulation (p = 0.0046), and their distribution shifted towards that of the 1/f spectrum during increasing intensities of stimulation. COMPARISON WITH EXISTING METHODS: High power event detection methods, measure duration of higher power bursts and omit portions of the neural signal. The baseline method captured the broadest distribution of burst durations and was more sensitive than high power detection methods in demonstrating the effect of neurostimulation on beta burst duration. CONCLUSIONS: The baseline method captured a broad range of fluctuations in beta band neural activity and demonstrated that subthalamic neurostimulation shortened burst durations in a dose (intensity) dependent manner, suggesting that beta burst duration is a useful control variable for closed loop algorithms.

Dual threshold neural closed loop deep brain stimulation in Parkinson disease patients.

BACKGROUND: Closed loop deep brain stimulation (clDBS) in Parkinson's disease (PD) using subthalamic (STN) neural feedback has been shown to be efficacious only in the acute post-operative setting, using externalized leads and stimulators. OBJECTIVE: To determine feasibility of neural (N)clDBS using the clinical implanted neurostimulator (Activa™ PC + S, FDA IDE approved) and a novel beta dual threshold algorithm in tremor and bradykinesia dominant PD patients on chronic DBS. METHODS: 13 PD subjects (20 STNs), on open loop (ol)DBS for 22 ±â€¯7.8 months, consented to NclDBS driven by beta (13-30 Hz) power using a dual threshold algorithm, based on patient specific therapeutic voltage windows. Tremor was assessed continuously, and bradykinesia was evaluated after 20 min of NclDBS using a repetitive wrist flexion-extension task (rWFE). Total electrical energy delivered (TEED) on NclDBS was compared to olDBS using the same active electrode. RESULTS: NclDBS was tolerated for 21.67 [21.10-26.15] minutes; no subject stopped early. Resting beta band power was measurable and similar between tremor and bradykinesia dominant patients. NclDBS improved bradykinesia and tremor while delivering only 56.86% of the TEED of olDBS; rWFE velocity (p = 0.003) and frequency (p < 0.001) increased; tremor was below 0.15 rad/sec for 95.4% of the trial and averaged 0.26 rad/sec when present. CONCLUSION: This is the first study to demonstrate that STN NclDBS is feasible, efficacious and more efficient than olDBS in tremor and bradykinesia dominant PD patients, on long-term DBS, using an implanted clinical neurostimulator and driven by beta power with a novel dual threshold algorithm, based on customized therapeutic voltage windows.

Aging with HIV-1 Infection: Motor Functions, Cognition, and Attention--A Comparison with Parkinson's Disease.

Recent advances in highly active anti-retroviral therapy (HAART) in their various combinations have dramatically increased the life expectancies of HIV-infected persons. People diagnosed with HIV are living beyond the age of 50 but are experiencing the cumulative effects of HIV infection and aging on brain function. In HIV-infected aging individuals, the potential synergy between immunosenescence and HIV viral loads increases susceptibility to HIV-related brain injury and functional brain network degradation similar to that seen in Parkinson's disease (PD), the second most common neurodegenerative disorder in the aging population. Although there are clear diagnostic differences in the primary pathology of both diseases, i.e., death of dopamine-generating cells in the substantia nigra in PD and neuroinflammation in HIV, neurotoxicity to dopaminergic terminals in the basal ganglia (BG) has been implied in the pathogenesis of HIV and neuroinflammation in the pathogenesis of PD. Similar to PD, HIV infection affects structures of the BG, which are part of interconnected circuits including mesocorticolimbic pathways linking brainstem nuclei to BG and cortices subserving attention, cognitive control, and motor functions. The present review discusses the combined effects of aging and neuroinflammation in HIV individuals on cognition and motor function in comparison with age-related neurodegenerative processes in PD. Despite the many challenges, some HIV patients manage to age successfully, most likely by redistribution of neural network resources to enhance function, as occurs in healthy elderly; such compensation could be curtailed by emerging PD.

Perceptual errors increase with movement duration and may contribute to hypokinesia in Parkinson's disease.

People with Parkinson's disease (PD) perceive that their movement amplitude is greater than what they actually perform. The neural mechanisms underlying one's perception of movement are believed to involve the sensorimotor integration process (SIP). How PD affects the SIP is not well understood. A previous study interrogating the SIP showed healthy adults (HAs) overestimated their limb position in the direction of movement and the error and its variance (VOE) depended on movement duration. We asked if PDs showed errors in perceived limb position and if the dependence on movement duration was different from HAs. We used an existing computational model of the SIP to explore mechanisms for the error and VOE as a function of movement duration. Twenty PDs, off medication, and 20 age-matched HAs were asked to estimate the position of their hand after performing 50, slow, non-visually guided wrist flexion or extension movements for a random period of time (<4.0 s). Both groups overestimated the amount they moved; however, the PDs' error and VOE were larger (p<0.001). HAs showed increasing error/VOE for small movement durations that reduced/stabilized for longer movement durations. PDs however showed increasing error/VOE with increasing movement duration that did not significantly improve/stabilize. The model suggested that the basis for such perceptual deficits may be abnormal proprioceptive feedback and/or processing of an abnormal internal impression (prediction) that underestimates movement amplitude. Simulation results imply that the PD's SIP could no longer effectively access sensory (proprioceptive) feedback to correct errors in other components of the SIP due to the abnormal processing of sensory feedback. We suggest from this study that an impaired perception of movement amplitude and sensory processing deficits contribute to hypokinesia in PD.

Deficits in visuospatial processing contribute to quantitative measures of freezing of gait in Parkinson's disease.

OBJECTIVES: The aim of this study was to investigate whether an objective measure of freezing of gait (FOG) using a validated alternating stepping in place (SIP) task, is related to executive and/or visuospatial cognitive impairment in Parkinson's disease (PD). METHODS: We studied prospectively 30 PD subjects with the Unified Parkinson's Disease Rating Scale (UPDRS) III, the FOGq, Trail Making Test Part B (TMTB), Wisconsin Card Sorting, Initiation/Perseveration, Matrix Reasoning (MR) and Block Design (BD). PD subjects performed three, 100s trials of alternative SIP while standing on two force platforms to assess the number and duration of freezing episodes (FE), SIP rhythmicity and symmetry. RESULTS: Freezers had larger cycle asymmetry and arrhythmicity than non-freezers (P<0.05). Performance on BD and MR tests differentiated freezers from non-freezers (P<0.04; P=0.001, respectively). BD performance negatively correlated with the FOGq total (P<0.05), the number and duration of FE (P<0.01), SIP arrhythmicity and asymmetry (P=0.01, P<0.05). MR performance negatively correlated with all FOGq #3 and total as well as SIP FE metrics (P≤0.01), except for SIP asymmetry. CONCLUSION: Deficits in visuospatial perception and reasoning not in executive function differentiated freezers from non-freezers. Deficits in visuospatial processing negatively correlated with all SIP freeze metrics, whereas deficits in executive function were only correlated with SIP arrhythmicity, the FOGq total and the duration of freezing episodes. These results suggest that deficits in visuospatial processing to perform a motor task contribute to FOG and that different cognitive deficits may contribute to different aspects of freezing in PD. This is the first study to our knowledge that has compared metrics of freezing to cognitive tasks in the visuospatial and visual reasoning domains.

Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To make evidence-based treatment recommendations for the medical and surgical treatment of patients with Parkinson disease (PD) with levodopa-induced motor fluctuations and dyskinesia. To that end, five questions were addressed. 1. Which medications reduce off time? 2. What is the relative efficacy of medications in reducing off time? 3. Which medications reduce dyskinesia? 4. Does deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus interna (GPi), or ventral intermediate (VIM) nucleus of the thalamus reduce off time, dyskinesia, and antiparkinsonian medication usage and improve motor function? 5. Which factors predict improvement after DBS? METHODS: A 10-member committee including movement disorder specialists and general neurologists evaluated the available evidence based on a structured literature review including MEDLINE, EMBASE, and Ovid databases from 1965 through June 2004. RESULTS, CONCLUSIONS, AND RECOMMENDATIONS: 1. Entacapone and rasagiline should be offered to reduce off time (Level A). Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B). Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C). 2. The available evidence does not establish superiority of one medicine over another in reducing off time (Level B). Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C). 3. Amantadine may be considered to reduce dyskinesia (Level C). 4. Deep brain stimulation of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C). There is insufficient evidence to support or refute the efficacy of DBS of the GPi or VIM nucleus of the thalamus in reducing off time, dyskinesia, or medication usage, or to improve motor function. 5. Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B).

The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer's type.

OBJECTIVE: To evaluate the production rate of CSF in patients with differing disease states. METHODS: The authors measured the production rate of CSF in three groups of patients: five patients with PD below age 60 (aged 51 +/- 4 years, mean +/- SD), nine with PD over age 60 (aged 69 +/- 6 years, mean +/- SD), and seven with dementia of the Alzheimer's type (AD) (aged 72 +/- 9 years, mean +/- SD). This method, based on the Masserman technique, employs ventricular rather than a lumbar access to the CSF space. Furthermore, the volume of CSF removed during the procedure is only 3 mL rather than 10 mL. RESULTS: These measurements indicate that the mean rate of CSF production in patients with PD under age 60 was 0.47 +/- 0.13 mL/minute, in patients with PD aged 60 or older the mean rate was 0.40 +/- 0.12 mL/minute, and in patients with AD the mean rate was 0.20 +/- 0.06 mL/minute. CONCLUSION: These results indicate that the rate of CSF production in patients with PD is normal, and that the rate of CSF production in patients with AD is markedly reduced.

Concurrent Parkinson tremors.

1. Concurrent resting and postural tremors of patients with idiopathic Parkinson's disease were monitored using transducers responding to angular velocity of rotation. Spectra and correlation functions were calculated for each pair of records. 2. When concurrent tremor spectra share indistinguishable fundamental frequencies, have statistically significant peaks in their coherence spectra at those fundamental frequencies, and show significant peaks in their cross-correlation functions near zero delay, they are classified as linearly dependent. When such tremor records are superimposed, their phase-locked behaviour is evident. 3. Pairs of correlated concurrent tremors, of varying duration, have been observed in both hands, both feet and in either hand and the contralateral or ipsilateral foot. Correlated tremors may be concurrent with other tremors that are independent. We hypothesize that correlated Parkinson tremors arise from one or more common (and possibly unilateral) central sources.

Quantitative digitography (QDG): a sensitive measure of digital motor control in idiopathic Parkinson's disease.

This study introduces a new method for studying, quantitatively, the dynamics of finger movement using data obtained from sequences of key strikes on a computer-interfaced piano keyboard. We have called this quantitative digitography (QDG). This initial article introduces the method in a group of patients with Parkinson's disease and in a group of healthy subjects using simple, repetitive, alternating finger-tapping for 60 seconds. Patients with idiopathic Parkinson's disease (IPD) were studied "ON" and "OFF" dopaminergic medication before and after pallidotomy. Customized software allowed the independent analysis of key strike velocity, duration of key strike, and frequency of tapping along with a quantitative measure of the regularity of performance. Quantitative measures of the improvement in performance after medication are presented for each parameter of movement. The technique also reveals correlates of some clinical phenomena of the temporal disturbances of repetitive motion in IPD, such as fatigue, tremor, freezing, and festination. We demonstrate that the performance of 60 seconds of alternating finger tapping on a computerized keyboard yields objective measures of motor performance that are significantly different in patients with IPD "OFF" when compared with "ON" medication and when compared with healthy subjects. This is the first time that such a method has been used in the measurement of specific kinematics of digital motion in Parkinson's disease. The equipment is inexpensive and portable and the data are rapidly and easily collected, making it suitable for the outpatient setting.

Neural basis for motor learning in the vestibuloocular reflex of primates. II. Changes in the responses of horizontal gaze velocity Purkinje cells in the cerebellar flocculus and ventral paraflocculus.

1. We made extracellular recordings from Purkinje cells in the flocculus and ventral paraflocculus of awake monkeys before and after motor learning in the vestibuloocular reflex (VOR). Three samples were recorded 1) after miniaturizing spectacles had reduced the gain of the VOR (eye speed divided by head speed) to 0.4; 2) when the gain of the VOR was near 1.0; and 3) after magnifying spectacles had increased the gain of the VOR to 1.6. 2. We studied Purkinje cells that showed stronger modulation of simple-spike firing rate during horizontal than during vertical pursuit. These cells corresponded to the previously identified "horizontal gaze velocity Purkinje cells" or HGVP-cells. During pursuit of smooth target motion with the head stationary, HGVP-cells showed strong modulation of firing rate with increases for ipsiversive eye motion (toward the side of recording). When the monkey canceled his VOR by tracking a target that moved exactly with him during sinusoidal head rotation in the horizontal plane, HGVP-cells again showed strong modulation of firing rate with increases for ipsiversive head motion. 3. The responses of HGVP-cells during pursuit with the head stationary and during cancellation of the VOR reveal separate components of firing rate related to eye and head velocity. We used these two behavioral conditions to test for effects of motor learning on the head and eye velocity components of the simple-spike firing of HGVP-cells. Our data confirm the previous observation that motor learning causes the sensitivity to head velocity to be larger when the gain of the VOR is high and smaller when the gain of the VOR is low. Thus we agree with the previous conclusion that changes in the vestibular sensitivity of HGVP-cells, measured during sinusoidal head motion at low frequencies, are in the wrong direction to cause changes in the gain of the VOR. 4. To determine whether the simple-spike output from the HGVP-cells plays a role in the VOR after motor learning, we recorded simple-spike firing during the VOR evoked by transient, rapid changes in head velocity in darkness. When the gain of the VOR was low, firing rate increased during the VOR evoked by ipsiversive head motion and decreased during the VOR evoked by contraversive head motion. When the gain of the VOR was high, the direction selectivity of the responses was reversed.(ABSTRACT TRUNCATED AT 400 WORDS)

Physiological properties of vestibular primary afferents that mediate motor learning and normal performance of the vestibulo-ocular reflex in monkeys.

We have used electrical stimulation of the vestibular apparatus to reveal parallels between the physiological responses of the vestibular afferents activated at different currents and the properties of the evoked eye movements before and after magnifying spectacles had been used to cause motor learning in the vestibulo-ocular reflex (VOR). Stimulation with the lowest currents caused little or no eye motion, but activated all the afferents with irregular spontaneous discharge, low sensitivities to head velocity, and highly phasic responses during rapid head turns. Stimulation with moderate currents caused substantial eye motion that was weakly affected by motor learning; these currents activated afferents with a wide range of physiological properties, including many that had intermediate discharge regularity, high sensitivity to head velocity, and clear phasic responses during rapid head turns. Stimulation at still higher currents caused still larger eye movements that were strongly altered by motor learning; these currents activated primarily afferents that had regular spontaneous discharge, lower sensitivities to head velocity, and tonic responses during rapid head turns. Stimulation at the highest currents did not cause any further increment in the amplitude of the evoked eye movement, but activated the afferents with the most regular spontaneous discharge and the lowest sensitivities to head velocity. The data imply that the VOR pathways receive substantial vestibular inputs from afferents with a middle range of thresholds for electrical stimulation. These afferents have a wide range of physiological properties, including a large group that shows substantial phasic responses during rapid head turns. The data also suggest that only a subset of these afferents, primarily those with more regular spontaneous discharge, project into the VOR pathways that are modified in association with motor learning.

Expression of motor learning in the response of the primate vestibuloocular reflex pathway to electrical stimulation.

1. The vestibuloocular reflex (VOR) undergoes long-term adaptive changes in the presence of persistent retinal image motion during head turns. Previous experiments using natural stimuli have provided evidence that the VOR is subserved by parallel pathways, including some that are modified during learning and some that are not. We have used electrical stimulation of the vestibular labyrinth to investigate the temporal properties of the signals that are transmitted through the modified pathways. 2. Electrodes were implanted chronically in the superior semi-circular canal, the horizontal canal, or the vestibule for electrical activation of the vestibular afferents. Learning was induced by fitting the monkeys with spectacles that magnified or miniaturized vision. Before, during, and after motor learning, we measured the eye movements evoked by electrical stimulation of the labyrinth as well as the gain of the VOR, defined as eye speed divided by head speed during natural vestibular stimulation in the dark. 3. Trains of pulses applied to the labyrinth caused the eyes to move away from the side of stimulation with an initial rapid change in eye velocity followed by a steady-state plateau. Changes in the gain of the VOR caused large changes in the trajectory and magnitude of eye velocity during the plateau, showing that our stimulating electrodes had access to the modified pathways. 4. A single, brief current pulse applied to the labyrinth evoked an eye movement that had a latency of 5 ms and consisted of a pulse of eye velocity away from the side of the stimulation followed by a rebound toward the side of stimulation. To quantify the effect of motor learning on these eye movements, we pooled the data across different VOR gains and computed the slope of the relationship between eye velocity and VOR gain at each millisecond after the stimulus. We refer to the slope as the "modification index." 5. In comparison with the evoked eye velocity, the modification index took longer to return to baseline and showed a large peak at the time of the rebound in eye velocity. Increases in stimulus current increased both the amplitude and the duration of the modification index and revealed several later peaks. These observations suggest that the full expression of motor learning requires activation of multisynaptic pathways and recruitment of primary vestibular afferents with higher thresholds for electrical stimulation. 6. The modification index was almost always positive during the initial deflection in eye velocity, and the latency of the first change in the modification index was usually the same as the latency of the evoked eye movement.(ABSTRACT TRUNCATED AT 400 WORDS)

Lacunar infarction of the basal ganglia as a complication of hemolytic-uremic syndrome. MRI and clinical correlations.

Central nervous system (CNS) complications of hemolytic-uremic syndrome (HUS) commonly consist of alterations in mental status, seizures, and rarely hemiparesis. The authors report the clinical evolution of left hemiparesis and later choreo-athetoid movements in a patient who sustained a right lacunar infarction as a complication of HUS. The infarction is demonstrated on magnetic resonance imaging (MRI).