Amy Peters

Doorway-Provoked Freezing of Gait in Parkinson’s Disease

Freezing of gait in Parkinsons disease can be difficult to study in the laboratory. Here we investigate the use of a variable‐width doorway to provoke freeze behavior together with new objective methods to measure it. With this approach we compare the effects of anti‐parkinsonian treatments (medications and deep‐brain stimulation of the subthalamic nucleus) on freezing and other gait impairments. Ten “freezers” and 10 control participants were studied. Whole‐body kinematics were measured while participants walked at preferred speed in each of 4 doorway conditions (no door present, door width at 100%, 125%, and 150% of shoulder width) and in 4 treatment states (offmeds/offstim, offmeds/onstim, onmeds/offstim, onmeds/onstim). With no doorway, the Parkinsons group showed characteristic gait disturbances including slow speed, short steps, and variable step timing. Treatments improved these disturbances. The Parkinsons group slowed further at doorways by an amount inversely proportional to door width, suggesting a visuomotor dysfunction. This was not improved by either treatment alone. Finally, freeze‐like events were successfully provoked near the doorway and their prevalence significantly increased in narrower doorways. These were defined clinically and by 2 objective criteria that correlated well with clinical ratings. The risk of freeze‐like events was reduced by medication but not by deep‐brain stimulation. Freeze behavior can be provoked in a replicable experimental setting using the variable‐width doorway paradigm, and measured objectively using 2 definitions introduced here. The differential effects of medication and deep‐brain stimulation on the gait disturbances highlight the complexity of Parkinsonian gait disorders and their management.

Evidence for early neurodegeneration in the cervical cord of patients with primary progressive multiple sclerosis

Spinal neurodegeneration is an important determinant of disability progression in patients with primary progressive multiple sclerosis. Advanced imaging techniques, such as single-voxel (1)H-magnetic resonance spectroscopy and q-space imaging, have increased pathological specificity for neurodegeneration, but are challenging to implement in the spinal cord and have yet to be applied in early primary progressive multiple sclerosis. By combining these imaging techniques with new clinical measures, which reflect spinal cord pathology more closely than conventional clinical tests, we explored the potential for spinal magnetic resonance spectroscopy and q-space imaging to detect early spinal neurodegeneration that may be responsible for clinical disability. Data from 21 patients with primary progressive multiple sclerosis within 6 years of disease onset, and 24 control subjects were analysed. Patients were clinically assessed on grip strength, vibration perception thresholds and postural stability, in addition to the Expanded Disability Status Scale, Nine Hole Peg Test, Timed 25-Foot Walk Test, Multiple Sclerosis Walking Scale-12, and Modified Ashworth Scale. All subjects underwent magnetic resonance spectroscopy and q-space imaging of the cervical cord and conventional brain and spinal magnetic resonance imaging at 3 T. Multivariate analyses and multiple regression models were used to assess the differences in imaging measures between groups and the relationship between magnetic resonance imaging measures and clinical scores, correcting for age, gender, spinal cord cross-sectional area, brain T2 lesion volume, and brain white matter and grey matter volume fractions. Although patients did not show significant cord atrophy when compared with healthy controls, they had significantly lower total N-acetyl-aspartate (mean 4.01 versus 5.31 mmol/l, P = 0.020) and glutamate-glutamine (mean 4.65 versus 5.93 mmol/l, P = 0.043) than controls. Patients showed an increase in q-space imaging-derived indices of perpendicular diffusivity in both the whole cord and major columns compared with controls (P < 0.05 for all indices). Lower total N-acetyl-aspartate was associated with higher disability, as assessed by the Expanded Disability Status Scale (coefficient = -0.41, 0.01 < P < 0.05), Modified Ashworth Scale (coefficient = -3.78, 0.01 < P < 0.05), vibration perception thresholds (coefficient = -4.37, P = 0.021) and postural sway (P < 0.001). Lower glutamate-glutamine predicted increased postural sway (P = 0.017). Increased perpendicular diffusivity in the whole cord and columns was associated with increased scores on the Modified Ashworth Scale, vibration perception thresholds and postural sway (P < 0.05 in all cases). These imaging findings indicate reduced structural integrity of neurons, demyelination, and abnormalities in the glutamatergic pathways in the cervical cord of early primary progressive multiple sclerosis, in the absence of extensive spinal cord atrophy. The observed relationship between imaging measures and disability suggests that early spinal neurodegeneration may underlie clinical impairment, and should be targeted in future clinical trials with neuroprotective agents to prevent the development of progressive disability.

Neuromechanical interference of posture on movement: evidence from Alexander technique teachers rising from a chair

While Alexander technique (AT) teachers have been reported to stand up by shifting weight gradually as they incline the trunk forward, healthy untrained (HU) adults appear unable to rise in this way. This study examines the hypothesis that HU have difficulty rising smoothly, and that this difficulty relates to reported differences in postural stiffness between groups. A wide range of movement durations (1–8 s) and anteroposterior foot placements were studied under the instruction to rise at a uniform rate. Before seat-off (SO) there were clear and profound performance differences between groups, particularly for slower movements, that could not be explained by strength differences. For each movement duration, HU used approximately twice the forward center-of-mass (CoM) velocity and vertical feet-loading rate as AT. For slow movements, HU violated task instruction by abruptly speeding up and rapidly shifting weight just before SO. In contrast, AT shifted weight gradually while smoothly advancing the CoM, achieving a more anterior CoM at SO. A neuromechanical model revealed a mechanism whereby stiffness affects standing up by exacerbating a conflict between postural and balance constraints. Thus activating leg extensors to take body weight hinders forward CoM progression toward the feet. HUs abrupt weight shift can be explained by reliance on momentum to stretch stiff leg extensors. ATs smooth rises can be explained by heightened dynamic tone control that reduces leg extensor resistance and improves force transmission across the trunk. Our results suggest postural control shapes movement coordination through a dynamic “postural frame” that affects the resistive behavior of the body.

Bilateral Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson Disease Dementia: A Randomized Clinical Trial

Importance Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a treatment option for Parkinson disease dementia. Objective To evaluate the safety and potential symptomatic effects of NBM DBS in patients with Parkinson disease dementia. Design, Setting, and Participants A randomized, double-blind, crossover clinical trial evaluated the results of 6 patients with Parkinson disease dementia who were treated with NBM DBS at a neurosurgical referral center in the United Kingdom from October 26, 2012, to July 31, 2015. Eligible patients met the diagnostic criteria for Parkinson disease dementia, had motor fluctuations, were appropriate surgical candidates aside from the coexistence of dementia, were age 35 to 80 years, were able to give informed consent, had a Mini-Mental State Examination score of 21 to 26, had minimal atrophy seen on results of brain magnetic resonance imaging, and lived at home with a caregiver-informant. Interventions After surgery, patients were assigned to receive either active stimulation (bilateral, low-frequency [20 Hz] NBM DBS) or sham stimulation for 6 weeks, followed by the opposite condition for 6 weeks. Main Outcomes and Measures The primary outcome was the difference in scores on each item of an abbreviated cognitive battery (California Verbal Learning Test-II, Wechsler Adult Intelligence Scale-III digit span, verbal fluency, Posner covert attention test, and simple and choice reaction times) between the 2 conditions. Secondary outcomes were exploratory and included differences in scores on standardized measurements of cognitive, psychiatric, and motor symptoms and resting state functional magnetic resonance imaging. Results Surgery and stimulation were well tolerated by all 6 patients (all men; mean [SD] age, 65.2 [10.7] years), with no serious adverse events during the trial. No consistent improvements were observed in the primary cognitive outcomes or in results of resting state functional magnetic resonance imaging. An improvement in scores on the Neuropsychiatric Inventory was observed with NBM DBS (8.5 points [range, 4-26 points]) compared with sham stimulation (12 points [range, 8-38 points]; median difference, 5 points; 95% CI, 2.5-8.5 points; P = .03) and the preoperative baseline (13 points [range, 5-25 points]; median difference, 2 points; 95% CI, −8 to 5.5 points; P = .69). Conclusions and Relevance Low-frequency NBM DBS was safely conducted in patients with Parkinson disease dementia; however, no improvements were observed in the primary cognitive outcomes. Further studies may be warranted to explore its potential to improve troublesome neuropsychiatric symptoms. Trial Registration clinicaltrials.gov Identifier: NCT01701544

Maintaining balance against force perturbations: impaired mechanisms unresponsive to levodopa in Parkinson's disease

We introduce a new method to investigate postural instability in Parkinsons disease (PD) using computer-controlled motors to deliver precise pulls to the shoulders of subjects while standing. It mimics the clinical pull test but uses forces with unpredictable timing, direction, and magnitude. It revealed a number of balance control deficits in PD. Notably, the identified deficits were not significantly altered by levodopa medication, suggesting that disruption to nondopaminergic systems contributes to postural instability in PD.

Assessment of the e-AR sensor for gait analysis of Parkinson;s Disease patients

This paper analyses gait patterns of patients with Parkinsons Disease (PD) based on the acceleration data given by an e-AR sensor. Ten PD patients wearing the e-AR sensor walked along a 7m walkway and each session contained 16 repeated trials. An iterative algorithm has been proposed to produce robust estimations in the case of measurement noise and short-duration of gait signals. Step-frequency as a gait parameter derived from the estimated heel-contacts is calculated and validated using the CODA motion-capture system. Intersession variability of step-frequency for each patient and the overall variability across patients demonstrate a good agreement between estimations from the e-AR and CODA systems.

Thalamic‐Caudal Zona Incerta Deep Brain Stimulation for Refractory Orthostatic Tremor: A Report of 3 Cases

Orthostatic tremor (OT) is a rare, disabling movement disorder characterized by the development of a high‐frequency tremor of the lower limbs and feelings of unsteadiness upon standing, which compel the patient to sit down or walk. Medical therapy is often unsatisfactory. Previous reports suggest that deep brain stimulation of the ventral intermediate nucleus of the thalamus may improve clinical outcomes. The authors report 3 patients who had intractable orthostatic tremor treated with bilateral deep brain stimulation of the ventral intermediate nucleus of the thalamus‐caudal zona incerta, resulting in improved and sustained clinical improvements in symptoms, although there were no apparent changes in the underlying tremor frequency or onset.