Anxiety‐provoked gait changes are selectively dopa‐responsive in Parkinson's disease

In order to understand how dopamine modulates the effect of anxiety on gait, the goal of this study was to use virtual reality to provoke anxiety in Parkinson's disease (PD) (in both ON and OFF states) and quantify its effect on gait. Seventeen participants with PD and 20 healthy age‐matched controls were instructed to walk in a virtual environment in two anxiety‐provoking conditions: (i) across a plank that was located on the GROUND and (ii) across an ELEVATED plank. All participants with PD completed this experiment in both the ON and OFF states, and were then striated into groups based on baseline trait anxiety scores for further analyses. Anxiety (skin conductance and self‐report) and spatiotemporal aspects of gait were measured. Overall, the ELEVATED condition resulted in greater skin conductance levels and self‐reported anxiety levels. Additionally, all participants demonstrated slower gait with increased step‐to‐step variability when crossing the ELEVATED plank compared with the plank on the GROUND. The results showed that dopaminergic treatment selectively improved gait in only the highly anxious PD group, by significantly improving velocity, step length, step time and step‐to‐step variability specifically when walking across the ELEVATED plank (ON vs. OFF comparison). In conclusion, only highly trait anxious participants with PD benefitted from dopaminergic treatment, specifically when walking in the anxiety‐provoking environment. Improvements to gait during anxious walking might be a result of dopaminergic medication acting in two ways: (i) improving the basal ganglia's capacity to process information and (ii) reducing the load from anxiety and subsequently making more resources available to effectively process other competing inputs.     

Saccade frequency response to visual cues during gait in Parkinson's disease: the selective role of attention

Gait impairment is a core feature of Parkinson's disease (PD) with implications for falls risk. Visual cues improve gait in PD, but the underlying mechanisms are unclear. Evidence suggests that attention and vision play an important role; however, the relative contribution from each is unclear. Measurement of visual exploration (specifically saccade frequency) during gait allows for real‐time measurement of attention and vision. Understanding how visual cues influence visual exploration may allow inferences of the underlying mechanisms to response which could help to develop effective therapeutics. This study aimed to examine saccade frequency during gait in response to a visual cue in PD and older adults and investigate the roles of attention and vision in visual cue response in PD. A mobile eye‐tracker measured saccade frequency during gait in 55 people with PD and 32 age‐matched controls. Participants walked in a straight line with and without a visual cue (50 cm transverse lines) presented under single task and dual‐task (concurrent digit span recall). Saccade frequency was reduced when walking in PD compared to controls; however, visual cues ameliorated saccadic deficit. Visual cues significantly increased saccade frequency in both PD and controls under both single task and dual‐task. Attention rather than visual function was central to saccade frequency and gait response to visual cues in PD. In conclusion, this study highlights the impact of visual cues on visual exploration when walking and the important role of attention in PD. Understanding these complex features will help inform intervention development.     

Examination of central gait control mechanisms in Parkinson's disease using movement‐related potentials

Gait disorders are common in people with Parkinson's disease. The pathophysiology of these disorders is not fully understood. Movement‐related potentials reflect supplementary motor area activity associated with the preparation and execution of voluntary movement. Our aim was to investigate movement‐related potentials associated with gait disturbances in patients with Parkinson's disease, as reflected by gait hypokinesia and initiation difficulties, in order to better understand the role of the basal ganglia in the pathogenesis of these conditions. Movement‐related potentials were back‐averaged from electroencephalography recordings performed on 11 participants with Parkinson's disease with no gait initiation difficulties, 9 participants with Parkinson's disease who suffered from gait initiation difficulties, 12 young healthy adults, and 8 healthy older adults. Participants took 3 steps forward, stepping off a force plate. Trigger signals from the force plate and electromyographic activity of the tibialis anterior muscle were used to identify gait initiation time. Participants' stride length was also measured using a 3‐dimensional motion analysis system. Movement‐related potentials showed significant group differences between the healthy young adults and the 2 Parkinson's disease groups as well as the Parkinson's disease group as a whole. No significant difference was found between the participants with Parkinson's disease and age‐matched controls. A significant inverse relationship between movement‐related potentials and stride length was found in patients with Parkinson's disease who did not experience gait initiation difficulties but not in those who did have this symptom. Gait‐generated movement‐related potentials appear to show electrical evidence of cortical disturbances correlated with stride length reduction in patients with Parkinson's disease without gait initiation difficulties. © 2011 Movement Disorder Society     

Impact of internal versus external cueing on driving performance in people with Parkinson's disease.

Numerous aspects of driving performance seem compromised in people with Parkinson's disease (PD). Measures of cognitive impairment consistently correlate with poor driving simulator performance in this population; however, the effects of specific cognitive difficulties on discrete aspects of driving behavior have not been investigated thoroughly. Previous studies have demonstrated that people with PD exhibit difficulties internally cueing cognitive processes. This study examined the impact of impaired internal cueing on specific driving behaviors. A simulator measured the driving behavior of 18 current drivers in the mild-to-moderate stages of PD and 18 matched controls. Participants navigated through different driving conditions where the opportunity to use internal and external cues was manipulated. People with PD exhibited difficulties using internal cues to regulate driving behavior around traffic signals and curves. Instead of using internal cues, participants with PD were more reliant on external cues to regulate driving behavior. They were also less able to adapt their driving behavior to suit driving conditions. Because all participants with PD were current drivers in the mild-to-moderate stages of the disease, findings challenge the widely-held assumption that cognitive difficulties only impact on driving performance in the moderate-to-severe stages of PD.     

Progression of gait dysfunction in incident Parkinson's disease: Impact of medication and phenotype

Gait impairment in Parkinson's disease (PD) persists despite the use of dopaminergic therapy. Motor phenotype associated with greater postural instability and gait difficulty is related to a greater risk of motor decline and may be influenced by non-dopaminergic pathology. This study documents the progression of gait impairment over 18 months in an incident cohort of PD with regard to phenotype and medication. Gait characteristics were measured in 121 PD and 184 controls, and 18 months later in 108 PD participants. Sixteen gait characteristics were examined with respect to five broad domains for PD and motor phenotype. Correlations between change in levodopa (l -dopa) equivalent daily dose and gait were used to identify dopa-responsive and nonresponsive characteristics. Pace and rhythm deteriorated over 18 months in people with PD, with other gait domains remaining stable. People with a postural instability and gait difficulty phenotype had more impaired gait at baseline compared with a tremor-dominant phenotype, which was most evident in temporal characteristics. In contrast, pace and variability deteriorated over the subsequent 18 months in the tremor-dominant phenotype only. Weak but statistically significant correlations were found between increased l -dopa medication and less deterioration in pace and asymmetry. Significant gait impairment is evident in very early disease despite optimal medication. Change over 18 months is subtle and discrete, and is more pronounced in the tremor-dominant phenotype. Some features of gait are refractory to dopaminergic therapy, implicating a non-dopaminergic contribution. This may explain more temporal gait disturbance in the postural instability and gait difficulty phenotype. © 2014 International Parkinson and Movement Disorder Society     

Influence of pallidal stimulation and levodopa on gait and preparatory postural adjustments in Parkinson's disease.

In order to assess the influence of the bilateral internal globus pallidus (GPi) stimulation on gait and postural instability in Parkinson's disease (PD), we compared gait kinematic parameters and preparatory postural adjustments before and 3 months after stimulation in off- and on-drug conditions for seven patients. Gait kinematic parameters and displacements of centre of pressure (CP) and shoulder computed before a lateral raising task of the leg, were recorded using optoelectric Vicon system. Levodopa (L-dopa) induced a clear benefit for gait velocity (related to an increase of stride length) and also an increase of swing phase duration. GPi stimulation had a limited effect, since the increase of gait velocity was induced by a concomitant increase of stride length and cadence corresponding to a compensatory mechanism. The benefit on swing phase duration was also moderate. Displacements of CP were improved mainly by L-dopa. GPi stimulation and L-dopa had the same beneficial effect on the speed at which the CP was transferred back towards the support side, the ankle velocity, the onset time for ankle displacement, and the decrease of shoulder amplitude towards the support side, which reflects a better postural adjustment phase. This study, based on an objective method, revealed that chronic bilateral GPi stimulation may improve gait and preparatory postural adjustments in severe PD patients with a more limited effect than L-dopa.     

Interaction of levodopa and cues on voluntary reaching in Parkinson's disease.

The bradykinesia associated with Parkinson's disease (PD) can be improved by both levodopa and the use of external cues. We examined the combined effect of levodopa and external cueing on the voluntary reaching movements of individuals with PD. Nine subjects with PD and nine matched controls were studied reaching to a ball target. Subjects with PD were studied after being off levodopa overnight and again on their morning dose. Kinematic data were collected as all subjects made both accurate and fast reaches under two different cue conditions: noncued (self-initiated) and cued (triggered by a light). Subjects with PD reached more slowly than controls under all conditions. PD subjects increased their reach velocity and decreased movement time after taking levodopa and also when moving to a cue. However, the effects of levodopa and cueing were not additive. Instead, levodopa improved reach velocity to a greater extent in the noncued vs. cued condition. We also found that levodopa improved accurate (self-paced) reaches more than fast reaches. These data suggest that levodopa may preferentially improve voluntary reaches that are more internally generated.     

Effects of augmented proprioceptive cues on the parameters of gait of individuals with Parkinson's disease

Context:

Impairment of initiating sequential movements and processing of proprioception contribute to characteristic Parkinson''s disease (PD) gait abnormalities. Many studies have used a single external cue or 2 different cues to correct PD gait.

Aim:

An aim of this study was to determine the influence of paired proprioceptive cues on gait parameters of individuals with PD.

Setting and Design:

Double-blind randomized controlled trial.

Materials and Methods:

Subjects were 30 PD patients who had mild to moderate impairment according to the United Parkinson''s Disease Rating Scale (UPDRS). They were randomly assigned to either a routine physiotherapy program or treadmill training with vibratory stimuli applied to the feet plantar surfaces and proprioceptive neuromuscular facilitation (PNF) as well as the same physiotherapy program. All Participants received a 45-minutes session of low intensity physiotherapy program, 3 times a week, for 8 weeks. The duration of treadmill training was 5 minutes at baseline and 25 minutes at the end of treatment. Walking speed and distance were recorded from the treadmill control panel for both groups before and immediately after the end of treatment. The Qualysis ProReflex motion analysis system was used to measure cadence, stride length, hip, knee, and ankle joints’ angular excursion.

Results:

The cadence, stride length, and lower limb joints’ angular excursion showed a significant improvement in both groups (P ≤ 0.05). These improvements in spatio-temporal parameters and angular excursion were higher in the study group than in the control group (P ≤ 0.05).

Conclusion:

Potentiated proprioceptive feedback improves parkinsonian gait kinematics, the hip, knee, and ankle joints’ angular excursion.     

Doorway-provoked freezing of gait in Parkinson's disease

Freezing of gait in Parkinson's 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 Parkinson's group showed characteristic gait disturbances including slow speed, short steps, and variable step timing. Treatments improved these disturbances. The Parkinson's 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.     

Ceftriaxone reduces L‐dopa–induced dyskinesia severity in 6‐hydroxydopamine parkinson's disease model

Background: Increased extracellular glutamate may contribute to l ‐dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l ‐dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT‐1 expression in a rat 6‐hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l ‐dopa, could reduce l ‐dopa–induced dyskinesia in an established dyskinesia model. Methods: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post‐6‐hydroxydopamine lesion (days 7‐13) and continued every other week (days 21‐27, 35‐39) until the end of the study (day 39 postlesion, 20 days of l ‐dopa). Results: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l ‐dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l ‐dopa was unaffected by ceftriaxone. The ceftriaxone‐treated l ‐dopa group had significantly increased striatal GLT‐1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l ‐dopa alone group. Conclusions: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l ‐dopa, may reduce dyskinesia severity without affecting l ‐dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. © 2017 International Parkinson and Movement Disorder Society     

Effect of high‐frequency subthalamic neurostimulation on gait and freezing of gait in Parkinson's disease: a systematic review and meta‐analysis

The aim of this meta‐analysis was to summarize the short‐ and long‐term effects of bilateral deep brain stimulation of the subthalamic nucleus (STN‐DBS) on gait and freezing of gait (FOG) in Parkinson's disease and to detect predictors of post‐stimulation outcome. A comprehensive review of the literature was conducted up to October 2015 using Medline Ovid databases for studies analyzing the effect of bilateral STN‐DBS on FOG and/or gait. Sixteen studies with available data for the gait item (no. 29) of the Unified Parkinson's Disease Rating Scale (UPDRS) and six studies with the FOG item (no. 14) were included. Data were summarized for the following follow‐up periods: 6–15, 24–48 and >48 months. For the medication (Med)‐Off/stimulation(Stim)‐On condition compared with baseline Med‐Off, STN‐DBS significantly improved gait on average from 2.43 to 0.96, 2.53 to 1.31 and 2.56 to 1.40 points at 6–15, 24–48 and >48 months, respectively (P < 0.05). Pre‐operative levodopa responsiveness of UPDRS‐III and Med‐Off severity of gait were the predictors of this beneficial effect. STN‐DBS significantly improved FOG for the Med‐Off/Stim‐On condition compared with baseline on average from 2.26 to 0.82, 2.43 to 1.13 and 2.48 to 1.38 points at 6–15, 24–48 and >48 months, respectively (P < 0.05). There was no significant effect in the Med‐On/Stim‐On condition. This meta‐analysis showed a robust improvement of gait and FOG by STN‐DBS for more than 4 years in the Med‐Off/Stim‐On condition. No beneficial effect was found for the On state of medication. Pre‐operative levodopa responsiveness of global motor performance (UPDRS‐III) is the strongest predictor of the effect of deep brain stimulation on gait.     

Speech and gait in Parkinson's disease: When rhythm matters

IntroductionSpeech disturbances in Parkinson's disease (PD) are heterogeneous, ranging from hypokinetic to hyperkinetic types. Repetitive speech disorder has been demonstrated in more advanced disease stages and has been considered the speech equivalent of freezing of gait (FOG). We aimed to verify a possible relationship between speech and FOG in patients with PD.MethodsForty-three consecutive PD patients and 20 healthy control subjects underwent standardized speech evaluation using the Italian version of the Dysarthria Profile (DP), for its motor component, and subsets of the Battery for the Analysis of the Aphasic Deficit (BADA), for its procedural component. DP is a scale composed of 7 sub-sections assessing different features of speech; the rate/prosody section of DP includes items investigating the presence of repetitive speech disorder. Severity of FOG was evaluated with the new freezing of gait questionnaire (NFGQ).ResultsPD patients performed worse at DP and BADA compared to healthy controls; patients with FOG or with Hoehn-Yahr >2 reported lower scores in the articulation, intellibility, rate/prosody sections of DP and in the semantic verbal fluency test. Logistic regression analysis showed that only age and rate/prosody scores were significantly associated to FOG in PD. Multiple regression analysis showed that only the severity of FOG was associated to rate/prosody score.ConclusionsOur data demonstrate that repetitive speech disorder is related to FOG and is associated to advanced disease stages and independent of disease duration. Speech dysfluency represents a disorder of motor speech control, possibly sharing pathophysiological mechanisms with FOG.     

The specific contributions of set‐shifting to freezing of gait in Parkinson's disease

Freezing of gait (FOG) in Parkinson's disease (PD) is common and the pathophysiology of FOG is poorly understood. It has been hypothesized to reflect complementary yet competing frontostriatal pathways that reduce the ability to keep different tasks (motor or cognitive) on‐line. This inability to “set‐shift” has been proposed to trigger a freezing episode. If correct, this hypothesis would predict a differential pattern of executive dysfunction with FOG being most specifically related to attentional set‐shifting. In this study, 31 patients with a range of self‐reported FOG symptom severities were administered tests of executive functioning. The results demonstrate that FOG symptoms were selectively correlated with poorer performance on tasks of set‐shifting, but not with a range of other executive tasks. This was apparent even after controlling for slowed processing speed, disease stage and depressive symptoms. The results support the recently proposed hypothesis for the pathophysiology underlying FOG in PD. © 2010 Movement Disorder Society     

Treadmill walking as an external pacemaker to improve gait rhythm and stability in Parkinson's disease.

Recent reports suggest that external cueing improves stride length and gait speed in Parkinson's disease (PD). The purpose of the present study was to examine the influence of treadmill walking on gait variability. The 36 PD patients (Hoehn and Yahr stage 2--2.5) were compared to 30 controls. Subjects walked three times for 2 minutes each: (1) walking on level ground (unassisted), (2) walking on level ground while using a walker, and (3) walking on a treadmill. Stride time variability and swing time variability were significantly increased in the patients compared to the control subjects when walking on level ground with a walker. In both groups, the use of a walking aid did not significantly affect stride time variability or swing time variability, but the treadmill reduced stride time variability and swing time variability in the patients and in the controls. These results indicate that, during treadmill walking, PD subjects are able to walk with a less variable and more stable gait. Because the treadmill walking speed was set to the gait speed on level ground and because this effect was not seen with a walking aid, we suggest that the treadmill may be acting as an external cue to enhance gait rhythmicity and reduce gait variability.     

Brain activation pattern related to gait disturbances in Parkinson's disease

Gait disturbances represent a therapeutic challenge in Parkinson's disease (PD). To further investigate their underlying pathophysiological mechanisms, we compared brain activation related to mental imagery of gait between 15 PD patients and 15 age‐matched controls using a block‐design functional MRI experiment. On average, patients showed altered locomotion relatively to controls, as assessed with a standardized gait test that evaluated the severity of PD‐related gait disturbances on a 25‐m path. The experiment was conducted in the subjects as they rehearsed themselves walking on the same path with a gait pattern similar as that during locomotor evaluation. Imagined walking times were measured on a trial‐by‐trial basis as a control of behavioral performance. In both groups, mean imagined walking time was not significantly different from that measured during real gait on the path used for evaluation. The between‐group comparison of the mental gait activation pattern with reference to mental imagery of standing showed hypoactivations within parieto‐occipital regions, along with the left hippocampus, midline/lateral cerebellum, and presumed pedunculopontine nucleus/mesencephalic locomotor area, in patients. More specifically, the activation level of the right posterior parietal cortex located within the impaired gait‐related cognitive network decreased proportionally with the severity of gait disturbances scored on the path used for gait evaluation and mental imagery. These novel findings suggest that the right posterior parietal cortex dysfunction is strongly related to the severity of gait disturbances in PD. This region may represent a target for the development of therapeutic interventions for PD‐related gait disturbances. © 2012 Movement Disorder Society