Prediction of the effect of deep brain stimulation on gait freezing of Parkinson's disease

ObjectiveThe response of freezing of gait (FOG) to deep brain stimulation of the subthalamic nucleus (STN-DBS) is controversial and depends on many poorly controlled factors. On the other hand, a clinical predictor for the individual patient is needed to counsel the patient regarding this symptom.MethodsA cohort of 124 patients undergoing STN-DBS was evaluated based on the video-documented Levodopa test at baseline in the OFF- and ON-drug condition and postoperatively in the best condition (ON-drug/ON-stim) and the worst condition (OFF-drug/ON-stim). We compared the freezing item of the Unified Parkinson's disease rating scale (#14), the UPDRS III total score, and FOG severity rated during four provoking situations with regard to its predictive value.ResultsWe found ‘FOG during the turning task’ to be the best predictor with an ROC-value of 0.857 compared to 0.603 for the UPDRS Item 14 and 0.583 for the total UPDRS III. An improvement of 1 or 2 grades of the turning item during the preoperative levodopa test predicts an improvement during the worst condition postoperatively of 1 grade or more with an 80% probability.ConclusionThis FOG prediction test is simple and clinically useful. The test needs to be studied in a prospective study.     

Postoperative gait deterioration after bilateral subthalamic nucleus stimulation in Parkinson's disease

Deep brain stimulation of the subthalamic nuclei (STN) is a good therapeutic option to reduce dyskinesias and improve appendicular motor signs in well‐selected patients with advanced Parkinson's disease (PD). Concerns about long‐term adverse effects play an increasingly role in the decision whether or not to refer patients for this treatment. Worsening of gait as a consequence of STN stimulation for PD has been described, but may be under‐recognized in clinical practice. The aim of this study was to evaluate the effects of STN stimulation on gait relative to global outcome in a group of consecutively operated patients. For this purpose, we used a standardized patient questionnaire that asked about global outcome and specific effects on gait, as experienced both 6 months postoperatively and currently (at the time of completing the questionnaire; mean: 2.7 +/? 1.1 years). A delayed worsening of gait after bilateral STN stimulation was experienced by a considerable proportion of patients (42% of subjects, for gait in the OFF phase), and this was apparently relatively “selective” because their global outcome scores continued to be improved. These findings highlight the presence of a hitherto poorly recognized long‐term complication of bilateral STN stimulation. Further systematic studies are required to pinpoint the clinical and surgical determinants of this late gait deterioration. © 2008 Movement Disorder Society     

Neural substrates of levodopa‐responsive gait disorders and freezing in advanced Parkinson's disease: A kinesthetic imagery approach

Gait disturbances, including freezing of gait, are frequent and disabling symptoms of Parkinson's disease. They often respond poorly to dopaminergic treatments. Although recent studies have shed some light on their neural correlates, their modulation by dopaminergic treatment remains quite unknown. Specifically, the influence of levodopa on the networks involved in motor imagery (MI) of parkinsonian gait has not been directly studied, comparing the off and on medication states in the same patients. We therefore conducted an [H₂¹⁵0] Positron emission tomography study in eight advanced parkinsonian patients (mean disease duration: 12.3 ± 3.8 years) presenting with levodopa‐responsive gait disorders and FoG, and eight age‐matched healthy subjects. All participants performed three tasks (MI of gait, visual imagery and a control task). Patients were tested off, after an overnight withdrawal of all antiparkinsonian treatment, and on medication, during consecutive mornings. The order of conditions was counterbalanced between subjects and sessions. Results showed that imagined gait elicited activations within motor and frontal associative areas, thalamus, basal ganglia and cerebellum in controls. Off medication, patients mainly activated premotor‐parietal and pontomesencephalic regions. Levodopa increased activation in motor regions, putamen, thalamus, and cerebellum, and reduced premotor‐parietal and brainstem involvement. Areas activated when patients are off medication may represent compensatory mechanisms. The recruitment of these accessory circuits has also been reported for upper‐limb movements in Parkinson's disease, suggesting a partly overlapping pathophysiology between imagined levodopa‐responsive gait disorders and appendicular signs. Our results also highlight a possible cerebellar contribution in the pathophysiology of parkinsonian gait disorders through kinesthetic imagery. Hum Brain Mapp 36:959–980, 2015. © 2014 Wiley Periodicals, Inc.     

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.     

Predicting the onset of freezing of gait: A longitudinal study

Background: Freezing of gait is a disabling symptom of Parkinson's disease that ultimately affects approximately 80% of patients, yet very little research has focused on predicting the onset of freezing of gait and tracking the longitudinal progression of symptoms prior to its onset. The objective of the current study was to examine longitudinal data spanning the transition period when patients with PD developed freezing of gait to identify symptoms that may precede freezing and create a prediction model that identifies those “at risk” for developing freezing of gait in the year to follow. Methods: Two hundred and twenty‐one patients with PD were divided into 3 groups (88 nonfreezers, 41 transitional freezers, and 92 continuing freezers) based on their responses to the validated Freezing of Gait‐Questionnaire item 3 at baseline and follow‐up. Critical measures across motor, cognitive, mood, and sleep domains were assessed at 2 times approximately 1 year apart. Results: A logistic regression model that included age, disease duration, gait symptoms, motor phenotype, attentional set‐shifting, and mood measures could predict with 70% and 90% accuracy those patients who would and would not develop, respectively, freezing of gait over the next year. Notably, the Freezing of Gait‐Questionnaire total and the anxiety section of the Hospital Anxiety and Depression Scale were the strongest predictors and alone could significantly predict if one might develop freezing of gait in the next 15 months with 82% accuracy. Conclusions: Our results suggest that it is possible to identify the majority of patients who will develop freezing of gait in the following year, potentially allowing targeted interventions to delay or possibly even prevent the onset of freezing. © 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.     

Modulation of gait coordination by subthalamic stimulation improves freezing of gait

The effect of subthalamic deep brain stimulation on gait coordination and freezing of gait in patients with Parkinson's disease is incompletely understood. The purpose of this study was to investigate the extent to which modulation of symmetry and coordination between legs by subthalamic deep brain stimulation alters the frequency and duration of freezing of gait in patients with Parkinson's disease. We recruited 13 post‐subthalamic deep brain stimulation patients with Parkinson's disease with off freezing of gait and evaluated them in the following 4 conditions: subthalamic deep brain stimulation on (ON) and stimulation off (OFF), 50% reduction of stimulation voltage for the leg with shorter step length (worse side reduction) and for the leg with longer step length (better side reduction). Gait analysis was performed on a treadmill and recorded by an optoelectronic analysis system. We measured frequency and duration of freezing of gait episodes. Bilateral coordination of gait was assessed by the Phase Coordination Index, quantifying the ability to generate antiphase stepping. From the OFF to the ON state, freezing of gait improved in frequency (2.0 ± 0.4 to 1.4 ± 0.5 episodes) and duration (12.2 ± 2.6 to 2.6 ± 0.8 seconds; P = .005). Compared with the ON state, only better side reduction further reduced freezing of gait frequency (0.2 ± 0.2) and duration of episodes (0.2 ± 0.2 seconds; P = .03); worse side reduction did not change frequency (1.3 ± 0.4) but increased freezing of gait duration (5.2 ± 2.1 seconds). The better side reduction–associated improvements were accompanied by normalization of gait coordination, as measured by phase coordination index (16.5% ± 6.0%), which was significantly lower than in the other 3 conditions. Reduction of stimulation voltage in the side contralateral to the leg with longer step length improves frequency and duration of freezing of gait through normalization of gait symmetry and coordination in subthalamic deep brain stimulation patients with Parkinson's disease. This identifies poor leg coordination as a risk factor for causing freezing of gait. © 2011 Movement Disorder Society     

Transcranial direct current stimulation in Parkinson's disease: Neurophysiological mechanisms and behavioral effects

Recent research has highlighted the potential of transcranial direct current stimulation (tDCS) to complement rehabilitation effects in the elderly and in patients with neurological diseases, including Parkinson's disease (PD). TDCS can modulate cortical excitability and enhance neurophysiological mechanisms that compensate for impaired learning in PD. The objective of this systematic review is to provide an overview of the effects of tDCS on neurophysiological and behavioral outcome measures in PD patients, both as a stand-alone and as an adjunctive therapy. We systematically reviewed the literature published throughout the last 10 years. Ten studies were included, most of which were sham controlled. Results confirmed that tDCS applied to the motor cortex had significant results on motor function and to a lesser extent on cognitive tests. However, the physiological mechanism underlying the long-term effects of tDCS on cortical excitability in the PD brain are still unclear and need to be clarified in order to apply this technique optimally to a wider population in the different disease stages and with different medication profiles.     

Different cerebral cortical areas influence the effect of subthalamic nucleus stimulation on parkinsonian motor deficits and freezing of gait.

Inconsistent response in freezing of gait (FOG) with levodopa treatment or STN DBS makes the pathogenesis difficult to understand. We studied brain areas associated with the expression of STN DBS effect on parkinsonian motor deficits and FOG. Ten Parkinson's disease patients with typical FOG were included. One month before STN DBS, we performed [(18)F]-deoxyglucose PET scans and measured the UPDRS motor and modified FOG (mFOG) scores during levodopa off and on periods. At two months after STN DBS, same rating scores were measured. The percentage improvement of mFOG and UPDRS motor scores by STN DBS during levodopa off period was calculated. We searched for brain areas in which glucose metabolism correlated with the improvement of mFOG and UPDRS motor scores by DBS. During levodopa off period, STN DBS improved the UPDRS motor scores by 32.3% and the mFOG scores by 56.6%. There was no correlation between the improvements of both scores. The improvement of UPDRS motor score by DBS correlated with the metabolic activities of rostral supplementary motor area (Brodmann's area 8; BA8), anterior cingulate cortex (BA32), and prefrontal cortex (BA9). On the other hand, there was a positive correlation between the improvement of mFOG score by DBS and the metabolic activity of the parietal, occipital, and temporal sensory association cortices. In conclusion, dysfunction of different cerebral cortical areas limits the beneficial effects of DBS on parkinsonian motor deficits and FOG.     

Deep brain stimulation effects on gait variability in Parkinson's disease

The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on fall risk in patients with Parkinson's disease (PD) currently remain unclear. Although several gait parameters, such as gait speed, have shown improvement with DBS, some studies have reported an increased fall risk following DBS. The purpose of this study was to examine the effect of bilateral DBS on gait variability, a marker of fall risk. The gait of 13 patients with idiopathic PD was analyzed to determine the influence of DBS, levodopa and both therapies together. Following treatment with both levodopa and STN DBS, subjects displayed improved gait speed, reduced gait variability (enhanced stability), and lower Unified Parkinson's Disease Rating Scale (UPDRS) scores. Although UPDRS scores improved with STN DBS alone, parallel improvements were not seen for gait variability. These findings suggest that different mechanisms may contribute to performance on UPDRS motor testing and gait stability in response to DBS. © 2009 Movement Disorder Society     

Noninvasive cortical stimulation with transcranial direct current stimulation in Parkinson's disease.

Electrical stimulation of deep brain structures, such as globus pallidus and subthalamic nucleus, is widely accepted as a therapeutic tool for patients with Parkinson's disease (PD). Cortical stimulation either with epidural implanted electrodes or repetitive transcranial magnetic stimulation can be associated with motor function enhancement in PD. We aimed to study the effects of another noninvasive technique of cortical brain stimulation, transcranial direct current stimulation (tDCS), on motor function and motor-evoked potential (MEP) characteristics of PD patients. We tested tDCS using different electrode montages [anodal stimulation of primary motor cortex (M1), cathodal stimulation of M1, anodal stimulation of dorsolateral prefrontal cortex (DLPFC), and sham-stimulation] and evaluated the effects on motor function--as indexed by Unified Parkinson's Disease Rating Scale (UPDRS), simple reaction time (sRT) and Purdue Pegboard test--and on corticospinal motor excitability (MEP characteristics). All experiments were performed in a double-blinded manner. Anodal stimulation of M1 was associated with a significant improvement of motor function compared to sham-stimulation in the UPDRS (P < 0.001) and sRT (P = 0.019). This effect was not observed for cathodal stimulation of M1 or anodal stimulation of DLPFC. Furthermore, whereas anodal stimulation of M1 significantly increased MEP amplitude and area, cathodal stimulation of M1 significantly decreased them. There was a trend toward a significant correlation between motor function improvement after M1 anodal-tDCS and MEP area increase. These results confirm and extend the notion that cortical brain stimulation might improve motor function in patients with PD.     

Freezing of gait after bilateral subthalamic nucleus stimulation for Parkinson's disease

OBJECTIVE: To determine the long-term effect of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on freezing of gait in Parkinson's disease patients. PATIENTS AND METHODS: Sixty-seven patients were followed 12 months after bilateral STN DBS and 32 patients were followed 24 months post-surgery. Patients were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) with medications on and off at baseline and again in both conditions with stimulation on at follow-up. Specific attention was paid to the freezing item of the ADL section. RESULTS: Freezing scores in the medication off state improved significantly with stimulation at 1 and 2 years. In the medication on state there were no significant improvements in freezing. CONCLUSION: Off period freezing of gait is significantly improved with STN DBS up to 24 months; however, on period freezing is not affected by STN DBS.     

Explaining freezing of gait in Parkinson's disease: Motor and cognitive determinants

Freezing of gait (FOG) is part of a complex clinical picture in Parkinson's disease (PD) and is largely refractory to standard care. Diverging hypotheses exist about its origins, but a consolidated view on what determines FOG is lacking. The aim of this study was to develop an integrative model of FOG in people with PD. This cross‐sectional study included 51 Parkinson subjects: 24 patients without FOG and 27 with FOG matched for age, gender, and disease severity. Subjects underwent an extensive clinical test battery evaluating general disease characteristics, gait and balance, nongait freezing, and cognitive functions. The relative contribution of these outcomes to FOG was determined using logistic regression analysis. The combination of the following four independent contributors provided the best explanatory model of FOG (R² = 0.49): nongait freezing; levodopa equivalent dose (LED); cognitive impairment; and falls and balance problems. The model yields a high‐risk profile for FOG (P > 95%) when Parkinson patients are affected by at least one type of nongait freezing (e.g., freezing of other repetitive movements), falls or balance problems during the last 3 months, and a Scales for Outcomes in Parkinson's Disease‐Cognition score below 28. A high LED further increases the risk of FOG to 99%. Nongait freezing, increased dopaminergic drug dose, cognitive deficits, and falls and balance problems are independent determinants of FOG in people with PD and may play a synergistic role in its manifestation. © 2012 Movement Disorder Society     

Obstacle avoidance to elicit freezing of gait during treadmill walking

Freezing of gait (FOG) is a common and disabling feature of Parkinson's disease (PD). Detailed pathophysiological studies are hampered by the fact that FOG episodes are difficult to elicit in a gait laboratory. We evaluated whether the need to avoid sudden obstacles on a treadmill can provoke FOG. We included 21 PD patients (15 with self‐reported off‐period FOG). Patients were tested in the off‐state. FOG during overground walking was assessed using a standardized gait trajectory and axial 360° turns. Subsequently, patients walked on a motorized treadmill with suddenly appearing obstacles that necessitated compensatory stepping. Performance was videotaped, and presence of FOG was scored visually by two independent raters. Thirteen patients showed FOG during overground walking. During treadmill walking, obstacle avoidance was associated with 13 unequivocal FOG episodes in eight patients, whereas only one patient froze during undisturbed treadmill walking (Wilcoxon z = ?2.0, P = 0.046). FOG episodes elicited by obstacle avoidance were brief (typically <1 s). Almost all episodes were provoked when subjects had a longer available response time. In conclusion, suddenly appearing obstacles on a treadmill can elicit FOG in a controlled laboratory setting. However, the moving treadmill and the obstacle both act as cues, which apparently help to immediately overcome the provoked FOG episode. This may limit the ecological validity of this new approach. © 2009 Movement Disorder Society     

Microstructural changes in white matter associated with freezing of gait in Parkinson's disease

In Parkinson's disease (PD), freezing of gait (FOG) is associated with widespread functional and structural gray matter changes throughout the brain. Previous study of freezing‐related white matter changes was restricted to brainstem and cerebellar locomotor tracts. This study was undertaken to determine the spatial distribution of white matter damage associated with FOG by combining whole brain and striatofrontal seed‐based diffusion tensor imaging. Diffusion‐weighted images were collected in 26 PD patients and 16 age‐matched controls. Parkinson's disease groups with (n = 11) and without freezing of gait (n = 15) were matched for age and disease severity. We applied tract‐based spatial statistics to compare fractional anisotropy and mean diffusivity of white matter structure across the whole brain between groups. Probabilistic tractography was used to evaluate fractional anisotropy and mean diffusivity of key subcortico‐cortical tracts. Tract‐based spatial statistics revealed decreased fractional anisotropy in PD with FOG in bilateral cerebellar and superior longitudinal fascicle clusters. Increased mean diffusivity values were apparent in the right internal capsule, superior frontal cortex, anterior corona radiata, the left anterior thalamic radiation, and cerebellum. Tractography showed consistent white matter alterations in striatofrontal tracts through the putamen, caudate, pallidum, subthalamic nucleus, and in connections of the cerebellar peduncle with subthalamic nucleus and pedunculopontine nucleus bilaterally. We conclude that FOG is associated with diffuse white matter damage involving major cortico‐cortical, corticofugal motor, and several striatofrontal tracts in addition to previously described cerebello‐pontine connectivity changes. These distributed white matter abnormalities may contribute to the motor and non‐motor correlates of FOG. © 2015 International Parkinson and Movement Disorder Society     

Transcranial direct current stimulation in psychiatric disorders

The interest in non-invasive brain stimulation techniques is increasing in recent years. Among these techniques, transcranial direct current stimulation (tDCS) has been the subject of great interest among researchers because of its easiness to use, low cost, benign profile of side effects and encouraging results of research in the field. This interest has generated several studies and randomized clinical trials, particularly in psychiatry. In this review, we provide a summary of the development of the technique and its mechanism of action as well as a review of the methodological aspects of randomized clinical trials in psychiatry, including studies in affective disorders, schizophrenia, obsessive compulsive disorder, child psychiatry and substance use disorder. Finally, we provide an overview of tDCS use in cognitive enhancement as well as a discussion regarding its clinical use and regulatory and ethical issues. Although many promising results regarding tDCS efficacy were described, the total number of studies is still low, highlighting the need of further studies aiming to replicate these findings in larger samples as to provide a definite picture regarding tDCS efficacy in psychiatry.