Subthalamic functional connectivity associated with freezing of gait dopa-response.

INTRODUCTION: Freezing of gait (FOG) is a prevalent and debilitating feature of Parkinson's Disease (PD). The subthalamic nucleus (STN) is a center for controlled locomotion and a common DBS target. The objective of this study was to identify STN circuitry associated with FOG response to dopaminergic medication. In this study, we compare BOLD functional connectivity of the subthalamic nucleus (STN) in participants with and without dopa-responsive FOG. METHODS: 55 PD participants either with FOG (n = 38) or without FOG (n = 17) were recruited. Among FOG participants 22 were dopa-responsive and 16 were dopa-unresponsive. STN whole-brain connectivity was performed using CONN toolbox. The relationship between the degree of self-reported FOG dopa-response and STN connectivity was evaluated using partial correlations corrected for age, disease duration, and levodopa equivalent daily dose. RESULTS: Right STN connectivity with the cerebellar locomotor region and the temporal/occipital cortex was greater in the dopa-responsive FOG group (voxel threshold p < 0.01, FWE corrected p < 0.05). Left STN connectivity with the occipital cortex was greater in the dopa-responsive FOG group and connectivity with the postcentral gyrus was greater in the dopa-unresponsive FOG group. Strength of connectivity to these regions correlated with l-dopa induced improvement in UPDRS Item-14 (FOG), but not UPDRS Part-III (overall motor score). DISCUSSION: We demonstrate that dopa-unresponsive FOG is associated with changes in BOLD functional connectivity between the STN and locomotor as well as sensory processing regions. This finding supports the conceptual framework that effective treatment for freezing of gait likely requires the engagement of both locomotor and sensory brain regions.

Cortical Disinhibition Drives Freezing of Gait in Parkinson's Disease and an Exploratory Repetitive Transcranial Magnetic Stimulation Study.

BACKGROUND: Dysfunction of the primary motor cortex, participating in regulation of posture and gait, is implicated in freezing of gait (FOG) in Parkinson's disease (PD). OBJECTIVE: The aim was to reveal the mechanisms of "OFF-period" FOG (OFF-FOG) and "levodopa-unresponsive" FOG (ONOFF-FOG) in PD. METHODS: We measured the transcranial magnetic stimulation (TMS) indicators and gait parameters in 21 healthy controls (HCs), 15 PD patients with ONOFF-FOG, 15 PD patients with OFF-FOG, and 15 PD patients without FOG (Non-FOG) in "ON" and "OFF" medication conditions. Difference of TMS indicators in the four groups and two conditions and its correlations with gait parameters were explored. Additionally, we explored the effect of 10 Hz repetitive TMS on gait and TMS indicators in ONOFF-FOG patients. RESULTS: In "OFF" condition, short interval intracortical inhibition (SICI) exhibited remarkable attenuation in FOG patients (both ONOFF-FOG and OFF-FOG) compared to Non-FOG patients and HCs. The weakening of SICI correlated with impaired gait characteristics in FOG. However, in "ON" condition, SICI in ONOFF-FOG patients reduced compared to OFF-FOG patients. Pharmacological treatment significantly improved SICI and gait in OFF-FOG patients, and high-frequency repetitive TMS distinctly improved gait in ONOFF-FOG patients, accompanied by enhanced SICI. CONCLUSIONS: Motor cortex disinhibition, represented by decreased SICI, is related to FOG in PD. Refractory freezing in ONOFF-FOG patients correlated with the their reduced SICI insensitive to dopaminergic medication. SICI can serve as an indicator of the severity of impaired gait characteristics in FOG and reflect treatments efficacy for FOG in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Botulinum toxin in the management of parkinsonian disorders.

Many studies have shown that botulinum toxin (BoNT) can be an option to treat motor and non-motor symptoms in Parkinson's disease (PD) and parkinsonian syndromes. The advantages of BoNT compared to oral medications include localized action and low incidence of systemic side effects, which is important in treating neurodegenerative disease. Motor symptoms that can be treated with BoNT include blepharospasm, apraxia of eyelid opening, tremor, cervical dystonia and limb dystonia. Other indications with less evidence include camptocormia, freezing of gait and dyskinesia. Non-motor symptoms that may improve with BoNT include sialorrhea, pain, overreactive bladder, dysphagia and constipation. However, the current evidence for use of BoNT in parkinsonism is mostly based on open-label studies and there are few randomized, controlled trials. BoNT can be a valuable tool to treat certain symptoms of PD and parkinsonian syndromes to improve the patient's quality of life. However, many of the uses are not supported by high quality studies and further studies are needed to provide further evidence of efficacy, define the optimal injection protocols such as doses and muscle selection.

Effect of freezing of gait and dopaminergic medication in the biomechanics of lower limbs in the gait of patients with Parkinson's disease compared to neurologically healthy.

INTRODUCTION: This study aims to evaluate the effects of medication, and the freezing of gait (FoG) on the kinematic and kinetic parameters of gait in people with Parkinson's disease (pwPD) compared to neurologically healthy. METHODS: Twenty-two people with a clinical diagnosis of idiopathic PD in ON and OFF medication (11 FoG), and 18 healthy participants (control) were selected from two open data sets. All participants walked on the floor on a 10-meter-long walkway. The joint kinematic and ground reaction forces (GRF) variables of gait and the clinical characteristics were compared: (1) PD with FoG (pwFoG) and PD without FoG (pwoFoG) in the ON condition and control; (2) PD with FoG and PD without FoG in the OFF condition and control; (3) Group (PD with FoG and PD without FoG) and Medication. RESULTS: (1) FoG mainly affects distal joints, such as the ankle and knee; (2) PD ON showed changes in the range of motion of both distal and proximal joints, which may explain the increase in step length and gait speed expected with the use of L-Dopa; and (3) the medication showed improvements in the kinematic and kinetic parameters of the gait of people with pwFoG and pwoFoG equally; (4) pwPD showed a smaller second peak of the vertical component of the GRF than the control. CONCLUSION: The presence of FoG mainly affects distal joints, such as the ankle and knee. PD presents a lower application of GRF during the impulse period than healthy people, causing lower gait performances.

Botulinum Toxin Treatment of Motor Disorders in Parkinson Disease-A Systematic Review.

This review provides an up-to-date literature account on the efficacy of Botulinum toxin treatment for common motor disorders of Parkinson Disease. The reviewed disorders include the common motor disorders in PD such as tremor, focal foot dystonia, rigidity and freezing of gait (FOG). In the area of Parkinson tremor, two newly described evaluation/injection techniques (Yale method in USA and Western University method in Canada) offer efficacy with low incidence of hand and finger weakness as side effects. Blinded studies conducted on foot dystonia of PD indicate that botulinum toxin injections into toe flexors are efficacious in alleviating this form of dystonia. Small, blinded studies suggest improvement of Parkinson rigidity after botulinum toxin injection; proof of this claim, however, requires information from larger, blinded clinical trials. In FOG, the improvement reported in open label studies could not be substantiated in blinded investigations. However, there is room for further controlled studies that include the proximal lower limb muscles in the injection plan and/or use higher doses of the injected toxin for this indication.

Levodopa responsive freezing of gait is associated with reduced norepinephrine transporter binding in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is a major cause of falling in Parkinson's disease (PD) and can be responsive or unresponsive to levodopa. Pathophysiology is poorly understood. OBJECTIVE: To examine the link between noradrenergic systems, the development of FOG in PD and its responsiveness to levodopa. METHODS: We examined norepinephrine transporter (NET) binding via brain positron emission tomography (PET) to evaluate changes in NET density associated with FOG using the high affinity selective NET antagonist radioligand [11C]MeNER (2S,3S)(2-[α-(2-methoxyphenoxy)benzyl]morpholine) in 52 parkinsonian patients. We used a rigorous levodopa challenge paradigm to characterize PD patients as non-freezing (NO-FOG, N = 16), levodopa responsive freezing (OFF-FOG, N = 10), and levodopa-unresponsive freezing (ONOFF-FOG, N = 21), and also included a non-PD FOG group, primary progressive freezing of gait (PP-FOG, N = 5). RESULTS: Linear mixed models identified significant reductions in whole brain NET binding in the OFF-FOG group compared to the NO-FOG group (-16.8%, P = 0.021) and regionally in the frontal lobe, left and right thalamus, temporal lobe, and locus coeruleus, with the strongest effect in right thalamus (P = 0.038). Additional regions examined in a post hoc secondary analysis including the left and right amygdalae confirmed the contrast between OFF-FOG and NO-FOG (P = 0.003). A linear regression analysis identified an association between reduced NET binding in the right thalamus and more severe New FOG Questionnaire (N-FOG-Q) score only in the OFF-FOG group (P = 0.022). CONCLUSION: This is the first study to examine brain noradrenergic innervation using NET-PET in PD patients with and without FOG. Based on the normal regional distribution of noradrenergic innervation and pathological studies in the thalamus of PD patients, the implications of our findings suggest that noradrenergic limbic pathways may play a key role in OFF-FOG in PD. This finding could have implications for clinical subtyping of FOG as well as development of therapies.

How resistant are levodopa-resistant axial symptoms? Response of freezing, posture, and voice to increasing levodopa intestinal infusion rates in Parkinson disease.

BACKGROUND AND PURPOSE: Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition. METHODS: We performed a pre-/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed. RESULTS: We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2 ± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean = 2.3 at T1, 1.7 at T2, 1.2 at T3; p = 0.013). Posture and speech features did not show significant changes, whereas stride length (p = 0.049), turn duration (p = 0.001), and turn velocity (p = 0.024) significantly improved on doubling the levodopa infusion rate. CONCLUSIONS: In a short-term evaluation, the increase of LCIG dose can improve "dopa-resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia.

Levodopa alters resting-state functional connectivity more selectively in Parkinson's disease with freezing of gait.

Freezing of gait (FOG) is a debilitating motor symptom of Parkinson's disease (PD). Although PD dopaminergic medication (L-DOPA) seems to generally reduce FOG severity, its effect on neural mechanisms of FOG remains to be determined. The purpose of this study was to quantify the effect of L-DOPA on brain resting-state functional connectivity in individuals with FOG. Functional magnetic resonance imaging was acquired at rest in 30 individuals living with PD (15 freezers) in the ON- and OFF- medication state. A seed-to-voxel analysis was performed with seeds in the bilateral basal ganglia nuclei, the thalamus and the mesencephalic locomotor region. In freezers, medication-state contrasts revealed numerous changes in resting-state functional connectivity, not modulated by L-DOPA in non-freezers. In freezers, L-DOPA increased the functional connectivity between the seeds and regions including the posterior parietal, the posterior cingulate, the motor and the medial prefrontal cortices. Comparisons with non-freezers revealed that L-DOPA generally normalizes brain functional connectivity to non-freezers levels but can also increase functional connectivity, possibly compensating for dysfunctional networks in freezers. Our findings suggest that L-DOPA could contribute to a better sensorimotor, attentional, response inhibition and limbic processing to prevent FOG when triggers are encountered but could also contribute to FOG by interfering with the processing capacity of the striatum. This study shows that levodopa taken to control PD symptoms induces changes in functional connectivity at rest, in freezers only. Increases (green) in functional connectivity of GPe, GPi, putamen and thalamus with cognitive, sensorimotor and limbic cortical regions of the Interference model (blue) was observed. Our results suggest that levodopa can normalize connections similar to non-freezers or increases connectivity to compensate for dysfunctional networks.

Classification of Parkinson's disease motor phenotype: a machine learning approach.

To assess the cortical activity in people with Parkinson's disease (PwP) with different motor phenotype (tremor-dominant-TD and postural instability and gait difficulty-PIGD) and to compare with controls. Twenty-four PwP (during OFF and ON medication) and twelve age-/sex-/handedness-matched healthy controls underwent electrophysiological assessment of spectral ratio analysis through electroencephalography (EEG) at resting state and during the hand movement. We performed a machine learning method with 35 attributes extracted from EEG. To verify the efficiency of the proposed phenotype-based EEG classification the random forest and random tree were tested (performed 30 times, using a tenfolds cross validation in Weka environment). The analyses based on phenotypes indicated a slowing down of cortical activity during OFF medication state in PwP. PD with TD phenotype presented this characteristic at resting and the individuals with PIGD presented during the hand movement. During the ON state, there is no difference between phenotypes at resting nor during the hand movement. PD phenotypes may influence spectral activity measured by EEG. Random forest machine learning provides a slightly more accurate, sensible and specific approach to distinguish different PD phenotypes. The phenotype of PD might be a clinical characteristic that could influence cortical activity.

IncobotulinumtoxinA Injection for Treating Children with Idiopathic Toe Walking: A Retrospective Efficacy and Safety Study.

There is no gold-standard treatment for idiopathic toe walking (ITW). Some previous evidence suggested that botulinum neurotoxin-A injection might improve ITW. This is a single-center retrospective study on children with ITW treated with incobotulinumtoxinA injection in the gastrocnemius medialis/lateralis muscles. We screened the charts of 97 ITW children treated with incobotulinumtoxinA (January 2019-December 2021), and the data of 28 of them, who satisfied the inclusion/exclusion criteria, were analyzed. The maximal passive ankle dorsiflexion (knee extended) was assessed at three time points, i.e., immediately before incobotulinumtoxinA injection (T0), after incobotulinumtoxinA injection during the timeframe of its effect (T1), and at follow-up, when the effect was expected to disappear (T2). The maximal passive ankle dorsiflexion was improved by incobotulinumtoxinA injection, and the effect lasted up to 6 months in some children. No adverse effects were reported to incobotulinumtoxinA injections. The treatment with incobotulinumtoxinA might improve the maximal passive ankle dorsiflexion and is safe and well-tolerated in ITW with a longer-than-expected effect in comparison to cerebral palsy. These results may offer ground to future randomized controlled trials and studies assessing the effect of BoNT-A in combination with other non-invasive approaches and exercise programs in children with ITW.

Efficacy of conservative treatment for spastic cerebral palsy children with equinus gait: a systematic review and meta-analysis.

BACKGROUND: Comparisons between various conservative managements of spastic equinus deformity in cerebral palsy demonstrated limited evidences, to evaluate the efficacy of conservative treatment among cerebral palsy children with spastic equinus foot regarding gait and ankle motion. METHODS: Studies were identified from PubMed and Scopus up to February 2022. Inclusion criteria were randomized controlled trial (RCT), conducted in spastic cerebral palsy children with equinus deformity, aged less than 18 years, compared any conservative treatments (Botulinum toxin A; BoNT-A, casting, physical therapy, and orthosis), and evaluated gait improvement (Physician Rating Scale or Video Gait Analysis), Observational Gait Scale, Clinical Gait Assessment Score, ankle dorsiflexion (ankle dorsiflexion at initial contact, and passive ankle dorsiflexion), or Gross Motor Function Measure. Any study with the participants who recently underwent surgery or received BoNT-A or insufficient data was excluded. Two authors were independently selected and extracted data. Risk of bias was assessed using a revised Cochrane risk-of-bias tool for randomized trials. I2 was performed to evaluate heterogeneity. Risk ratio (RR), the unstandardized mean difference (USMD), and the standardized mean difference were used to estimate treatment effects with 95% confidence interval (CI). RESULTS: From 20 included studies (716 children), 15 RCTs were eligible for meta-analysis (35% had low risk of bias). BoNT-A had higher number of gait improvements than placebo (RR 2.64, 95% CI 1.71, 4.07, I2 = 0). Its combination with physical therapy yielded better passive ankle dorsiflexion at knee extension than physical therapy alone (USMD = 4.16 degrees; 95% CI 1.54, 6.78, I2 = 36%). Casting with or without BoNT-A had no different gait improvement and ankle dorsiflexion at knee extension when compared to BoNT-A. Orthosis significantly increased ankle dorsiflexion at initial contact comparing to control (USMD 10.22 degrees, 95 CI% 5.13, 15.31, I2 = 87%). CONCLUSION: BoNT-A and casting contribute to gait improvement and ankle dorsiflexion at knee extension. BoNT-A specifically provided gait improvement over the placebo and additive effect to physical therapy for passive ankle dorsiflexion. Orthosis would be useful for ankle dorsiflexion at initial contact. Trial registration PROSPERO number CRD42019146373.

Motor and nonmotor symptoms in patients treated with 24-hour daily levodopa-carbidopa intestinal gel infusion: Analysis of the COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS).

INTRODUCTION: Patients with advanced Parkinson's disease (APD) commonly experience motor and nonmotor symptoms (NMS) associated with functional limitations and decreased quality of life. We compared motor and nonmotor outcomes in patients with APD receiving 24- versus 16-h levodopa-carbidopa intestinal gel (LCIG). METHODS: Data from COSMOS, a large, real-world, retrospective and cross-sectional, observational study on LCIG and comedication in APD were obtained from medical records and a single patient visit for patients receiving 24- and 16-h LCIG infusion. Changes from baseline were evaluated for motor symptoms, NMS, and clinical characteristics. Safety was also assessed. RESULTS: Data for 401 patients were included in this subanalysis. At the patient visit there were 35 patients on 24-h LCIG and 366 on 16-h LCIG. "Off" time and dyskinesia (duration and severity) were reduced in both groups. In both LCIG treatment groups, prevalence of most symptoms was reduced. There were significant differences in the change from baseline in severity and frequency of freezing of gait with 24-h LCIG versus 16-h LCIG (p = 0.011 and p = 0.038), severity of urinary symptoms (p = 0.006), and frequency of cognitive impairment (p = 0.014) with 24-h LCIG versus 16-h LCIG. Adverse events were similar for both treatment groups and considered tolerable. CONCLUSIONS: LCIG 24-h infusion may be a useful treatment option, when clinically justified, for select patients with APD. CLINICAL TRIAL NUMBER: NCT03362879.

The correlation between genetic factors and freezing of gait in patients with Parkinson's disease.

BACKGROUND: Clinical-related risk factors to freezing of gait (FOG) in Parkinson's disease (PD) have been identified. Still, the influence of genetic variations on the FOG occurrence has been poorly studied thus far. AIM: We aimed to evaluate the association of six selected polymorphisms of DRD2, ANKK1, and COMT genes with the FOG occurrence and explore the influence of ANNK1/DRD2 haplotypes on the onset of FOG in the group of PD patients. METHOD: PD patients (n = 234), treated with levodopa for at least two years, were genotyped for the rs4680 in COMT, rs6277, rs1076560, and rs2283265 in DRD2, and rs1800497 and rs2734849 polymorphisms in ANKK1 genes. FOG was evaluated by posing a direct question. In addition, a comprehensive set of clinical scales was applied to all patients. RESULTS: FOG occurred in 132 (56.4%) PD patients in our cohort. Freezers were younger at PD onset, had longer disease duration, used higher levodopa daily doses and dopaminergic agents, and had higher motor and non-motor scales scores than non-freezers. FOG was more frequent among AA rs4680 COMT carriers than AG and GG rs4680 COMT carriers. Independent predictors of FOG were: disease duration of more than ten years, levodopa daily dose higher than 500 mg/day, motor status, and COMT AA genotype. AGGAA and GGAAA haplotypes were revealed as protective and vulnerability factors for FOG occurrence. CONCLUSION: In addition to previously identified disease- and therapy-related risk factors, our results suggested a possible contribution of dopamine-related genes to the FOG occurrence.

Neurodegeneration of the Globus Pallidus Internus as a Neural Correlate to Dopa-Response in Freezing of Gait.

BACKGROUND: Background: Parkinson's disease (PD) patients who develop freezing of gait (FOG) have reduced mobility and independence. While some patients experience improvement in their FOG symptoms with dopaminergic therapies, a subset of patients have little to no response. To date, it is unknown what changes in brain structure underlie dopa-response and whether this can be measured using neuroimaging approaches. OBJECTIVE: We tested the hypothesis that structural integrity of brain regions (subthalamic nucleus and globus pallidus internus, GPi) which link basal ganglia to the mesencephalic locomotor region (MLR), a region involved in automatic gait, would be associated with FOG response to dopaminergic therapy. METHODS: In this observational study, thirty-six participants with PD and definite FOG were recruited to undergo diffusion kurtosis imaging (DKI) and multiple assessments of dopa responsiveness (UPDRS scores, gait times ON versus OFF medication). RESULTS: The right GPi in participants with dopa-unresponsive FOG showed reduced fractional anisotropy, mean kurtosis (MK), and increased radial diffusivity relative to those with dopa-responsive FOG. Furthermore, using probabilistic tractography, we observed reduced MK and increased mean diffusivity along the right GPi-MLR tract in dopa-unresponsive FOG. MK in the right GPi was associated with a subjective dopa-response for FOG (r = -0.360, df = 30, p = 0.043) but not overall motor dopa-response. CONCLUSION: These results support structural integrity of the GPi as a correlate to dopa-response in FOG. Additionally, this study suggests DKI metrics may be a sensitive biomarker for clinical studies targeting dopaminergic circuitry and improvements in FOG behavior.

Freezing of gait: overview on etiology, treatment, and future directions.

BACKGROUND: Freezing of gait (FOG) is a disabling motor symptom occurring mainly in the advanced stage of Parkinson's disease (PD). METHODS: This review outlines the clinical manifestation of FOG and its relationship with levodopa treatment, the differential diagnosis with respect to other neurodegenerative and secondary forms and the available treatment. RESULTS: We report the proposed models explaining the FOG phenomenon and summarize the available knowledge on FOG etiology's potential genetic contribution. A complete understanding of the mechanisms underlying FOG in PD is essential to find the best therapy. Different treatment options exist but are still not entirely successful, and often a combination of approaches is needed. CONCLUSIONS: Further studies focusing on the potential genetic role in FOG may increase the knowledge on the FOG etiology and pathophysiology, allowing further individualized treatment strategies for this very disabling phenomenon.

The effects of levodopa in the spatiotemporal gait parameters are mediated by self-selected gait speed in Parkinson's disease.

In individuals with Parkinson's disease (PD), the medication induces different and inconsistent results in the spatiotemporal parameters of gait, making it difficult to understand its effects on gait. As spatiotemporal gait parameters have been reported to be affected by gait speed, it is essential to consider the gait speed when studying walking biomechanics to interpret the results better when comparing the gait pattern of different conditions. Since the medication alters the self-selected gait speed of individuals with PD, this study analysed whether the change in gait speed can explain the selective effects of l-DOPA on the spatiotemporal parameters of gait in individuals with PD. We analysed the spatiotemporal gait parameters at the self-selected speed of 22 individuals with PD under ON and OFF states of l-DOPA medication. Bayesian mediation analysis evaluated which gait variables were affected by the medication state and checked if those effects were mediated by speed changes induced by medication. The gait speed was significantly higher among ON compared with OFF medication. All the spatiotemporal parameters of the gait were mediated by speed, with proportions of mediation close to 1 (effect entirely explained by speed changes). Our results show that a change in gait speed better explains the changes in the spatiotemporal gait parameters than the ON-OFF phenomenon. As an implication for rehabilitation, our results suggest that it is possible to assess the effect of l-DOPA on improving motor symptoms related to gait disorders by measuring gait speed.

Fields of Forel Brain Stimulation Improves Levodopa-Unresponsive Gait and Balance Disorders in Parkinson's Disease.

BACKGROUND: Gait and balance disturbance are challenging symptoms in advanced Parkinson's disease (PD). Anatomic and clinical data suggest that the fields of Forel may be a potential surgical target to treat these symptoms. OBJECTIVE: To test whether bilateral stimulation centered at the fields of Forel improves levodopa unresponsive freezing of gait (FOG), balance problems, postural instability, and falls in PD. METHODS: A total of 13 patients with levodopa-unresponsive gait disturbance (Hoehn and Yahr stage ≥3) were included. Patients were evaluated before (on-medication condition) and 1 yr after surgery (on-medication-on-stimulation condition). Motor symptoms and quality of life were assessed with the Unified Parkinson's Disease Rating scale (UPDRS III) and Quality of Life scale (PDQ-39). Clinical and instrumented analyses assessed gait, balance, postural instability, and falls. RESULTS: Surgery improved balance by 43% (95% confidence interval [CI]: 21.2-36.4 to 35.2-47.1; P = .0012), reduced FOG by 35% (95% CI: 15.1-20.3 to 8.1-15.3; P = .0021), and the monthly number of falls by 82.2% (95% CI: 2.2-6.9 to -0.2-1.7; P = .0039). Anticipatory postural adjustments, velocity to turn, and postural sway measurements also improved 1 yr after deep brain stimulation (DBS). UPDRS III motor scores were reduced by 27.2% postoperatively (95% CI: 42.6-54.3 to 30.2-40.5; P < .0001). Quality of life improved 27.5% (95% CI: 34.6-48.8 to 22.4-37.9; P = .0100). CONCLUSION: Our results suggest that DBS of the fields of Forel improved motor symptoms in PD, as well as the FOG, falls, balance, postural instability, and quality of life.

α4ß2* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders.

OBJECTIVE: Attentional deficits following degeneration of brain cholinergic systems contribute to gait-balance deficits in Parkinson disease (PD). As a step toward assessing whether α4ß2* nicotinic acetylcholine receptor (nAChR) stimulation improves gait-balance function, we assessed target engagement of the α4ß2* nAChR partial agonist varenicline. METHODS: Nondemented PD participants with cholinergic deficits were identified with [18 F]fluoroethoxybenzovesamicol positron emission tomography (PET). α4ß2* nAChR occupancy after subacute oral varenicline treatment was measured with [18 F]flubatine PET. With a dose selected from the nAChR occupancy experiment, varenicline effects on gait, balance, and cognition were assessed in a double-masked placebo-controlled crossover study. Primary endpoints were normal pace gait speed and a measure of postural stability. RESULTS: Varenicline doses (0.25mg per day, 0.25mg twice daily [b.i.d.], 0.5mg b.i.d., and 1.0mg b.i.d.) produced 60 to 70% receptor occupancy. We selected 0.5mg orally b.i.d for the crossover study. Thirty-three participants completed the crossover study with excellent tolerability. Varenicline had no significant impact on the postural stability measure and caused slower normal pace gait speed. Varenicline narrowed the difference in normal pace gait speed between dual task and no dual task gait conditions, reduced dual task cost, and improved sustained attention test performance. We obtained identical conclusions in 28 participants with treatment compliance confirmed by plasma varenicline measurements. INTERPRETATION: Varenicline occupied α4ß2* nicotinic acetylcholine receptors, was tolerated well, enhanced attention, and altered gait performance. These results are consistent with target engagement. α4ß2* agonists may be worth further evaluation for mitigation of gait and balance disorders in PD. ANN NEUROL 2021;90:130-142.

[Optimal dose of levodopa-carbidopa intestinal gel in the treatment of diphasic dyskinesia and freezing of gait].

A 58-year-old man who was diagnosed with Parkinson's disease (PD) at age 46 developed levodopa-induced motor complications seven years after diagnosis, along with dyskinesia. Treatment with levodopa-carbidopa intestinal gel (LCIG) was introduced at age 57. His dyskinesia and freezing of gait (FOG) worsened after the introduction of LCIG. Considering the pathophysiological mechanism of diphasic dyskinesia, the dose of levodopa was increased since it was considered necessary to exceed the upper threshold of diphasic dyskinesia. As a result, dyskinesia and FOG became severe and he was admitted to our hospital. After reducing the levodopa equivalent dose to control the dyskinesia to an almost negligible level, his FOG also improved and his activities of daily living improved markedly. This case highlights the difficulty in treating dyskinesia and FOG in advanced-stage PD patients with a narrow therapeutic window.