Gait variability is sensitive to detect Parkinson's disease patients at high fall risk.

BACKGROUND: Gait disturbance is an important risk factor for falls in Parkinson's disease (PD). Using wearable sensors, we can obtain the spatiotemporal parameters of gait and calculate the gait variability. This prospective study aims to objectively evaluate the gait characteristics of PD fallers, and further explore the relationship between spatiotemporal parameters of gait, gait variability and falls in PD patients followed for six months. METHODS: Fifty-one PD patients were enrolled in this study. A seven-meter timed up and go test was performed. Gait characteristics were determined by a gait analysis system. Patients were followed monthly by telephone until the occurrence of falls or till the end of six months. The patients were categorized into fallers and non-fallers based on whether fell during the follow-up period. Gait parameters were compared between two groups, and binary logistic regression was used to establish the falls prediction model. In the receiver-operating characteristic curve, area under the curve (AUC) was utilized to evaluate the prediction accuracy of each indicator. RESULTS: All subjects completed the follow-up, and 14 (27.5%) patients reported falls. PD fallers had greater gait variability. The range of motion of the trunk in sagittal plane variability was an independent risk factor for falls and achieved moderate prediction accuracy (AUC = 0.751), and the logistic regression model achieved a good accuracy of falls prediction (AUC = 0.838). CONCLUSIONS: Increased gait variability is a significant feature of PD fallers and is more sensitive to detect PD patients at high risk of falls than spatiotemporal parameters.

Impaired Formation and Expression of Goal-Directed and Habitual Control in Parkinson's Disease.

Selective depletion of dopaminergic neurotransmission in the caudal sensorimotor striatum, a subdivision implicated in habitual control, is a major pathological feature in Parkinson's disease (PD). Here, we evaluated the effects of PD on the formation of goal-directed and habitual control during learning, and for the first time investigated the conflict between these two strategies in the expression of acquired learning. Twenty PD patients and 20 healthy individuals participated in a set of tasks designed to assess relative goal-directed versus habitual behavioral control. In the instrumental training phase, participants first learned by trial and error to respond to different pictured stimuli in order to gain rewarding outcomes. Three associations were trained, with standard and congruent associations mediated predominantly by goal-directed action, and incongruent association regulated predominantly by habitual control. In a subsequent "slips-of-action" test, participants were assessed to determine whether they can flexibly adjust their behavior to changes in the desirability of the outcomes. A baseline test was then administered to rule out the possibility of general inhibitory deficit, and a questionnaire was finally adopted to test the explicit knowledge of the relationships between stimuli, responses, and outcomes. Our results showed that during the instrumental training phase, PD patients had impaired learning not only of the standard and congruent associations (mediated by goal-directed system), but also the incongruent association (mediated by habitual control system). In the slips-of-action test, PD patients responded less for valuable outcomes and more often to stimuli that were associated with devalued outcomes, with poor performance predicted by symptom severity. No significant difference was found between PD and healthy subjects for the baseline test and questionnaire performance. These results collectively demonstrate that the formation of both goal-directed and habitual control are impaired in PD patients. Furthermore, PD patients are more prone to slips of action, suggesting PD patients exhibit an impairment in engaging the goal-directed system with a relatively excessive reliance on habitual control in the expression of acquired learning.

Altered Functional Segregated Sensorimotor, Associative, and Limbic Cortical-Striatal Connections in Parkinson's Disease: An fMRI Investigation.

Multiple studies have identified segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. It has been suggested that in PD, preferential loss of dopamine in the posterior putamen may cause a major deficit in habitual control (mediated by the sensorimotor cortical-striatal loop), and the patients may therefore be forced into a progressive reliance on the goal-directed behavior (regulated by the associative cortical-striatal loop). Functional evidence supporting this point is scarce at present. This study aims to verify the functional connectivity changes within the sensorimotor, associative, and limbic cortical-striatal loops in PD. Resting-state fMRI of 70 PD patients and 30 controls were collected. Bilateral tripartite functional territories of basal ganglia and their associated cortical structures were chosen as regions of interest, including ventral striatum and ventromedial prefrontal cortex for limbic loop; dorsomedial striatum and dorsolateral prefrontal cortex for associative loop; dorsolateral striatum and sensorimotor cortex for sensorimotor loop. Pearson's correlation coefficients for each seed pair were calculated to obtain the functional connectivity. The relationships between functional connectivity and disease severity were further investigated. Functional connectivity between dorsolateral striatum and sensorimotor cortex is decreased in PD patients, and negatively correlated with disease duration; whereas functional connectivity between dorsomedial striatum and dorsolateral prefrontal cortex is also decreased but postitively correlated with disease duration. The functional connectivity within the sensorimotor loop is pathologically decreased in PD, while the altered connectivity within the associative loop may indicate a failed attempt to compensate for the loss of connectivity within the sensorimotor loop.

High-Frequency Repetitive Transcranial Magnetic Stimulation Over the Left Dorsolateral Prefrontal Cortex Shortly Alleviates Fatigue in Patients With Multiple System Atrophy: A Randomized Controlled Trial.

Background: Fatigue is a common symptom in patients with Multiple system atrophy (MSA), but effective treatments remain elusive. The present study aims to investigate whether high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) could relieve fatigue in patients with MSA. Methods: This is a single-center, randomized and double-blind trial. Twenty-two patients with MSA and fatigue were randomly allocated to receive 10 sessions of either active (N = 11) or sham (N = 11) 10 Hz rTMS over the left DLPFC. The participants were assessed at baseline (T0), after the last session of treatment (T1), and at 2-week (T2), and 4-week (T3) follow-up timepoints. The primary outcomes were Fatigue Severity Scale-9 (FSS-9) scores, with Unified Multiple System Atrophy Rating Scale (UMSARS), 17-item Hamilton Depression Scale (HAMD-17), and Hamilton Anxiety Scale (HAMA) as secondary outcomes. Results: Two-way repeated ANOVAs revealed significant group × time interactions for FSS-9 scores (p < 0.001), HAMD-17 scores (p = 0.01), HAMA scores (p = 0.01), and UMRSA part II (p = 0.05). Post-hoc analyses showed that compared to T0, the active group exhibited remarkable improvements in FSS-9 and UMRSA part II scores at T1 and T2, but not at T3, and also in HAMD-17 and HAMA scores at T1, T2, and T3. No significant improvement was found in the sham group. Conclusion: High-frequency rTMS over the left DLPFC could provide short-term improvements for alleviating fatigue in patients with MSA, but the beneficial effects last no more than 4 weeks.

High-frequency repetitive transcranial magnetic stimulation over the primary motor cortex relieves musculoskeletal pain in patients with Parkinson's disease: A randomized controlled trial.

BACKGROUND: Pain is common in Parkinson's disease, and there is no effective treatment. We conducted a clinical trial to determine whether high-frequency repetitive transcranial magnetic stimulation over the primary motor cortex alleviates musculoskeletal pain in patients with Parkinson's disease. METHODS: In this single-center and double-blind trial, 52 patients with Parkinson's disease and musculoskeletal pain were randomly allocated to 26-member groups receiving 5 sessions of either 20-Hz repetitive transcranial magnetic stimulation or sham stimulation over the primary motor cortex. The participants underwent assessments in the "ON" medication state at baseline, after the fifth session, and at 2- and 4-week follow-up timepoints. The primary outcomes were pain scores on a numeric rating scale. The secondary outcomes were scores on clinical scales assessing motor symptoms, depression, anxiety, autonomic symptoms, sleep quality, and the overall severity of Parkinson's disease. RESULTS: Analyses revealed significant group × time interactions for numeric rating scale pain scores (p < 0.001), motor symptom scores (p < 0.001), depression scores (p = 0.009), anxiety scores (p = 0.013), and overall disease severity scores (p < 0.001). Post hoc analyses confirmed that the repetitive transcranial magnetic stimulation group, but not the sham stimulation group, exhibited significant improvements in numeric rating scale pain scores, motor symptom scores, depression scores, anxiety scores, and overall disease severity scores. CONCLUSION: High-frequency repetitive transcranial magnetic stimulation over the primary motor cortex may be an effective adjunct therapy for alleviating musculoskeletal pain in patients with Parkinson's disease.

Repetitive transcranial magnetic stimulation improves Parkinson's freezing of gait via normalizing brain connectivity.

Robust, effective treatments for Parkinson's freezing of gait remain elusive. Our previous study revealed beneficial effects of high-frequency rTMS over the supplementary motor area. The present study aims to explore the neural mechanisms of rTMS treatments utilizing novel exploratory multivariate approaches. We first conducted a resting-state functional MRI study with a group of 40 Parkinson's disease patients with freezing of gait, 31 without freezing of gait, and 30 normal controls. A subset of 30 patients with freezing of gait (verum group: N = 20; sham group: N = 10) who participated the aforementioned rTMS study underwent another scan after the treatments. Using the baseline scans, the imaging biomarkers for freezing of gait and Parkinson's disease were developed by contrasting the connectivity profiles of patients with freezing of gait to those without freezing of gait and normal controls, respectively. These two biomarkers were then interrogated to assess the rTMS effects on connectivity patterns. Results showed that the freezing of gait biomarker was negatively correlated with Freezing of Gait Questionnaire score (r = -0.6723, p < 0.0001); while the Parkinson's disease biomarker was negatively correlated with MDS-UPDRS motor score (r = -0.7281, p < 0.0001). After the rTMS treatment, both the freezing of gait biomarker (0.326 ± 0.125 vs. 0.486 ± 0.193, p = 0.0071) and Parkinson's disease biomarker (0.313 ± 0.126 vs. 0.379 ± 0.155, p = 0.0378) were significantly improved in the verum group; whereas no significant biomarker changes were found in the sham group. Our findings indicate that high-frequency rTMS over the supplementary motor area confers the beneficial effect jointly through normalizing abnormal brain functional connectivity patterns specifically associated with freezing of gait, in addition to normalizing overall disrupted connectivity patterns seen in Parkinson's disease.

High-frequency rTMS over the supplementary motor area improves freezing of gait in Parkinson's disease: a randomized controlled trial.

INTRODUCTION: Freezing of gait (FOG) contributes to falls in Parkinson's disease (PD), but robust, effective treatments remain elusive. There is evidence indicating that the supplementary motor area (SMA) plays an important role in the pathogenesis of FOG and may therefore be a potential neuromodulation target. The present study explored the clinical efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the SMA on FOG in PD patients. METHODS: A group of 30 PD patients with FOG were enrolled in a randomized, double-blind, sham-controlled trial. Patients were randomly allocated 2:1 to receive ten sessions of either real (N = 20) or sham (N = 10) 10 Hz rTMS over SMA. The patients were assessed at baseline (T0), after the 5th (T1) and 10th (T2) sessions, and then 2 weeks (T3) and 4 weeks (T4) after the last session. The primary clinical outcome was the Freezing of Gait Questionnaire score (FOGQ), with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores (MDS-UPDRS III) and Timed Up and Go test as secondary clinical outcomes. All the assessments were carried out at the "ON" state. RESULTS: With a four week's follow-up, there were significant interaction effects in the FOGQ (effect of group*time, p = 0.04), MDS-UPDRS III (p = 0.02) and several gait variables (total duration, p < 0.01; cadence, p = 0.04; turn duration, p = 0.01; and turn to sit duration, p = 0.02). Post-hoc analyses revealed a significantly decreased FOGQ score at T2 and T4, and significant improvements of MDS-UPDRS III and gait variables at T1, T2, T3 and T4 in the rTMS group. No significant improvements were found in the sham group. CONCLUSION: High-frequency rTMS over SMA may ultimately serve as an add-on therapy for alleviating FOG in PD patients.

Author Correction: Altered resting-state brain activity in Parkinson's disease patients with freezing of gait.

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Altered resting-state brain activity in Parkinson's disease patients with freezing of gait.

Freezing of gait (FOG) is a common and debilitating symptom in Parkinson's disease (PD). The current study investigated alterations of resting-state spontaneous brain activity in PD patients with FOG. A total of 29 patients with FOG, 28 patients without FOG and 31 controls were included. All subjects underwent resting-state functional MRI, and the amplitude of low-frequency fluctuation (ALFF) was calculated to measure the spontaneous brain activity. Between-group differences and correlations with FOG severity (both subjective and objective measures) were analyzed. Compared to those without FOG, patients with FOG showed increased ALFF in right anterior cingulate cortex (ACC) and left inferior parietal lobule (IPL), as well as decreased ALFF in right superior frontal gyrus (SFG), bilateral cerebellum and left thalamus. Correlation analyses demonstrated that ALFF within the right SFG, right ACC and bilateral pallidum were positively correlated with FOG; while ALFF within the thalamus, putamen, cerebellum and sensorimotor regions were negatively correlated. Our results indicate that FOG is associated with dysfunction within frontal-parietal regions, along with increased inhibitory outputs from basal ganglia. Additionally, altered activity of cerebellum implicates its role in the pathophysiology of FOG. These findings provide further insight into the underlying neural mechanisms of FOG in PD patients.

Primary familial brain calcifications linked with a novel SLC20A2 gene mutation in a Chinese family.

It has been recently reported that mutations in SLC20A2 gene are a major cause of primary familial brain calcifications, a rare neurodegenerative disorder characterized by symmetrical and bilateral intracranial calcification. We conducted a pedigree study by performing next Generation Sequencing in a Chinese family with three generations. Three members in this family developed Parkinsonism in their sixth decade, also, the proband presented with schizophrenia for 40 years. Next Generation Sequencing identified a novel nonsense heterozygous substitution c.1158C > A (p.Thr 386*) of SLC20A2 gene, introducing a stop codon in exon 10. The mutation was present in symptomatic and asymptomatic individuals with intracranial calcification, but absent in the individual without calcification, suggesting the mutation segregates with brain calcification. mRNA expression was decreased by 35% in the proband. We are the first to demonstrate a novel c.1158C > A mutation of SLC20A2 gene in a Chinese family with primary familial brain calcifications.