Relationship Between Iron Distribution in Deep Gray Matter Nuclei Measured by Quantitative Susceptibility Mapping and Motor Outcome After Deep Brain Stimulation in Patients With Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor deficits in advanced Parkinson's disease (PD) patients, but the degree of motor improvement varies across individuals. PD pathology involves the changes of iron spatial distribution in the deep gray matter nuclei. PURPOSE: To explore the relationship between the iron spatial distribution and motor improvement among PD patients who underwent STN-DBS surgery in three regions: substantia nigra (SN), STN, and dentate nucleus (DN). STUDY TYPE: Prospective. SUBJECTS: Forty PD patients (49.7 ± 8.8 years, 22 males/18 females) who underwent bilateral STN-DBS. FIELD STRENGTH/SEQUENCE: A 3 T preoperative three-dimensional spoiled bipolar-readout multi-echo gradient recalled echo and two-dimensional fast spin echo sequences. ASSESSMENT: Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) scores were assessed 2-3 days before and 6 months after STN-DBS. The first- and second-order texture features in regions of interest were measured on susceptibility maps. STATISTICAL TESTS: Intraclass correlation coefficient was used to determine the consistency of the region of interest volumes delineated by the two raters. Pearson or Spearman's correlation coefficients were used to assess the relationship between motor improvement after DBS and texture features. A P-value <0.05 was considered statistically significant. RESULTS: MDS-UPDRS III scores were reduced by 59.9% after STN-DBS in 40 PD patients. Motor improvement correlated with second-order texture parameters in the SN including angular second moment (r = -0.449), correlation (rho = 0.326), sum of squares (r = 0.402), sum of entropy (rho = 0.421), and entropy (r = 0.410). Additionally, DBS outcome negatively correlated with mean susceptibility values in the DN (r = -0.400). DATA CONCLUSION: PD patients with a more homogeneous iron distribution throughout the SN or a higher iron concentration in the DN responded worse to STN-DBS. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Motor improvement in Parkinson's disease patients receiving caffeine adjuvants: A double-blind randomized controlled trial in Indonesia.

Parkinson's disease (PD) manifests as a movement and brain function disorder characterized by symptoms such as resting tremors, rigidity, bradykinesia, and postural instability, leading to disability among patients. The use of psychostimulants such as caffeine has been associated with the improvement of motor symptoms in PD patients; however, studies regarding the effect of caffeine adjuvant therapy on motor function among PD patients in the Indonesian population are lacking. The aim of this study was to evaluate motor improvement as measured by the change in scores of the Movement Disorder Society - Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) among PD patients receiving caffeine adjuvant. A double-blind randomized controlled trial (RCT) was conducted among PD patients at Dr. Soetomo General Academic Hospital and Universitas Airlangga Hospital, Surabaya, Indonesia, from April to August 2023. A total of 27 patients were enrolled and randomly assigned to an intervention (receiving caffeine adjuvant, n=15) and control group (receiving placebo, n=12). Motor improvement was measured using the UPDRS III score prior to intervention and three weeks after. The Chi-squared test was used to analyze the difference in UPDRS III scores between the two groups. Motor improvement, as demonstrated by a reduction in the UPDRS III score, was observed in patients receiving caffeine adjuvant compared to those receiving placebo (80.0% vs 16.7%; p=0.004). Regarding the safety profile, only four out of 15 (26.6%) patients treated with caffeine reported minor adverse events. These conditions improved over time during the intervention. None of the 12 patients in the placebo reported adverse events. This study provides valuable insights into the initial dosage of caffeine that improves motor function in PD patients with minimum adverse effects.

Surgicogenomics: The Role of Genetics in Deep Brain Stimulation in Parkinson's Disease Patients.

Parkinson's disease (PD) is the second-most common neurodegenerative disease, affecting 1% of people aged over 60. Currently, there is only symptomatic relief for PD patients, with levodopa being the gold standard of PD treatment. Deep brain stimulation (DBS) is a surgical option to treat PD patients. DBS improves motor functions and may also allow a significant reduction in dopaminergic medication. Important parameters for DBS outcomes are the disease duration, the age of disease onset, responsiveness to levodopa and cognitive or psychiatric comorbidities. Emerging data also highlight the need to carefully consider the genetic background in the preoperative assessment of PD patients who are candidates for DBS, as genetic factors may affect the effectiveness of DBS in these patients. This review article discusses the role of genetics in DBS for PD patients, in an attempt to better understand inter-individual variability in DBS response, control of motor PD symptoms and appearance of non-motor symptoms, especially cognitive decline.

BOLD frequency-dependent alterations in resting-state functional connectivity by pallidal deep brain stimulation in patients with Parkinson's disease.

OBJECTIVE: Functional MRI (fMRI) has been used to investigate the therapeutic mechanisms underlying deep brain stimulation (DBS) for Parkinson's disease (PD). However, the alterations in stimulation site-seeded functional connectivity induced by DBS at the internal globus pallidus (GPi) remain unclear. Furthermore, whether DBS-modulated functional connectivity is differentially affected within particular frequency bands remains unknown. The present study aimed to reveal the alterations in stimulation site-seeded functional connectivity induced by GPi-DBS and to examine whether there exists a frequency band effect in blood oxygen level-dependent (BOLD) signals related to DBS. METHODS: Patients with PD receiving GPi-DBS (n = 28) were recruited for resting-state fMRI with DBS on and DBS off under a 1.5-T MR scanner. Age- and sex-matched healthy controls (n = 16) and DBS-naïve PD patients (n = 24) also received fMRI scanning. The alterations in stimulation site-seeded functional connectivity in the stimulation-on state versus stimulation-off state, as well as the relationship between alterations in connectivity and improvement in motor function induced by GPi-DBS, were examined. Furthermore, the modulatory effect of GPi-DBS on the BOLD signals within the 4 frequency subbands (slow-2 to slow-5) was investigated. Finally, the functional connectivity of the motor-related network, consisting of multiple cortical and subcortical regions, was also examined among the groups. In this study, p < 0.05 with Gaussian random field correction indicates statistical significance. RESULTS: Functional connectivity seeding from the stimulation site (i.e., the volume of tissue activated [VTA]) increased in the cortical sensorimotor areas and decreased in the prefrontal regions with GPi-DBS. Alterations in connectivity between the VTA and the cortical motor areas were correlated with motor improvement by pallidal stimulation. The alterations in connectivity were dissociable between the frequency subbands in the occipital and cerebellar areas. The motor network analysis indicated decreased connectivity among most cortical and subcortical regions but increased connectivity between the motor thalamus and the cortical motor area in patients with GPi-DBS compared with those in DBS-naïve patients. The DBS-induced decrease in several cortical-subcortical connectivities within the slow-5 band correlated with motor improvement with GPi-DBS. CONCLUSIONS: These findings indicate that the alterations in functional connectivity from the stimulation site to the cortical motor areas, as well as multiple connectivities among the motor-related network, were associated with the efficacy of GPi-DBS for PD. Furthermore, the changing pattern of functional connectivity within the 4 BOLD frequency subbands is partially dissociable.

Technology-based therapy-response evaluation of axial motor symptoms under daily drug regimen of patients with Parkinson's disease.

Background: Axial disturbances are the most disabling symptoms of Parkinson's disease (PD). Kinect-based objective measures could extract motion characteristics with high reliability and validity. Purpose: The present research aimed to quantify the therapy-response of axial motor symptoms to daily medication regimen and to explore the correlates of the improvement rate (IR) of axial motor symptoms based on a Kinect camera. Materials and methods: We enrolled 44 patients with PD and 21 healthy controls. All 65 participants performed the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III and the Kinect-based kinematic evaluation to assess arising from a chair, gait, posture, and postural stability before and after medication. Spearman's correlation analysis and multiple linear regression model were performed to explore the relationships between motor feature IR and clinical data. Results: All the features arising from a chair (P = 0.001), stride length (P = 0.001), velocity (P < 0.001), the height of foot lift (P < 0.001), and turning time (P = 0.001) improved significantly after a daily drug regimen in patients with PD. In addition, the anterior trunk flexion (lumbar level) exhibited significant improvement (P = 0.004). The IR of the axial motor symptoms score was significantly correlated with the IRs of kinematic features for gait velocity, stride length, foot lift height, and sitting speed (r s = 0.345, P = 0.022; r s = 0.382, P = 0.010; r s = 0.314, P = 0.038; r s = 0.518, P < 0.001, respectively). A multivariable regression analysis showed that the improvement in axial motor symptoms was associated with the IR of gait velocity only (ß = 0.593, 95% CI = 0.023-1.164, P = 0.042). Conclusion: Axial symptoms were not completely drug-resistant, and some kinematic features can be improved after the daily medication regimen of patients with PD.

Characterization and localization of upper and lower extremity motor improvements in STN DBS for Parkinson's disease.

INTRODUCTION: Subthalamic deep brain stimulation (STN DBS) may have differential effects on cardinal motor signs of Parkinson's disease (PD) in the upper and lower extremities. In addition, sites of maximally effective DBS for each sign and extremity may be distinct. Our study seeks to elucidate these structure-function relationships. METHODS: We applied an ordinary least squares linear regression model to measure motor effects of STN DBS on upper (UE) and lower (LE) extremity tremor, rigidity, and bradykinesia. We then applied an atlas-independent electrical-field model to identify sites of maximally effective stimulation for each sign and each extremity. Distances between sites and statistical power to resolve differences were calculated. RESULTS: In our study population (n = 78 patients), STN DBS improved all cardinal motor signs (ß = 0.64, p < .05). Improvement magnitudes were tremor > rigidity > bradykinesia. Effects of STN DBS on UE versus LE signs were statistically equal for tremor and bradykinesia, but greater for UE rigidity than LE rigidity (ß = 0.19, p < .05). UE maximal-effect loci were lateral, anterior, and dorsal to LE loci, but were not statistically resolved, despite sufficient statistical power to resolve differences of ≤0.48 mm (p < .05) between maximally effective loci of stimulation. CONCLUSION: STN DBS produces differential effects on UE and LE rigidity, but not for tremor or bradykinesia. This finding is not explained by distinct UE and LE loci of maximally effective stimulation. Instead, we hypothesize that downstream effects of STN DBS on motor networks and limb biomechanics are responsible for observed differences in UE and LE responses.

Transcranial magnetic stimulation as a diagnostic and therapeutic tool in cerebral palsy.

Purpose: Cerebral palsy (CP) is one of the leading causes of child disability, which profoundly affects the lives of whole families and contributes to the burden of health care. Despite the extensive rehabilitative, surgical and other therapeutic efforts of an array of specialists, a significant proportion of patients remain severely disabled. Transcranial magnetic stimulation (TMS) is a non-invasive diagnostic tool in various diseases of the cerebral cortex and cortico-spinal tract (CST). Repetitive TMS (rTMS) is able to induce a long-lasting cerebral plasticity, which is associated with a therapeutic effect in a number of psychiatric and neurological diseases. This article reviews the diagnostic findings gained with TMS in CP as well as therapeutic trials performed with rTMS. Views: The absence of responses in the motor cortex in the first months of life, as revealed by TMS, may predict the development of CP in children at risk. In a proportion of children with the unilateral form of CP, TMS documents the pathological preservation of ipsilateral, cortico-spinal connections from the non-lesioned hemisphere, which is associated with poor outcome. rTMS seems to be a safe method with significant therapeutic potential in CP. The data published so far reveals an almost unanimously significant therapeutic benefit in motor performance over placebo. However, the studies conducted to date have almost without exception involved children with unilateral palsy, and have focused nearly exclusively on therapy for motor symptoms. Conclusions: Magnetic stimulation brings significant diagnostic and therapeutic effects in CP. However, more studies that go beyond the limits specified above are still awaited.

Is more frequent physical therapy associated with increased gross motor improvement in children with cerebral palsy? A national prospective cohort study.

Purpose: To investigate the association between physical therapy frequency and gross motor improvement in children with cerebral palsy (CP).Materials and methods: This is a prospective cohort study of 442 children aged 2-12 years, Gross Motor Function Classification System levels I-V, from the Cerebral Palsy Follow-up Program and the Cerebral Palsy Register of Norway. Outcome was change in reference percentiles for the Gross Motor Function Measure (GMFM-66) between two subsequent assessments (N = 1056) analyzed in a linear mixed model.Results: It was a dose response association between physical therapy frequency and gross motor improvement. Mean change was 4.2 (95% CI: 1.4-7.1) percentiles larger for physical therapy 1-2 times per week and 7.1 (95% CI: 2.6-11.6) percentiles larger for physical therapy >2 times per week, compared to less frequent physical therapy when analyzed in a multivariable model including multiple child and intervention factors. The only statistically significant confounder was number of contractures which was negatively associated with gross motor improvement.Conclusions: When gross motor improvement is a goal for children with CP, more frequent physical therapy should be considered.Implications for rehabilitationIn general, the gross motor development of Norwegian children with cerebral palsy was as expected according to the reference percentiles for the GMFM-66.When gross motor improvement is a goal for children with cerebral palsy, high-frequency physical therapy should be considered.Contractures should be addressed in order to optimize gross motor improvement for children with cerebral palsy.

FTY720 Improves Behavior, Increases Brain Derived Neurotrophic Factor Levels and Reduces α-Synuclein Pathology in Parkinsonian GM2+/- Mice.

Parkinson's disease (PD) is a progressive aging disorder that affects millions worldwide, thus, disease-modifying-therapies are urgently needed. PD pathology includes α-synuclein (aSyn) accumulation as synucleinopathy. Loss of GM1 gangliosides occurs in PD brain, which is modeled in GM2 synthase transgenic mice. GM2+/- mice have low, not absent GM1 and develop age-onset motor deficits, making them an excellent PD drug testing model. FTY720 (fingolimod) reduces synucleinopathy in A53T aSyn mice and motor dysfunction in 6-OHDA and rotenone PD models, but no one has tested FTY720 in mice that develop age-onset PD-like motor problems. We confirmed that GM2+/-mice had equivalent rotarod, hindlimb reflexes, and adhesive removal functions at 9 mo. From 11 mo, GM2+/- mice received oral FTY720 or vehicle 3x/week to 16 mo. As bladder problems occur in PD, we also assessed GM2+/- bladder function. This allowed us to demonstrate improved motor and bladder function in GM2+/- mice treated with FTY720. By immunoblot, FTY720 reduced levels of proNGF, a biomarker of bladder dysfunction. In humans with PD, arm swing becomes abnormal, and brachial plexus modulates arm swing. Ultrastructure of brachial plexus in wild type and GM2 transgenic mice confirmed abnormal myelination and axons in GM2 transgenics. FTY720 treated GM2+/- brachial plexus sustained myelin associated protein levels and reduced aggregated aSyn and PSer129 aSyn levels. FTY720 increases brain derived neurotrophic factor (BDNF) and we noted increased BDNF in GM2+/- brachial plexus and cerebellum, which contribute to rotarod performance. These findings provide further support for testing low dose FTY720 in patients with PD.

Subjective Perceived Motor Improvement after Acute Levodopa Challenge in Parkinson's Disease.

BACKGROUND: Previous studies found a poor association between parkinsonian patient's reported subjective improvement after commencing dopaminergic treatment and improvements in objective measures of motor impairment by clinician. OBJECTIVE: To compare PD patient's subjective perceived motor improvement after acute levodopa challenge test with objective motor improvement assessed by the clinician using the UPDRS part III. To analyze clinical characteristics, i.e. age, disease duration, cognitive performance or severity of axial features, that may have influenced patient's perception. METHODS: Fifty-seven consecutive PD patients (23 women, 34 men; mean age, 63.4±7.7 years) (Hoehn and Yahr off score, 2.5±0.7; mean disease duration, 11.4±4.1 years) completed the acute levodopa challenge. The percentage of improvement in motor disability, i.e. objective motor improvement, was determined with respect to the off-drug condition. RESULTS: Bland & Altman visual analysis reveals a high degree of correlation between objective and subjective perceived motor improvement. Both the axial sub-scores in the off- and on-state (respectively, P = 0.006 and P = 0.024) and the presence of peak-dose dyskinesia (P = 0.043) significantly influence the difference between objective and subjective perceived motor improvement. CONCLUSIONS: This is the first study reporting on how PD patients assessed their motor improvement after acute levodopa challenge. These findings suggest a strong correlation between objective motor improvement assessed by the clinician using the UPDRS part III and subjective perceived motor improvement reported by the patient.

Stimulation sites in the subthalamic nucleus and clinical improvement in Parkinson's disease: a new approach for active contact localization.

OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely used in patients with Parkinson's disease (PD). However, which target area of this region results in the highest antiparkinsonian efficacy is still a matter of debate. The aim of this study was to develop a more accurate methodology to locate the electrodes and the contacts used for chronic stimulation (active contacts) in the subthalamic region, and to determine the position at which stimulation conveys the greatest clinical benefit. METHODS The study group comprised 40 patients with PD in whom bilateral DBS electrodes had been implanted in the STN. Based on the Morel atlas, the authors created an adaptable 3D atlas that takes into account individual anatomical variability and divides the STN into functional territories. The locations of the electrodes and active contacts were obtained from an accurate volumetric assessment of the artifact using preoperative and postoperative MR images. Active contacts were positioned in the 3D atlas using stereotactic coordinates and a new volumetric method based on an ellipsoid representation created from all voxels that belong to a set of contacts. The antiparkinsonian benefit of the stimulation was evaluated by the reduction in the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score and in the levodopa equivalent daily dose (LEDD) at 6 months. A homogeneous group classification for contact position and the respective clinical improvement was applied using a hierarchical clustering method. RESULTS Subthalamic stimulation induced a significant reduction of 58.0% ± 16.5% in the UPDRS-III score (p < 0.001) and 64.9% ± 21.0% in the LEDD (p < 0.001). The greatest reductions in the total and contralateral UPDRS-III scores (64% and 76%, respectively) and in the LEDD (73%) were obtained when the active contacts were placed approximately 12 mm lateral to the midline, with no influence of the position being observed in the anteroposterior and dorsoventral axes. In contrast, contacts located about 10 mm from the midline only reduced the global and contralateral UPDRS-III scores by 47% and 41%, respectively, and the LEDD by 33%. Using the ellipsoid method of location, active contacts with the highest benefit were positioned in the rostral and most lateral portion of the STN and at the interface between this subthalamic region, the zona incerta, and the thalamic fasciculus. Contacts placed in the most medial regions of the motor STN area provided the lowest clinical efficacy. CONCLUSIONS The authors report an accurate new methodology to assess the position of electrodes and contacts used for chronic subthalamic stimulation. Using this approach, the highest antiparkinsonian benefit is achieved when active contacts are located within the rostral and the most lateral parts of the motor region of the STN and at the interface of this region and adjacent areas (zona incerta and thalamic fasciculus).

Music-supported motor training after stroke reveals no superiority of synchronization in group therapy.

BACKGROUND: Music-supported therapy has been shown to be an effective tool for rehabilitation of motor deficits after stroke. A unique feature of music performance is that it is inherently social: music can be played together in synchrony. AIM: The present study explored the potential of synchronized music playing during therapy, asking whether synchronized playing could improve fine motor rehabilitation and mood. METHOD: Twenty-eight patients in neurological early rehabilitation after stroke with no substantial previous musical training were included. Patients learned to play simple finger exercises and familiar children's songs on the piano for 10 sessions of half an hour. Patients first received three individual therapy sessions and then continued in pairs. The patient pairs were divided into two groups. Patients in one group played synchronously (together group) whereas the patients in the other group played one after the other (in-turn group). To assess fine motor skill recovery the patients performed standard clinical tests such as the nine-hole-pegboard test (9HPT) and index finger-tapping speed and regularity, and metronome-paced finger tapping. Patients' mood was established using the Profile of Mood States (POMS). RESULTS: Both groups showed improvements in fine motor control. In metronome-paced finger tapping, patients in both groups improved significantly. Mood tests revealed reductions in depression and fatigue in both groups. During therapy, patients in the in-turn group rated their partner as more sympathetic than the together-group in a visual-analog scale. CONCLUSIONS: Our results suggest that music-supported stroke rehabilitation can improve fine motor control and mood not only individually but also in patient pairs. Patients who were playing in turn rather than simultaneously tended to reveal greater improvement in fine motor skill. We speculate that patients in the former group may benefit from the opportunity to learn from observation.