Effect of cerebrospinal dual-site magnetic stimulation on freezing of gait in Parkinson's disease.

Addressing levodopa-unresponsive freezing of gait (FOG) in Parkinson's disease (PD) presents a significant challenge. A randomized double-blinded trial evaluated the effects of repetitive transcranial magnetic stimulation (rTMS) in conjunction with transcutaneous magnetic spinal cord stimulation among 57 PD individuals experiencing levodopa-unresponsive FOG. Patients were randomized to receive dual-site stimulation involving bilateral primary motor cortex of the lower leg (M1-LL) and the lumbar spinal cord, single-site stimulation targeting bilateral M1-LL alone, or sham stimulation for 10 sessions. Low-frequency rTMS induced remarkable improvements in FOG, gait, and motor functions compared to sham at 1 day and 1 month postintervention. Notably, the dual-site protocol demonstrated superior efficacy in mitigating FOG and improving gait compared to the single-site approach, which correlated with a pronounced increase in short-interval intracortical inhibition of the abductor pollicis brevis. These findings underscore the potential of the cerebrospinal dual-site regimen as a promising approach for levodopa-unresponsive FOG and gait in PD.

Shared and distinct cortical morphometric alterations in five neuropsychiatric symptoms of Parkinson's disease.

Neuropsychiatric symptoms (including anxiety, depression, apathy, impulse-compulsive behaviors and hallucinations) are among the most common non-motor features of Parkinson's disease. Whether these symptoms should be considered as a direct consequence of the pathophysiologic mechanisms of Parkinson's disease is controversial. Morphometric similarity network analysis and epicenter mapping approach were performed on T1-weighted images of 505 patients with Parkinson's disease and 167 age- and sex-matched healthy participants from Parkinson's Progression Markers Initiative database to reveal the commonalities and specificities of distinct neuropsychiatric symptoms. Abnormal cortical co-alteration pattern in patients with neuropsychiatric symptoms was in somatomotor, vision and frontoparietal regions, with epicenters in somatomotor regions. Apathy, impulse-compulsive behaviors and hallucinations shares structural abnormalities in somatomotor and vision regions, with epicenters in somatomotor regions. In contrast, the cortical abnormalities and epicenters of anxiety and depression were prominent in the default mode network regions. By embedding each symptom within their co-alteration space, we observed a cluster composed of apathy, impulse-compulsive behaviors and hallucinations, while anxiety and depression remained separate. Our findings indicate different structural mechanisms underlie the occurrence and progression of different neuropsychiatric symptoms. Based upon these results, we propose that apathy, impulse-compulsive behaviors and hallucinations are directly related to damage of motor circuit, while anxiety and depression may be the combination effects of primary pathophysiology of Parkinson's disease and psychosocial causes.

Association between the functional connectivity of ventral tegmental area-prefrontal network and pure apathy in Parkinson's disease: a cross-sectional study.

Background: Apathy, characterized by diminished goal-directed behaviors, frequently occurs in patients with Parkinson's disease (PD). The dopamine-releasing neurons of the ventral tegmental area (VTA) have been closely related to this behavioral disruption and project widely to the corticolimbic areas, yet their functional and structural connectivity in regard to other brain regions remain unknown in patients with PD and pure apathy (PD-PA). This study thus aimed to characterize the alterations of functional connectivity (FC) of the VTA and white matter structural connectivity in PD-PA. Methods: In this study, 29 patients with PD-PA, 37 with PD but not pure apathy (PD-NPA), and 28 matched healthy controls (HCs) underwent T1-weighted, resting state functional magnetic resonance imaging, and diffusion tensor imaging scans. Patients of this cross-sectional retrospective study were consecutively recruited from The First Affiliated Hospital of Nanjing Medical University between April 2017 and October 2021. Meanwhile, HCs were consecutively recruited from the local community and the Health Examination Center of our hospital. An analysis of covariance and a general linear model were respectively conducted to investigate the functional and structural connectivity among three groups. The tract-based spatial statistics (TBSS) approach was used to investigate the white matter structural connectivity. Results: Patients with PD-PA showed reduced FC of the VTA with the left medial superior frontal gyrus (SFGmed) when compared to the patients with PD-NPA [t=-3.67; voxel-level P<0.001; cluster-level family-wise error-corrected P (PFWE)<0.05]. Relative to the HCs, patients with PD-PA demonstrated reduced FC of the VTA with the left SFGmed (t=-4.98; voxel-level P<0.001; cluster-level PFWE<0.05), right orbital superior frontal gyrus (SFGorb) (t=-5.08; voxel-level P<0.001; cluster-level PFWE<0.05), and right middle frontal gyrus (MFG) (t=-5.08; voxel-level P<0.001; cluster-level PFWE<0.05). Moreover, the reductions in VTA FC with the left SFGmed were associated with severe apathy symptoms in patients with PD-PA (r=-0.600; P=0.003). However, a TBSS approach did not reveal any significant differences in fiber tracts between the three groups. Conclusions: This study identified reduced FC within the mesocortical network (VTA-SFGmed) of patients with PD-PA. These findings may provide valuable information for administering neuromodulation therapies in the alleviation of apathy symptoms in those with PD.

Transcutaneous auricular vagus nerve stimulation improves anxiety symptoms and cortical activity during verbal fluency task in Parkinson's disease with anxiety.

OBJECTIVE: To investigate the effect of 20/4Hz transcutaneous auricular vagus nerve stimulation (taVNS) on anxiety symptoms in Parkinson's disease (PD) and the potential neural mechanism. METHODS: In the current randomized, double-blind, sham-controlled trial, 30 PD patients with anxiety (PD-A), 30 PD patients without anxiety (PD-nA), and 30 healthy controls (HCs) were enrolled. PD-A patients were randomly (1:1) allotted to real taVNS stimulation group (RS) or sham stimulation group (SS) to explore the efficacy of a two-week treatment of taVNS to promote anxiety recovery. Simultaneously, all participants were measured activation in the bilateral prefrontal cortex during verbal fluency task (VFT) using functional near-infrared spectroscopy. RESULTS: PD-A patients showed significantly decreased oxyhemoglobin in the left triangle part of the inferior frontal gyrus (IFG) during VFT, which was negatively related to the severity of anxiety symptoms. After two-week treatment of taVNS, the interaction of group and time had significant effect on HAMA scores (F = 18.476, p < 0.001, η2 = 0.398). In RS group, compared with baseline, HAMA scores decreased significantly in the post-treatment and follow-up condition (both p < 0.001). Meanwhile, in RS group, HAMA scores were lower than those in SS group in the post-treatment and follow-up condition (p = 0.006, <0.001, respectively). Furthermore, the 20/4Hz taVNS remarkably ameliorated anxiety symptoms in PD patients, directly correlated with the increased activation of the left triangle part of the IFG during VFT in RS group. CONCLUSION: Our results depicted that taVNS could ameliorate the anxiety symptoms of PD-A patients and regulated the function of the left triangle part of the IFG.

Multimodal neuroimaging fusion unravel structural-functional-neurotransmitter change in Parkinson's disease with impulse control disorders.

BACKGROUND: Impulse control disorders (ICD) in Parkinson's disease (PD) is highly multifactorial in etiology and has intricate neural mechanisms. Our multimodal neuroimaging study aimed to investigate the specific patterns of structure-function-neurotransmitter interactions underlying ICD. METHODS: Thirty PD patients with ICD (PD-ICD), 30 without ICD (PD-NICD) and 32 healthy controls (HCs) were recruited. Gyrification and perivascular spaces (PVS) were computed to capture the alternations of cortical surface morphology and glymphatic function. Seed-based functional connectivity (FC) were performed to identify the corresponding functional changes. Further, JuSpace toolbox were employed for cross-modal correlations to evaluate whether the spatial patterns of functional alterations in ICD patients were associated with specific neurotransmitter system. RESULTS: Compared to PD-NICD, PD-ICD patients showed hypogyrification and enlarged PVS volume fraction in the left orbitofrontal gyrus (OFG), as well as decreased FC between interhemispheric OFG. The interhemispheric OFG connectivity reduction was associated with spatial distribution of µ-opioid pathway (r = -0.186, p = 0.029, false discovery rate corrected). ICD severity was positively associated with the PVS volume fraction of left OFG (r = 0.422, p = 0.032). Furthermore, gyrification index (LGI) and percent PVS (pPVS) in OFG and their combined indicator showed good performance in differentiating PD-ICD from PD-NICD. CONCLUSIONS: Our findings indicated that the co-altered structure-function-neurotransmitter interactions of OFG might be involved in the pathogenesis of ICD.

Sleep disturbances, cognitive decline, and AD biomarkers alterations in early Parkinson's disease.

OBJECTIVE: We aimed to investigate whether each type of sleep disturbances (i.e., pRBD, EDS, and insomnia) is specifically associated with faster decline in global cognition and different cognitive domains among de novo PD patients. We also assessed the influence of sleep disturbances on core AD CSF biomarkers alterations and conversion to dementia. METHODS: Prospectively longitudinal data were obtained from the PPMI cohort. Sleep disturbances and cognition ability were assessed by questionnaires at baseline and follow-up visits. Generalized linear mixed models were utilized to assess the effect of sleep disturbances on cognitive decline and core AD CSF biomarkers change. The associations between sleep disturbances and conversion to dementia were analyzed using Cox regression analysis. RESULTS: Baseline pRBD was associated with faster decline in global cognition and all cognitive domains, including verbal episodic memory, visuospatial ability, executive function, language, and processing speed. EDS was associated with faster decline in three cognitive domains, including verbal episodic memory, executive function/working memory, and processing speed. Insomnia was associated with faster decline in global cognition and verbal episodic memory. Meanwhile, pRBD and EDS were associated with longitudinal decrease of CSF Aß42. Baseline pRBD increased the risk of conversion to dementia. The risk of dementia in PD patients with multiple sleep disturbances also increased compared with those without sleep disturbance. INTERPRETATION: Sleep disturbances (i.e., pRBD, EDS, and insomnia) were associated with cognitive decline in early PD. EDS and pRBD were associated with decrease of CSF Aß42. Moreover, pRBD was associated with conversion to dementia.

Aberrant brain topological organization and granger causality connectivity in Parkinson's disease with impulse control disorders.

Introduction: Impulse control disorders (ICDs) refer to the common neuropsychiatric complication of Parkinson's disease (PD). The white matter (WM) topological organization and its impact on brain networks remain to be established. Methods: A total of 17 PD patients with ICD (PD-ICD), 17 without ICD (PD-NICD), and 18 healthy controls (HCs) were recruited. Graph theoretic analyses and Granger causality analyses were combined to investigate WM topological organization and the directional connection patterns of key regions. Results: Compared to PD-NICD, ICD patients showed abnormal global properties, including decreased shortest path length (Lp) and increased global efficiency (Eg). Locally, the ICD group manifested abnormal nodal topological parameters predominantly in the left middle cingulate gyrus (MCG) and left superior cerebellum. Decreased directional connectivity from the left MCG to the right medial superior frontal gyrus was observed in the PD-ICD group. ICD severity was significantly correlated with Lp and Eg. Discussion: Our findings reflected that ICD patients had excessively optimized WM topological organization, abnormally strengthened nodal structure connections within the reward network, and aberrant causal connectivity in specific cortical- limbic circuits. We hypothesized that the aberrant reward and motor inhibition circuit could play a crucial role in the emergence of ICDs.

Altered perivascular spaces in subcortical white matter in Parkinson's disease patients with levodopa-induced dyskinesia.

Dilated perivascular spaces (PVS) have emerged as a pathological hallmark in various neurological conditions, including Parkinson's disease (PD). Levodopa-induced dyskinesia (LID), an intractable motor complication of PD, remains enigmatic regarding the distribution patterns of PVS. Our objective was to scrutinize the percent PVS (pPVS) changes within PD patients with LID (PD-LID). In total, 132 individuals were enrolled, including PD-LID (n = 42), PD patients without LID (PD-nLID, n = 45), and healthy controls (HCs, n = 45). Employing an automated approach for PVS quantification based on structural magnetic resonance imaging, we comprehensively evaluated total pPVS in subcortical white matter globally and regionally. A significant increase in global pPVS was observed in PD patients versus HCs, particularly evident in PD-LID relative to HCs. Within the PD-LID group, elevated pPVS was discerned in the right inferior frontal gyrus region (rIFG) (pars opercularis), contrasting with PD-nLID and HCs. Moreover, PD patients exhibited increased pPVS in bilateral superior temporal regions compared to HCs. Notably, pPVS in the rIFG positively correlated with dyskinetic symptoms and could well identify LID. Our findings unveiled PVS alternations in subcortical white matter in PD-LID at both global and regional levels, highlighting the increased pPVS in rIFG as a prospective imaging marker for LID.

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.

Dynamic functional connectivity reveals hyper-connected pattern and abnormal variability in freezing of gait of Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is an intractable and paroxysmal gait disorder that seriously affects the quality of life of Parkinson's disease (PD) patients. Emerging studies have reported abnormal brain activity of distributed networks in FOG patients, whereas ignoring the intrinsic dynamic fluctuations of functional connectivity. The purpose of this study was to examine the dynamic functional network connectivity (dFNC) of PD-FOG. METHODS: In total, 52 PD patients with FOG (PD-FOG), 73 without FOG (PD-NFOG) and 38 healthy controls (HCs) received resting state functional magnetic resonance imaging (rs-fMRI). Sliding window method, k-means clustering and graph theory analysis were employed to retrieve dynamic characteristics of PD-FOG. Partial correlation analysis was conducted to verify whether the dFNC was related to freezing gait severity. RESULTS: Seven brain networks were identified and configured into seven states. Compared to PD-NFOG, significant spatial pattern was identified for state 2 in freezers, showing increased functional coupling between default mode network (DMN) and basal ganglia network (BG), as a concrete manifestation of increased precuneus-caudate coupling. The mean dwell time and fractional window of state 2 had a positive correlation with FOG severity. Furthermore, PD-FOG group exhibited lower variance in nodal efficiency of independent components (IC) 7 (left precuneus). CONCLUSIONS: Our study suggested that aberrant coupling of precuneus-caudate and disrupted variability of precuneus efficiency might be associated to the neural mechanisms of FOG.

Transcutaneous auricular vagus nerve stimulation improves gait and cortical activity in Parkinson's disease: A pilot randomized study.

OBJECTIVE: In this randomized, double-blind, sham-controlled trial, we explored the effect of 20 Hz transcutaneous auricular vagus nerve stimulation (taVNS) on gait impairments in Parkinson's disease (PD) patients and investigated the underlying neural mechanism. METHODS: In total, 22 PD patients and 14 healthy controls were enrolled. PD patients were randomized (1:1) to receive active or sham taVNS (same position as active taVNS group but without releasing current) twice a day for 1 week. Meanwhile, all subjects were measured activation in the bilateral frontal and sensorimotor cortex during usual walking by functional near-infrared spectroscopy. RESULTS: PD patients showed instable gait with insufficient range of motion during usual walking. Active taVNS improved gait characteristics including step length, stride velocity, stride length, and step length variability compared with sham taVNS after completion of the 7-day therapy. No difference was found in the Unified Parkinson's Disease Rating Scale III, Timed Up and Go, Tinetti Balance, and Gait scores. Moreover, PD patients had higher relative change of oxyhemoglobin in the left dorsolateral prefrontal cortex, pre-motor area, supplementary motor area, primary motor cortex, and primary somatosensory cortex than HCs group during usual walking. Hemodynamic responses in the left primary somatosensory cortex were significantly decreased after taVNS therapy. CONCLUSION: taVNS can relieve gait impairments and remodel sensorimotor integration in PD patients.

Aberrant voxel-based degree centrality and functional connectivity in Parkinson's disease patients with fatigue.

AIMS: The study aimed to investigate alterations in the inherent connectivity pattern of global functional networks in Parkinson's disease (PD) patients with fatigue. METHODS: Eighteen PD patients with fatigue (PD-F), 20 PD patients without fatigue (PD-NF), and 23 healthy controls (HCs) were recruited and analyzed by the voxel-wise degree centrality (DC) and the seed-based functional connectivity (FC) analysis. Meanwhile, the surface-based morphometry (SBM) analysis was also commanded to explore the structural alternations among groups. RESULTS: PD-F patients displayed reduced DC values in the left postcentral gyrus relative to PD-NF and HCs groups, while increased DC values in the bilateral precuneus compared to HCs. Simultaneously, altered DC value in the left postcentral gyrus negatively corresponded to the mean fatigue severity scale (FSS) in PD-F patients. Additionally, the receiver operating characteristic (ROC) curves uncovered that the reduced DC value of the left postcentral gyrus could discriminate PD-F from PD-NF and HCs groups. Our FC analysis further revealed that altered FC was located predominantly in the sensorimotor network in the PD-F group. Moreover, we discovered no statistically significant differences between the three groups concerning cortical thickness. CONCLUSION: Our findings indicated that the altered functional connectivity in the sensorimotor network centering on the left postcentral gyrus and the bilateral precuneus might be the potential pathogenesis of PD with fatigue.

Cholinergic basal forebrain atrophy in Parkinson's disease with freezing of gait.

BACKGROUND: Mounting research support that cholinergic dysfunction plays a prominent role in freezing of gait (FOG), which commonly occurs in Parkinson's disease (PD). Basal forebrain (BF), especially the cholinergic nuclei 4 (Ch4), provides the primary source of the brain cholinergic input. However, whether the degeneration of BF and its innervated cortex contribute to the pathogenesis of FOG is unknown. OBJECTIVE: To explore the role of structural alterations of BF and its innervated cortical brain regions in the pathogenesis of PD patients with freezing. METHODS: Magnetic resonance imaging assessments and neurological assessments were performed on 20 PD patients with FOG (PD-FOG), 20 without FOG (PD-NFOG), and 21 healthy participants. Subregion volumes of the BF were compared among groups. Local gyrification index (LGI) was computed to reveal the cortical alternations. Relationships among subregional BF volumes, LGI, and the severity of FOG were evaluated by multiple linear regression. RESULTS: Our study discovered that, compared to PD-NFOG, PD-FOG exhibited significant Ch4 atrophy (p = 4.6 × 10-5 ), accompanied by decreased LGI values in the left entorhinal cortex (p = 3.00 × 10-5 ) and parahippocampal gyrus (p = 2.90 × 10-5 ). Based on the regression analysis, Ch4 volume was negatively associated with FOG severity in PD-FOG group (ß = -12.224, T = -2.556, p = 0.031). INTERPRETATION: Our results imply that Ch4 degeneration and microstructural disorganization of its innervated cortical brain regions may play important roles in PD-FOG.

Impaired structural and reserved functional topological organizations of brain networks in Parkinson's disease with freezing of gait.

Background: Freezing of gait (FOG) is a common disabling motor disturbance in Parkinson's disease (PD). Our study aimed to probe the topological organizations of structural and functional brain networks and their coupling in FOG. Methods: In this cross-sectional retrospective study, a total of 30 PD patients with FOG (PD-FOG), 40 patients without FOG, and 25 healthy controls (HCs) underwent clinical assessments and magnetic resonance imaging (MRI) scanning. Large-scale structural and functional brain networks were constructed. Subsequently, global and nodal graph theoretical properties and functional-structural coupling were investigated. Finally, correlations between the altered brain topological properties and freezing severity were analyzed in PD-FOG. Results: For structural networks, at the global level, PD-FOG exhibited increased normalized characteristic path length (P=0.040, Bonferroni-corrected) and decreased global efficiency (P=0.005, Bonferroni-corrected) compared with controls, and showed reduced global (P=0.001, Bonferroni-corrected) and local (P=0.032, Bonferroni-corrected) efficiency relative to patients without FOG. At the nodal level, nodal efficiency of structural networks was reduced in PD-FOG compared with PD patients without FOG, located in the left supplementary motor area (SMA), gyrus rectus, and middle cingulate cortex (MCC) (all P<0.05, Bonferroni-corrected). Notably, altered global and nodal properties of structural networks were significantly correlated with Freezing of Gait Questionnaire scores [all P<0.05, false discovery rate (FDR)-corrected]. However, only an increase in local efficiency (P=0.003, Bonferroni-corrected) of functional networks was identified in PD-FOG compared with those without FOG. No significant structural-functional coupling was detected among the 3 groups. Conclusions: This study demonstrates the extensively impaired structural and relatively reserved functional network topological organizations in PD-FOG. Our results also provide evidence that the pathogenesis of PD-FOG is primarily attributable to network vulnerability established by crucial structural damage, especially in the left SMA, gyrus rectus, and MCC.

Altered dynamic functional network connectivity in levodopa-induced dyskinesia of Parkinson's disease.

AIMS: The aim of this study was to clarify the dynamic neural activity of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). METHODS: Using dynamic functional network connectivity (dFNC) analysis, we evaluated 41 PD patients with LID (LID group) and 34 PD patients without LID (No-LID group). Group spatial independent component analysis and sliding-window approach were employed. Moreover, we applied a k-means clustering algorithm on windowed functional connectivity (FC) matrices to identify reoccurring FC patterns (i.e., states). RESULTS: The optimal number of states was determined to be five, the so-called State 1, 2, 3, 4, and 5. In ON phase, compared with No-LID group, LID group occurred more frequently and dwelled longer in strongly connected State 1, characterized by strong positive connections between visual network (VIS) and sensorimotor network (SMN). When switching from OFF to ON phase, LID group occurred less frequently in State 3 and State 4. Meanwhile, LID group dwelled longer in State 2 and shorter in State 3. No-LID group occurred more frequently in State 5 and less frequently in State 3. Additionally, correlation analysis demonstrated that dyskinesia's severity was associated with frequency of occurrence and dwell time in State 2, dominated by inferior frontal cortex in cognitive executive network (CEN). CONCLUSION: Using dFNC analysis, we found that dyskinesia may be related to the dysfunctional inhibition of CEN on motor loops and excessive excitation of VIS and SMN, which provided evidence of the changes in brain dynamics associated with the occurrence of dyskinesia.

Reduced Short-Latency Afferent Inhibition in Parkinson's Disease Patients with L-dopa-Unresponsive Freezing of Gait.

BACKGROUND: Freezing of gait (FOG) in Parkinson's disease (PD), especially the "L-dopa-unresponsive" subtype, is associated with the dysfunction of non-dopaminergic circuits. OBJECTIVE: We sought to determine whether cortical sensorimotor inhibition evaluated by short-latency afferent inhibition (SAI) related to cholinergic and gamma-aminobutyric acid (GABA)-ergic activities is impaired in PD patients with L-dopa-unresponsive FOG (ONOFF-FOG). METHODS: SAI protocol was performed in 28 PD patients with ONOFF-FOG, 15 PD patients with "off" FOG (OFF-FOG), and 25 PD patients without FOG during medication "on" state. Additionally, 10 ONOFF-FOG patients underwent SAI testing during both "off" and "on" states. Twenty healthy controls participated in this study. Gait was measured objectively using a portable Inertial Measurement Unit system, and participants performed 5-meter Timed Up and Go single- and dual-task conditions. Spatiotemporal gait characteristics and their variability were determined. FOG manifestations and cognition were assessed with clinical scales. RESULTS: Compared to controls, PD patients without FOG and with OFF-FOG, ONOFF-FOG PD patients showed significantly reduced SAI. Further, dopaminergic therapy had no remarkable effect on this SAI alterations in ONOFF-FOG. Meanwhile, OFF-FOG patients presented decreased SAI only relative to controls. PD patients with ONOFF-FOG exhibited decreased gait speed, stride length, and increased gait variability relative to PD patients without FOG and controls under both walking conditions. For ONOFF-FOG patients, significant associations were found between SAI and FOG severity, gait characteristics and variability. CONCLUSION: Reduced SAI was associated with severe FOG manifestations, impaired gait characteristics and variability in PD patients with ONOFF-FOG, suggesting the impaired thalamocortical cholinergic-GABAergic SAI pathways underlying ONOFF-FOG.

Impaired interhemispheric synchrony in Parkinson's disease patients with apathy.

BACKGROUND: Apathy is a common non-motor symptom in Parkinson's disease (PD), yet the neural mechanism remains unknown. It has been reported that the lateralization of dopamine levels is correlated with apathetic symptoms. We aimed to ascertain the role of lateralization in the neuropathogenesis of apathy in PD. METHODS: Twenty-six apathetic PD patients (PD-A), twenty-seven nonapathetic PD patients (PD-NA), and twenty-three healthy controls (HCs) were recruited. All subjects underwent T1-weighted and resting state functional MRI scanning during OFF medication state. Voxel-mirrored Homotopic Connectivity (VMHC) and asymmetry voxel-based morphometry (asymmetry VBM) analysis were applied to detect the synchrony of homotopic connections between hemispheres and grey matter asymmetry index. RESULTS: Compared with both PD-NA and HCs groups, the PD-A group showed excessively decreased z-VMHC values in the nucleus accumbens (NAcc) and putamen. Additionally, both PD subgroups exhibited decreased z-VMHC values in the cerebellum lobule VIII compared with controls. However, no corresponding alteration in grey matter asymmetry index was found. Further, a negative correlation between the z-VMHC values of the NAcc and the Apathy Scale (AS) was confirmed in the PD-A group. Meanwhile, the same relationship was also confirmed between the putamen and AS. Notably, ROC curve analyses uncovered that the z-VMHC values of the NAcc and putamen could be a potential neuroimaging feature discerning apathetic PD patient, respectively. LIMITATIONS: This is a cross-sectional study. CONCLUSION: Our findings demonstrated that the asymmetric functional connectivity in the mesocorticolimbic and nigrostriatal systems might induce the pathophysiological mechanisms of apathy in PD.

Altered functional connectivity of cerebellar dentate nucleus in peak-dose dyskinesia in Parkinson's disease.

The cerebellum is associated with the emergence of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), yet the neural mechanism remains obscure. Our aim was to ascertain the role of functional connectivity (FC) patterns of the cerebellar dentate nucleus (DN) in the pathogenesis of peak-dose dyskinesia in PD. Twenty-three peak-dose dyskinetic PD patients, 27 non-dyskinetic PD patients, and 36 healthy controls (HCs) were enrolled and underwent T1-weighted and resting-state functional magnetic resonance imaging (rs-fMRI) scans after dopaminergic medication intake. We selected left and right DN as the regions of interest and then employed voxel-wise FC analysis and voxel-based morphometry analysis (VBM). The correlations between the altered FC pattern and clinical scores were also examined. Finally, receiver operating characteristic (ROC) curve analysis was performed to assess the potential of DN FC measures as a feature of peak-dose dyskinesia in PD. Dyskinetic PD patients showed excessively increased FC between the left DN and right putamen compared with the non-dyskinetic. When compared with controls, dyskinetic PD patients mainly exhibited increased FC between left DN and bilateral putamen, left paracentral lobule, right postcentral gyrus, and supplementary motor area. Additionally, non-dyskinetic PD patients displayed increased FC between left DN and left precentral gyrus and right paracentral lobule compared with controls. Meanwhile, increased FC between DN (left/right) and ipsilateral cerebellum lobule VIII was observed in both PD subgroups. However, no corresponding alteration in gray matter volume (GMV) was found. Further, a positive correlation between the z-FC values of left DN-right putamen and the Unified Dyskinesia Rating Scale (UDysRS) was confirmed in dyskinetic PD patients. Notably, ROC curve analyses revealed that the z-FC values of left DN-right putamen could be a potential neuroimaging feature identifying dyskinetic PD patients. Our findings demonstrated that the excessively strengthened connectivity of DN-putamen might contribute to the pathophysiological mechanisms of peak-dose dyskinesia in PD.

BDNF rs6265 single-nucleotide polymorphism is involved in levodopa-induced dyskinesia in Parkinson's disease via its regulation of the cortical thickness of the left postcentral gyrus.

Background: Brain-derived neurotrophic factor (BDNF) gene rs6265 single-nucleotide polymorphism (SNP) is thought to be involved in neuroplasticity and influence the development of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). This study aimed to determine how the BDNF rs6265 SNP regulates cortical thickness and to investigate the association between BDNF and the pathological mechanisms of LID in PD. Methods: This cross-sectional study recruited 75 patients with PD, including 37 patients with LID and 38 patients without LID, and 33 healthy controls. All the participants underwent T1-weighted magnetic resonance imaging (MRI) scans, clinical evaluations, and BDNF rs6265 genotyping. Two-way factorial analysis of covariance (ANCOVA) was used to explore the primary effects of disease status, rs6265 genotype, and their interactions on cortical thickness. Associations between cortical thickness in the regions of the brain affected by disease status-genotype interactions and clinical symptoms were detected using Spearman's rank-order correlation. Receiver operating characteristic (ROC) curve analysis was used to test cortical thickness measurements as an indicator of LID. Results: The main effects of disease status were observed in the right pars orbitalis (F=4.229, P=0.017), medial orbitofrontal cortex (F=3.639, P=0.030), and left banks superior temporal sulcus (F=3.172, P=0.046). The left pars orbitalis (F=4.541, P=0.036) and lingual gyrus (F=4.307, P=0.041) were thicker in carriers of the CC genotype than in carriers of the TC/TT genotype. Interaction between disease status and genotype showed that in the LID group, carriers of the CC genotype had a thicker left postcentral gyrus (mean difference =0.103, 95% confidence interval, 0.036 to 0.107, Bonferroni-corrected P<0.005) than did carriers of the TC/TT genotype, whereas no difference was found in the non-LID and healthy control (HC) groups. In carriers of the CC genotype, the cortical thickness of the left postcentral gyrus could identify whether patients with PD had LID, with an area under the receiver operating curve (AUC) of 0.757 (P=0.033, optimal cut-off =2.102). The cortical thickness of the left postcentral gyrus was also positively correlated with the Unified Dyskinesia Rating Scale (UDysRS) score in the LID-CC subgroup (r=0.825, P=0.001). Conclusions: The BDNF rs6265 SNP might be associated with dyskinesia symptoms in patients with PD and LID through its regulation of cortical thickness in the left postcentral gyrus.

Impaired Interhemispheric Synchrony in Parkinson's Disease with Fatigue.

The characteristics of interhemispheric resting-state functional connectivity (FC) in Parkinson's disease (PD) with fatigue remain unclear; therefore, we aimed to explore the changes in interhemispheric FC in PD patients with fatigue. Sixteen PD patients with fatigue (PDF), 16 PD patients without fatigue (PDNF) and 15 matched healthy controls (HCs) were enrolled in the retrospective cross-sectional study. We used voxel-mirrored homotopic connectivity (VMHC) to analyze the resting-state functional magnetic resonance imaging (fMRI) data of these subjects. Compared to PDNF, PDF patients had decreased VMHC values in the supramarginal gyri (SMG). Furthermore, the mean VMHC values of the SMG were negatively correlated with the mean fatigue severity scale (FSS/9) scores (r = -0.754, p = 0.001). Compared to HCs, PDF patients had decreased VMHC in the SMG and in the opercular parts of the inferior frontal gyri (IFG operc). The VMHC values in the IFG operc and middle frontal gyri (MFG) were notably decreased in PDNF patients compared with HCs. Our findings suggest that the reduced VMHC values within the bilateral SMG may be the unique imaging features of fatigue in PD, and may illuminate the neural mechanisms of fatigue in PD.