Project description:Parkinson's disease (PD) patients with postural instability and gait disorder phenotype (PIGD) are at high risk of cognitive deficits compared to those with tremor dominant phenotype (TD). Alterations of white matter (WM) integrity can occur in patients with normal cognitive functions (PD-N). However, the alterations of WM integrity related to cognitive functions in PD-N, especially in these two motor phenotypes, remain unclear. Diffusion tensor imaging (DTI) is a non-invasive neuroimaging method to evaluate WM properties and by applying DTI tractography, one can identify WM tracts connecting functional regions. Here, we 1) compared the executive function (EF) in PIGD phenotype with normal cognitive functions (PIGD-N) and TD phenotype with normal cognitive functions (TD-N) phenotypes; 2) used DTI tractography to evaluated differences in WM alterations between these two phenotypes within a task-based functional network; and 3) examined the WM integrity alterations related to EF in a whole brain network for PD-N patients regardless of phenotypes. Thirty-four idiopathic PD-N patients were classified into two groups based on phenotypes: TD-N and PIGD-N, using an algorithm based on UPDRS part III. Neuropsychological tests were used to evaluate patients' EF, including the Trail making test part A and B, the Stroop color naming, the Stroop word naming, the Stroop color-word interference task, as well as the FAS verbal fluency task and the animal category fluency tasks. DTI measures were calculated among WM regions associated with the verbal fluency network defined from previous task fMRI studies and compared between PIGD-N and TD-N groups. In addition, the relationship of DTI measures and verbal fluency scores were evaluated for our full cohort of PD-N patients within the whole brain network. These values were also correlated with the scores of the FAS verbal fluency task. Only the FAS verbal fluency test showed significant group differences, having lower scores in PIGD-N when compared to TD-N phenotype (p < 0.05). Compared to the TD-N, PIGD-N group exhibited significantly higher MD and RD in the tracts connecting the left superior temporal gyrus and left insula, and those connecting the right pars opercularis and right insula. Moreover, compared to TD-N, PIGD-N group had significantly higher RD in the tracts connecting right pars opercularis and right pars triangularis, and the tracts connecting right inferior temporal gyrus and right middle temporal gyrus. For the entire PD-N cohort, FAS verbal fluency scores positively correlated with MD in the superior longitudinal fasciculus (SLF). This study confirmed that PIGD-N phenotype has more deficits in verbal fluency task than TD-N phenotype. Additionally, our findings suggest: (1) PIGD-N shows more microstructural changes related to FAS verbal fluency task when compared to TD-N phenotype; (2) SLF plays an important role in FAS verbal fluency task in PD-N patients regardless of motor phenotypes.

Project description:IntroductionApathy is one of the most common neuropsychiatric manifestations in Parkinson's disease (PD). Recent proposals consider apathy as a multidimensional construct, which can manifest in behavioral, cognitive, emotional, and/or social dimensions. Apathy also overlaps conceptually and clinically with other non-motor comorbidities, particularly depression. Whether all of these dimensions are applicable to the apathetic syndrome experienced by people with PD is unclear. In the present study, we investigated the multidimensional pattern of apathy associated with PD, using the recently developed Apathy Motivation Index (AMI) which probes behavioral, emotional, and social apathy dimensions. We then examined the relationship between these dimensions and other features of PD commonly associated with apathy, including depression, anxiety, cognition, and motor state.MethodsA total of 211 participants were identified from the New Zealand Brain Research Institute (NZBRI) longitudinal PD cohort. One hundred eight patients and 45 controls completed the AMI, administered as an online questionnaire, and additional assessments including neuropsychiatric, neuropsychological, and motor scores. The pattern of dimensional apathy in PD was assessed using a repeated-measured analysis of variance, while simple linear regressions were performed to evaluate relationships between these dimensions and other variables.ResultsWe found a significant interaction between group (PD versus control) and apathy subscale, driven mainly by higher levels of social and behavioral-but not emotional-apathy in those with PD. This result was strikingly similar to a previous study investigating social apathy in PD. Distinct patterns of dimensional apathy were associated with depression and anxiety, with social and behavioral apathy positively associated with depression, and emotional apathy negatively associated with anxiety.ConclusionThis work provides further evidence for a distinct pattern of apathy in people with PD in which deficits manifest in some-but not all-dimensions of motivated behavior. It emphasizes the importance of considering apathy as a multidimensional construct in clinical and research settings.

Project description:BackgroundThis multicenter, double-blind, placebo-controlled study assessed the efficacy of rotigotine transdermal patch on apathy and motor symptoms in patients with Parkinson's disease (PD).MethodsPatients with PD-associated apathy (Unified Parkinson's Disease Rating Scale [UPDRS] I item 4 [motivation] ≥2 and patient-rated Apathy Scale [AS] ≥14) were randomized 1:1:1 to "low-dose" rotigotine (≤6 mg/24 h for early PD [those not receiving levodopa] or ≤8 mg/24 h for advanced PD [those receiving levodopa]), "high-dose" rotigotine (≤8 mg/24 h for early PD or ≤16 mg/24 h for advanced PD), or placebo, and maintained at optimal/maximal dose for 12 weeks. Coprimary efficacy variables were: change from baseline to End of Maintenance in patient-rated AS and UPDRS II + III total score. Recruitment was stopped after an interim futility analysis; therefore, all p values are exploratory.ResultsOf 122 patients randomized, 81.1 % completed the study (placebo, n = 32/40 [80.0 %]; low-dose rotigotine, n = 30/41 [73.2 %]; high-dose rotigotine, n = 37/41 [90.2 %]). No treatment difference was observed in the change in patient-rated AS (least squares mean [95 % confidence interval (CI)] difference: low-dose, 0.04 [-2.42, 2.50], p =0.977; high-dose, -0.22 [-2.61, 2.18], p = 0.859). Rotigotine improved UPDRS II + III total scores versus placebo (least squares mean [95 % CI] treatment difference: low-dose, -7.29 [-12.30, -2.28], p = 0.005; high-dose, -6.06 [-10.90, -1.21], p = 0.015), and the "mood/apathy" domain of the Non-Motor Symptom Scale as rated by the investigator (secondary outcome). The most frequent adverse events in rotigotine-treated patients were application site reactions, somnolence, and nausea.ConclusionsRotigotine did not improve PD-associated apathy as rated by the patient but provided clinically relevant improvement in motor control and activities of daily living.Trial registrationClinicalTrials.gov identifier NCT01782222 . Trial registration date: January 30, 2013.

Project description:Background: Impaired motor vigor (MV) is a critical aspect of Parkinson's disease (PD) pathophysiology. While MV is predominantly encoded in the basal ganglia, deriving (cortical) EEG measures of MV may provide valuable targets for modulation via galvanic vestibular stimulation (GVS). Objective: To find EEG features predictive of MV and examine the effects of high-frequency GVS. Methods: Data were collected from 20 healthy control (HC) and 18 PD adults performing 30 trials total of a squeeze bulb task with sham or multi-sine (50-100 Hz "GVS1" or 100-150 Hz "GVS2") stimuli. For each trial, we determined the time to reach maximum force after a "Go" signal, defined MV as the inverse of this time, and used the EEG data 1-sec prior to this time for prediction. We utilized 53 standard EEG features, including relative spectral power, harmonic parameters, and amplitude and phase of bispectrum corresponding to standard EEG bands from each of 27 EEG channels. We then used LASSO regression to select a sparse set of features to predict MV. The regression weights were examined, and separate band-specific models were developed by including only band-specific features (Delta, Theta, Alpha-low, Alpha-high, Beta, Gamma). The correlation between MV prediction and measured MV was used to assess model performance. Results: Models utilizing broadband EEG features were capable of accurately predicting MV (controls: 75%, PD: 81% of the variance). In controls, all EEG bands performed roughly equally in predicting MV, while in the PD group, the model using only beta band features did not predict MV well compared to other bands. Despite having minimal effects on the EEG feature values themselves, both GVS stimuli had significant effects on MV and profound effects on MV predictability via the EEG. With the GVS1 stimulus, beta-band activity in PD subjects became more closely associated with MV compared to the sham condition. With GVS2 stimulus, MV could no longer be accurately predicted from the EEG. Conclusions: EEG features can be a proxy for MV. However, GVS stimuli have profound effects on the relationship between EEG and MV, possibly via direct vestibulo-basal ganglia connections not measurable by the EEG.

Project description:Apathy is a common and disabling complication of Parkinson's disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson's disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson's disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient's apathy severity measured using the Lille Apathy Rating Scale (R = -0.46, P < 0.001). Computational modelling of the patient's choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = -0.5, P < 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson's disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson's patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson's disease.

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Apathy scores in Parkinson’s disease relate to EEG components in an incentivized motor task

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