Altered neural oscillations during complex sequential movements in patients with Parkinson's disease.

The sequelae of Parkinson's disease (PD) includes both motor- and cognitive-related symptoms. Although traditionally considered a subcortical disease, there is increasing evidence that PD has a major impact on cortical function as well. Prior studies have reported alterations in cortical neural function in patients with PD during movement, but to date such studies have not examined whether the complexity of multicomponent movements modulate these alterations. In this study, 23 patients with PD (medication "off" state) and 27 matched healthy controls performed simple and complex finger tapping sequences during magnetoencephalography (MEG), and the resulting MEG data were imaged to identify the cortical oscillatory dynamics serving motor performance. The patients with PD were significantly slower than controls at executing the sequences overall, and both groups took longer to complete the complex sequences than the simple. In terms of neural differences, patients also exhibited weaker beta complexity-related effects in the right medial frontal gyrus and weaker complexity-related alpha activity in the right posterior and inferior parietal lobules, suggesting impaired motor sequence execution. Characterizing the cortical pathophysiology of PD could inform current and future therapeutic interventions that address both motor and cognitive symptoms.

The cortical signature of symptom laterality in Parkinson's disease.

Patients with Parkinson's disease (PD) often present with unilateral motor symptoms that eventually spread to the other side. This symptom lateralization is diagnostically important, as it serves to distinguish PD from other motor disorders with overlapping symptom profiles. Further, recent studies have shown that the side of symptom onset is important for prognosis, as there are differences in the rate of disease progression and the incidence of secondary symptoms between right- and left-dominant (RD, LD) patients. Physiologically, previous studies have shown asymmetrical decline in structure and metabolism throughout the basal ganglia, although connecting this directly to motor function has been difficult. To identify the neurophysiological basis of symptom laterality in PD, we recorded magnetoencephalography (MEG) during left- and right-hand movement paradigms in patients with PD who exhibited either RD or LD symptomatology. The beta oscillations serving these movements were then imaged using beamforming methods, and we extracted the time series of the peak voxel in the left and right primary motor cortices for each movement. In addition, each patient's symptom asymmetry was quantitated using the Unified Parkinson's Disease Rating Scale (UPDRS), which allowed the relationship between symptom asymmetry and neural asymmetry to be assessed. We found that LD patients had stronger beta suppression during movement, as well as greater post-movement beta rebound compared to patients with RD symptoms, independent of the hand that was moved. Interestingly, the asymmetry of beta activity during right-hand movement uniquely correlated with symptom asymmetry, such that the more LD the symptom profile, the more left-lateralized (i.e., contralateral to movement) the beta response; conversely, the more RD the symptom profile, the more right-lateralized (i.e., ipsilateral to movement) the beta response. This study is the first to directly probe the relationship between symptom asymmetry and the laterality of neural activity during movement in patients with PD, and suggests that LD patients have a fundamentally different and more "healthy" oscillatory pattern relative to RD patients.

Quiet connections: Reduced fronto-temporal connectivity in nondemented Parkinson's Disease during working memory encoding.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized primarily by motor symptoms such as bradykinesia, muscle rigidity, and resting tremor. It is now broadly accepted that these motor symptoms frequently co-occur with cognitive impairments, with deficits in working memory and attention being among the most common cognitive sequelae associated with PD. While these cognitive impairments are now recognized, the underlying neural dynamics and precise regions involved remain largely unknown. To this end, we examined the oscillatory dynamics and interregional functional connectivity that serve working memory processing in a group of unmedicated adults with PD and a matched group without PD. Each participant completed a high-load, Sternberg-type working memory task during magnetoencephalography (MEG), and we focused on the encoding and maintenance phases. All data were transformed into the time-frequency domain and significant oscillatory activity was imaged using a beamforming approach. Phase-coherence (connectivity) was also computed among the brain subregions exhibiting the strongest responses. Our most important findings were that unmedicated patients with PD had significantly diminished working memory performance (i.e., accuracy), and reduced functional connectivity between left inferior frontal cortices and left supramarginal-superior temporal cortices compared to participants without PD during the encoding phase of working memory processing. We conclude that patients with PD have reduced neural interactions between left prefrontal executive circuits and temporary verbal storage centers in the left supramarginal/superior temporal cortices during the stimulus encoding phase, which may underlie their diminished working memory function. Hum Brain Mapp 37:3224-3235, 2016. © 2016 Wiley Periodicals, Inc.

Hypersynchrony despite pathologically reduced beta oscillations in patients with Parkinson's disease: a pharmaco-magnetoencephalography study.

Parkinson's disease (PD) is a progressive debilitating neurodegenerative disorder clinically manifest by motor, posture and gait abnormalities. Human neurophysiological studies recording local field potentials within the subthalamic nucleus and scalp-based electroencephalography have shown pathological beta synchrony throughout the basal ganglia-thalamic-cortical motor network in PD. Notably, suppression of this pathological beta synchrony by dopamine replacement therapy or deep-brain stimulation has been associated with improved motor function. However, due to the invasive nature of these studies, it remains unknown whether this "pathological beta" is actually stronger than that observed in healthy demographically matched controls. We used magnetoencephalography to investigate neuronal synchrony and oscillatory amplitude in the beta range and lower frequencies during the resting state in patients with PD and a matched group of patients without neurological disease. Patients with PD were studied both in the practically defined drug "OFF" state, and after administration of dopamine replacements. We found that beta oscillatory amplitude was reduced bilaterally in the primary motor regions of unmedicated patients with PD compared with controls. Administration of dopaminergic medications significantly increased beta oscillatory activity, thus having a normalizing effect. Interestingly, we also found significantly stronger beta synchrony (i.e., hypersynchrony) between the primary motor regions in unmedicated patients with PD compared with controls, and that medication reduced this coupling which is in agreement with the intraoperative studies. These results are consistent with the known functionality of the basal ganglia-thalamic-cortical motor circuit and the likely consequences of beta hypersynchrony in the subthalamic nucleus of patients with PD.

Neuromagnetic evidence of abnormal movement-related beta desynchronization in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder associated with debilitating motor, posture, and gait abnormalities. Human studies recording local field potentials within the subthalamic nucleus and scalp-based electroencephalography have shown pathological beta synchronization throughout the cortical-basal ganglia motor network in PD. Suppression of such pathological beta synchronization has been associated with improved motor function, which may explain the effectiveness of deep-brain stimulation. We used magnetoencephalography (MEG) to investigate neural population-level beta responses, and other oscillatory activity, during a motor task in unmedicated patients with PD and a matched group of healthy adults. MEG is a noninvasive neurophysiological technique that permits the recording of oscillatory activity during movement planning, execution, and termination phases. Each of these phases was independently examined using beamforming to distinguish the brain areas and movement phases, where pathological oscillations exist during motor control. Patients with PD exhibited significantly diminished beta desynchronization compared with controls prior to and during movement, which paralleled reduced alpha desynchronization. This study is the first to systematically investigate neural oscillatory responses in PD during distinct stages of motor control (e.g. planning, execution, and termination) and indicates that these patients have significant difficulty suppressing cortical beta synchronization during movement planning, which may contribute to their diminished movement capacities.

CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson's disease.

Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson's disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and α4ß7+ CD4+ T cells were associated with progressive Unified Parkinson's Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs.