The basal ganglia are characterized by somatotopic representation and are organized in parallel, functionally segregated corticostriatal circuits, but the impact of Parkinson’s disease (PD) on this architecture is unknown, and both anatomical and functional segregation were lost in PD.
Abstract
The basal ganglia are characterized by somatotopic representation and are organized in parallel, functionally segregated corticostriatal circuits, but the impact of Parkinson’s disease (PD) on this architecture is unknown. We mapped task-evoked dopamine release using [11C]raclopride positron emission tomography/magnetic resonance in 13 early PD and 15 healthy control (HC) subjects during the performance of motor, cognitive, and reward tasks. In PD, motor tasks elicited decreased relative dopamine release in dorsal putamen but increased in less affected caudate and ventral striatum compared to HC. HC showed distinct dopaminergic topographies for upper versus lower limb activation; this somatotopy was absent in PD. HC exhibited segregated patterns of dopamine release across all tasks, but both anatomical and functional segregation were lost in PD. Compensatory effects of altered dopamine release topography may help to maintain function in patients with PD, but loss of segregation may contribute to challenges in discrete selection of movement and in multitasking.
Progressive, age-dependent remodeling of motor cortex somatotopic remodeling is demonstrated in 5XFAD mice, characterized by early expansion of specific simple movement cortical sites followed by deterioration of both complex and simple motor cortical maps as disease advances.
SE Moss, Cassandra C. Wolsh, Rmii Brown et al.· bioRxiv· 0 citations
INTRODUCTION
Cortical inhibitory-excitatory imbalance may contribute to motor dysfunction in Parkinson's disease (PD), but in vivo primary motor cortex (M1) neurochemistry remains incompletely characterized.
METHODS
We used 7T proton MR spectroscopy to quantify γ-aminobutyric acid (GABA) and glutamate (Glu) in M1 in patients with mild-to-moderate PD and healthy controls. The inhibitory/excitatory ratio (I/E ratio, GABA/Glu) was derived as an exploratory measure. After quality control, baseline analyses included 32 patients and 28 controls. A self-paced bilateral handgrip task was conducted in a subgroup with15 patients and 14 controls.
RESULTS
At rest, patients with PD showed higher GABA concentrations than controls, but this did not survive FDR correction across the two primary metabolites (pFDR = 0.06). There was no difference in Glu between the two groups. The I/E ratio was also higher in PD. Higher GABA showed nominal associations with greater MDS-UPDRS III scores, but these did not survive correction. During the motor task, Glu increased across groups, with no significant group × condition interaction for GABA, Glu. Task findings were preliminary given limited power.
CONCLUSIONS
Ultra-high-field MRS preliminary evidence for altered resting M1 GABAergic neurochemistry in mild-to-moderate PD. Task-related findings require validation in larger cohorts. These findings support the utility of 7T MRS for probing motor-cortical neurochemistry in PD.
Ning Wei, Dong-Ning Su, Zhe Zhang et al.· Parkinsonism & Related Disor...· 0 citations
Bradykinesia is a cardinal motor feature of Parkinson’s disease and is characterised by a reduced ability to generate movements with normal speed and force. Although nigrostriatal dopamine loss is regarded as the primary cause, direct human evidence linking dopaminergic degeneration to striatal dysfunction and impaired motor output and vigour remains limited. To investigate this relationship, we developed a grip-force paradigm that quantified movement vigour as the ability to rapidly generate force. Fifty-three individuals with Parkinson’s disease, 30 with levodopa-induced dyskinesia and 23 without, and 25 age-matched healthy controls performed the task during 3T functional MRI. Thirty-five patients additionally underwent dopamine transporter PET imaging to assess associations among nigrostriatal dopaminergic integrity, striatal activity and motor performance. Patients with Parkinson’s disease showed marked reductions in initial movement vigour accompanied by reduced bilateral putaminal activation during force generation. Lower putaminal dopamine transporter binding was associated with both poorer movement vigour and weaker grip-related putaminal activation during functional MRI, establishing a direct link between nigrostriatal degeneration, impaired striatal recruitment and motor slowing. Functional MRI further revealed reduced reward-related responses in the nucleus accumbens. Across participants, stronger reward-related ventral striatal activity was associated with greater movement vigour, suggesting that motivational processes contribute independently to motor performance. Patients with levodopa-induced dyskinesia exhibited more severe putaminal dopaminergic denervation than patients without dyskinesia but showed no additional impairment of movement vigour or striatal task responses. These findings provide direct in vivo evidence that dorsal nigrostriatal dopaminergic degeneration constrains movement vigour in Parkinson’s disease through reduced striatal recruitment during action generation. Impaired reward-related signalling in ventral striatum emerges as an additional, partly independent mechanism influencing motor performance, highlighting distinct motor and motivational contributions to bradykinesia.
B. L. C. Thomsen, V. Labanauskas, N. Raaf et al.· bioRxiv· 0 citations
The human substantia nigra (SN) is a central hub for dopaminergic signalling and a key site of pathology in Parkinson's disease (PD). However, its internal functional organization in human individuals is not well understood. To fill this knowledge gap, here we applied connectopic mapping to the SN in more than 1000 participants from four independent datasets. We identified two main gradients or axes of functional organization within the SN-a mediolateral and a posteroanterior-each showing distinct transcriptomic, behavioural, and pathological associations. Specifically, the mediolateral gradient was related to motor and executive functions, aging and α-synuclein pathology in both PD and Alzheimer's disease (AD). In contrast, the posteroanterior gradient was linked to memory, anxiety, depression and other neuropsychiatric symptoms in all cohorts. We found gradient-specific associations with gene expression profiles, neurotransmitter maps and cerebrospinal fluid biomarkers that further supported their neurobiological differences. Together, these results reveal a dual-gradient architecture that reflects the functional heterogeneity of the SN and offers new markers, grounded in behaviour and pathology, for stratifying neurodegenerative disease risk in aging, PD and AD.
D. Veréb, Blanca Zufiria-Gerbolés, M. Passaretti et al.· Molecular Psychiatry· 0 citations
Improved movement initiation and increased impulsivity under stimulation of the subthalamic nucleus are linked to a shared anatomical and functional substrate, namely the subthalamic nucleus-supplementary motor cortex loop supporting automatic response inhibition.
Garance M. Meyer, Marion Albares, Guillaume Lio et al.· Brain Communications· 0 citations
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