Task specific influences of Parkinson’s disease on the striato-thalamo-cortical and cerebello-thalamo-cortical motor circuitries

doi:10.1016/j.neuroscience.2007.04.006

Neuroscience

Volume 147, Issue 1, 15 June 2007, Pages 224-235

https://doi.org/10.1016/j.neuroscience.2007.04.006 Get rights and content

Abstract

The motor deficits in Parkinson’s disease (PD) have been primarily associated with internally guided (IG), but not externally guided (EG), tasks. This study investigated the functional mechanisms underlying this phenomenon using genetically-matched twins. Functional magnetic resonance images were obtained from a monozygotic twin pair discordant for clinical PD. Single-photon emission computed tomography neuroimaging using [¹²³I](−)-2-β-carboxymethoxy-3-β-(4-iodophenyl)tropane confirmed their disease-discordant status by demonstrating a severe loss of transporter binding in the PD-twin, whereas the non-PD-twin was normal. Six runs of functional magnetic resonance imaging (fMRI) data were acquired from each twin performing EG and IG right-hand finger sequential tasks. The percentage of voxels activated in each of several regions of interest (ROI) was calculated. Multiple analysis of variance was used to compare each twin’s activity in ROIs constituting the striato-thalamo-cortical motor circuits [basal ganglia (BG)-cortical circuitry, but including the globus pallidus/putamen, thalamus, supplementary motor area, and primary motor cortex] and cerebello-thalamo-cortical circuits (cerebellar–cortical circuitry, including the cerebellum, thalamus, somatosensory cortex, and lateral premotor cortex). During the EG task, there were no significant differences between the twins in bilateral BG–cortical pathways, either basally or after levodopa, whereas the PD-twin had relatively increased activity in the cerebellar–cortical pathways basally that was normalized by levodopa. During the IG task, the PD-twin had less activation than the non-PD-twin in ROIs of the bilateral BG–cortical and cerebellar–cortical pathways. Levodopa normalized the hypoactivation in the contralateral BG–cortical pathway, but “over-corrected” the activation in the ipsilateral BG–cortical and bilateral cerebellar–cortical pathways. In this first fMRI study of twins discordant for PD, the data support the hypothesis that BG–cortical and cerebellar–cortical pathways are task-specifically influenced by PD. The levodopa-induced “over-activation” of BG–cortical and cerebellar–cortical pathways, and its relevance to both compensatory changes in PD and the long-term effects of levodopa in PD, merit further exploration.

Section snippets

Identical twin pair discordant for PD

A 37-year-old identical twin pair was identified through a tertiary-care movement disorders clinic. The life histories of the twins were remarkably similar in terms of upbringing, education, and occupation. Neither had smoked, but both drank alcohol occasionally, and drank coffee (regularly for non-PD-twin, occasionally for PD-twin).

Two years prior to this study, the PD-twin developed right-hand resting tremor and rigidity, the latter attenuated by pramipexole. The PD-twin also had been treated

EG task

Representative functional t-maps for the twin subjects performing the EG task at three axial levels are shown in Fig. 2. The twins displayed similar neural activation patterns, except that the PD-twin displayed relatively lower activation in subcortical structures and relatively heightened activity in cerebellum and PreMC areas.

Multivariate analysis indicated that there were no significant differences in bilateral BG–cortical pathways during the EG task between the twins prior to levodopa

Discussion

The results of this study support directly the hypothesis that, in PD, a deficit in the BG–cortical pathway occurs in a task-specific manner (i.e. for the IG task only). This finding provides a functional mechanism underlying the clinical phenomenon that motor deficits in PD have been associated primarily with IG tasks that can be overcome by external visual or auditory cues (Jahanshahi et al 1995, Chuma et al 2006, Nowak et al 2006). In addition, this study identified a potential alternative

Conclusion

In conclusion, the current results support the hypothesis that the BG–cortical and cerebellar–cortical pathways are functionally-related circuits and task-specifically influenced by PD. The results supported a new working model of motor control with integration of these two functionally related circuitries, and the finding of levodopa “over-activation” of some structures in the BG–cortical and cerebellar–cortical pathways in PD is clearly worthy of further exploration. Above and beyond the

Acknowledgments

We want to thank the twin pair who participated in our studies. We want to recognize the assistance of Peter Chen, Colleen A. Hanlon, Jennifer Woodward, Jennifer Simmons, and Anna Dow, support from the UNC fMRI Center and General Clinical Research Center, and the computational consulting of Josh Bizzell of UNC-Duke Brain Imaging and Analysis Center (BIAC). This work was supported in part by NIH grants AG21491 (X.H.), MH058251 (A.B.), RR00046 (UNC General Clinical Research Center), a Parkinson’s

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Systems neuroscienceTask specific influences of Parkinson’s disease on the striato-thalamo-cortical and cerebello-thalamo-cortical motor circuitries

Abstract

Section snippets

Identical twin pair discordant for PD

EG task

Discussion

Conclusion

Acknowledgments

Trends Neurosci

J Clin Neurosci

Brain Res Bull

Neuroimage

Neuroimage

Parkinsonism Relat Disord

J Neurol Sci

Lancet

Neuroimage

Functional neuroanatomy: Text and atlas

Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions

Prog Brain Res

Parallel organization of functionally segregated circuits linking basal ganglia and cortex

Annu Rev Neurosci

Spatio-temporal and kinematic analysis of pointing movements performed by cerebellar patients with limb ataxia

Exp Brain Res

Pharmacologically modulated fMRI-cortical responsiveness to levodopa in drug-naive hemiparkinsonian patients

Brain

Motor learning of hands with auditory cue in patients with Parkinson’s disease

J Neural Transm

Mesial motor areas in self-initiated versus externally triggered movements examined with fMRI: Effect of movement type and rate

J Neurophysiol

Role of basal ganglia in limb movements

Hum Neurobiol

Increased pre-SMA activation in early PD patients during simple self-initiated hand movements

J Neurol

Differential gene expression induced by chronic levodopa treatment in the striatum of rats with lesions of the nigrostriatal system

J Neurochem

Systems neuroscience
Task specific influences of Parkinson’s disease on the striato-thalamo-cortical and cerebello-thalamo-cortical motor circuitries