Neural activity changes in the Supplementary Motor Area induced by dopaminergic treatment in parkinsonian patients
Introduction
Nigrostriatal dopaminergic (DA) neurons play a central role in the correct preparation and execution of the cortically started movements. Imaging techniques have been used to demonstrate that basal ganglia (BG) are involved in supporting automatic execution of movements generated at cortical motor areas and to modify motor behaviour of routine in reply to new contexts or necessities. Previous researches in normal and parkinsonian subjects using PET and SPECT have supported the theory that the supplementary motor area (SMA) plays a crucial role in preparing and generating complex motor programmes [1]. In these studies, the common finding of underactivation in Parkinson disease (PD) [10], [11], [14] is not unanimous. Recently, Hsu et al. [7] did not find significant cerebral blood flow (rCBF) changes in the SMA of PD patients using an independent component analysis, while Sestini et al. [15] reported significant rCBF increase in the pre-supplementary motor area (pre-SMA) with deep-brain stimulation of subthalamic nucleus (STN).
Recent advances in functional magnetic resonance imaging (fMRI) offer the possibility to study the DA system in vivo, in relation with the functional activity of the prefrontal medial cortex including SMA. These areas can be activated using motor paradigms, such as self-induced motor task and changes into new contexts. fMRI activation represents a change in signal intensity caused by increased blood flow and oxygen use in brain areas associated with certain cognitive or sensorimotor task [9]. By measuring the fMRI response in targets of projection neurons and cortex, it is possible to make inferences about the local changes in neural activity. The main assumption of this approach is that the measured haemodynamic response function (HRF) is proportional to underlying neural activity.
If cortical activity in PD is affected by the decrease in the positive efferent feedback arising from the basal ganglia thalamocortical motor loop, it is possible to expect normalization in the activation of those areas following dopaminergic treatment, presumably correlated with the resolution of akinesia. Recent fMRI studies in PD patients [6], [13] have confirmed reduced activity in rostral SMA, but hypoactivity [6] as well as hyperactivity [13] was reported in the caudal SMA.
This unexpected hyperactivity has been interpreted as a compensatory mechanism of a damaged motor system and it is in disagreement with the BG circuit model [2] and with a recent study using electrophysiological techniques in MPTP-treated monkey [3], which showed that SMA neurons are in a state of hypoactivity in symptomatic animals. However, hyperactivity could be related to long-term dopaminergic treatment. This hypothesis is supported by imaging studies in patients with L-dopa-associated dyskinesia [1].
The aim of this research was to supply evidence of the inappropriate functioning of SMA and clarify the real state of SMA neurons in drug-naïve PD patients. We investigated the changes in neural activity after dopaminergic stimulation. To further clarify the responsibility of SMA in the cardinal symptoms of PD we have compared motor activation in normal subject and in akinetic patients before and after treatment with dopaminergic pathways (DOPA) and independently related these with changes in akinesia, tremor, rigidity and total motor performance using UPDRS motor scores.
Section snippets
Subjects and clinical evaluation
A total of 12 right-handed patients (mean age±SE=51.3±7.5 years, 10 male and 2 female) with early stage akinetic PD (Hoehn and Yahr stage I or II) participated in the study. Every patient was studied twice, once during the “drug-off” state and after reaching the “drug-on” state. To rate the severity of the patient's motor function Unified Parkinson's Disease Rating Scale (UPDRS), motor scores were evaluated immediately before being scanned. Four healthy age-matched control subjects were studied.
Motor activation
Pre-SMA and SMAp were activated during the task in all subjects under study. Fig. 1A shows, from left to right, the normalized functional activation maps superimposed on a T1 weighted anatomical image from a normal subject, a patient with PD and the same patient after pharmacological treatment. These patterns were representatives of all subjects and patients, as illustrated in Fig. 1B, which shows histograms of the mean (±SD) activation intensity.
Within group comparison
When comparing between brain hemispheres, the
Discussion
Task-related activations in SMA could be identified in all normal and parkinsonian subjects. These results provide clear evidence for a role of SMA in the ‘higher order’ programming of movement sequences and are consisting with previous studies using PET and fMRI [13], [16].
When compared with the normal activity, patients show a pattern of activation characterized by bilaterally decreased fMRI signal in SMA. This hypoactive condition is thought to reflect a disturbance in neural metabolism
Conclusions
The study indicates that fMRI enables the quantitative evaluation of abnormal activation pattern in PD and the effect of therapeutic intervention. These results indicate that cardinal symptoms in PD are associated with inappropriate underactivity in SMA in parkinsonian condition, due to striatal dopamine depletion. This effect is partially normalized after DOPA administration.
Rafael Rodriguez-Rojas received the Diploma in Physics in 1996 and the M.Sc. degree in Nuclear Physics in 2000, both from the Higher Institute of Nuclear Sciences in Havana. He is currently Research Scientist at the Brain Images Processing Group, CIREN, Havana, Cuba. He has an academic position as Associate Professor at the ISPJAE, Havana. He has worked in human brain mapping using anatomical and functional imaging, images acquisition, processing and analysis. His main research interests
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Rafael Rodriguez-Rojas received the Diploma in Physics in 1996 and the M.Sc. degree in Nuclear Physics in 2000, both from the Higher Institute of Nuclear Sciences in Havana. He is currently Research Scientist at the Brain Images Processing Group, CIREN, Havana, Cuba. He has an academic position as Associate Professor at the ISPJAE, Havana. He has worked in human brain mapping using anatomical and functional imaging, images acquisition, processing and analysis. His main research interests include fMRI, application and brain connectivity. He is author or coauthor of 16 papers published in scientific journals and international conference proceedings.
Lazaro Alvarez received his degree as Medical Doctor from the ISCMH Victoria de Giron, Havana in 1982, and his degree in Neurology in 1988 at the National Institute of Neurology and Neurosurgery (INN), Havana. He has an academic position as Associate Professor of Neurology and a degree in Research as Associate Researcher. At the present time, he is the Director of the Movement Disorders and Neurodegenerative Diseases Clinic and Head of the Basal Ganglia Project at CIREN. He has been working on Movement Disorders, Dementias and Brain Aging in the last 15 years. His main contributions were related to neural grafting and functional stereotactic neurosurgery in Parkinson's Disease. He has already published (as author or collaborator) more than 50 papers and reviews and participates in some chapters of widely used textbox of Movement's Disorders.
Rolando Palmero received his degree as Medical Doctor from the ISCMH Victoria de Giron, Havana in 1994, and his degree in Internal Medicine in 2000 at the center for Medical and Surgical Researches, Havana. His research areas of interest are structural and functional MRI and applications, diffusion images and spectroscopy.
Mario Alvarez received his degree as Medical Doctor from the ISCMH Victoria de Giron, Havana in 1998, and his degree in Neurology in 2003 at the National Institute of Neurology and Neurosurgery (INN), Havana.
Maylen Carballo received her B.Sc. degree in Computer Science from the University of Havana in 1998. She is currently Research Scientist and Head of the Brain Images Processing Group, CIREN, Havana. She has an academic position as Associate Professor at the ISPJAE, Havana. She has worked in the development of surgical planning systems for PC, medical images processing and computer graphics. Her research areas of interest are 3D imaging and image processing, images fusion and software development. She has been involved in research project and has authored or coauthored scientific papers in the field of neuroimaging.
Raul Macias received his MD degree in 1976 and his degree in Neurophysiology in 1984, both from the ISCMH Victoria de Giron, Havana. He is currently vice director at CIREN and Associate Professor of the Latin American School of Medical Sciences (ELACM), Havana, Cuba. His research areas of interest are neural grafting and functional stereotactic neurosurgery in Parkinson's Disease and others movement disorder. He is author or coauthor of more than 50 papers published in scientific journals, books, and international conference proceedings.