ReviewCritical involvement of the motor cortex in the pathophysiology and treatment of Parkinson's disease
Introduction
The pathological hallmark of Parkinson's disease (PD) is the death of dopamine (DA) cells in the substantia nigra pars compacta (SNc), which causes bradykinesia, akinesia, resting tremor, rigidity and postural instability (Dauer and Przedborski, 2003, Jankovic, 2008). Treatment with l-DOPA or synthetic DA receptor agonists relieves PD symptoms, but often causes drug-induced dyskinesias (Ahlskog and Muenter, 2001, Stowe et al., 2009). Likewise, deep brain stimulation (DBS) with the electrode placed in either the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi) improves movement in PD patients, but concerns about surgical complications such as hemorrhages or infection can limit their widespread use (Bronstein et al., 2011, Follett et al., 2010).
In devising new therapeutic approaches to PD, the motor cortex has been gaining momentum as a potential target. Evidence for motor cortex involvement in PD pathophysiology and treatment is strong as dynamic changes in motor cortex function are seen in PD patients and in animal models of PD (Lefaucheur, 2005, Ceballos-Baumann, 2003, Goldberg et al., 2004). According to accepted cannon, PD symptoms are thought to result from degeneration of DA-secreting SNc neurons, which synapse in the striatum to facilitate controlled movement (Dauer and Przedborski, 2003). However, this nigrostriatal pathology causes functional alterations in a variety of structures connected to the striatum including the motor cortex (Obeso et al., 2008). At the same time, DA projections from the midbrain directly to the motor cortex are reduced in PD patients, providing a second source of dysfunction (Gaspar et al., 1991). Convergent evidence suggests that the motor cortex is a therapeutic target in PD: direct motor cortex stimulation can reduce the symptoms of PD and l-DOPA-induced dyskinesia (LID; Elahi et al., 2009) while antiparkinsonian therapy modulates the activity of the motor cortex (Lefaucheur, 2005).
Given increasing evidence that abnormal motor cortex function is an important component of PD pathophysiology, this review outlines critical findings while identifying key unanswered questions for the research field. This review will first highlight the intrinsic connectivity of the motor cortex and the basal ganglia before turning to motor cortex pathology in PD. Functional changes in the motor cortex of PD patients before and after treatment will be covered from a “top-down” perspective by examining, in order: regional blood flow and metabolism, gross excitability, plasticity, motor maps, oscillations and synchrony, and lastly, individual cellular activity. For the purposes of this review, the term “motor cortex” is defined as including the primary motor cortex (M1), the supplementary motor area (SMA), and the premotor cortex (PMC).
Section snippets
Motor cortex afferents
The ventrolateral nucleus of thalamus constitutes most thalamocortical input to the motor cortex, innervating M1, the posterior SMA (SMA proper), the ventral PMC (PMCv) and parts of the dorsal PMC (PMCd) (Geyer et al., 2000; see Fig. 1). The ventroanterior thalamic nucleus projects to the anterior SMA (pre-SMA) and parts of the PMCd (Geyer et al., 2000, Martin, 2003). In parts of the anterior motor cortex, these thalamocortical connections synapse in layer IV, following the general pattern for
Brainstem neurotransmitter innervation
Generally, PD patients have reduced motor cortex neurotransmitter innervation from brainstem nuclei as a result of disease progression. At autopsy, patients generally have lost more than 75% of locus coeruleus NE neurons and SNc DA neurons (Dauer and Przedborski, 2003, Zarow et al., 2003). At the same time, DA-secreting cells in the VTA and RRA, acetylcholine neurons of the nucleus basalis of meynert and 5-HT cells of raphe nuclei are all pathologically affected to some extent although average
Regional blood flow and metabolism
Advances in medical imaging have allowed for the non-invasive visualization of blood flow changes in the motor cortex of PD patients, first with positron emission tomography (PET) or single photon emission computed tomography (SPECT) and later with functional magnetic resonance imaging (fMRI). The use of fMRI provides high spatial resolution, but safety concerns often preclude scanning PD patients with implanted DBS electrodes (Ceballos-Baumann, 2003). Importantly, most imaging studies have
Transcranial magnetic stimulation
Given the evidence for pathological motor cortex activity in PD, there has been considerable interest in electrophysiological therapies targeting this region. Bidirectional effects on cortical activity can be produced in PD patients depending on the frequency of TMS stimulation: cortical stimulation at 5 Hz or greater has a net excitatory effect while a frequency of 1 Hz or lower reduces cortical excitability (Fitzgerald et al., 2006). Measureable changes in cortical excitability generally
Conclusions and future directions
In summary, compelling evidence for pathological motor cortex activity in PD continues to accrue. Despite such findings, several essential questions remain unanswered. For example, it is not clear whether abnormal cortical activities are primarily attributable to striatal DA depletion or whether motor cortex DA depletion also contributes. This remains an open question since (at least in a rat) the same SNc cells which project to the striatum also project to the motor cortex (Debeir et al., 2005
Acknowledgements
The authors wish to thank Dr. Patricia M. Di Lorenzo, Dr. Lisa M. Savage, Corinne Ostock, Melissa Conti, Adam Goldenberg and Jennifer Gold for reading drafts of this manuscript.
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke Grant R01-NS059600 (C.B.) and the Center for Development and Behavioral Neuroscience at Binghamton University (C.B.). The authors have no conflicts of interest to disclose.
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