- Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital and Division of Neurology, University of Toronto, Toronto, Ontario, Canada
- Department of Neurology, Jackson Memorial Hospital and University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Neurosurgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA
- Krembil Research Institute, Toronto, Ontario, Canada
Correspondence Address:
Karlo J. Lizarraga
Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital and Division of Neurology, University of Toronto, Toronto, Ontario, Canada
Krembil Research Institute, Toronto, Ontario, Canada
DOI:10.4103/sni.sni_292_17
Copyright: © 2017 Surgical Neurology International This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.How to cite this article: Karlo J. Lizarraga, Corneliu C. Luca, Antonio De Salles, Alessandra Gorgulho, Anthony E. Lang, Alfonso Fasano. Asymmetric neuromodulation of motor circuits in Parkinson's disease: The role of subthalamic deep brain stimulation. 24-Oct-2017;8:261
How to cite this URL: Karlo J. Lizarraga, Corneliu C. Luca, Antonio De Salles, Alessandra Gorgulho, Anthony E. Lang, Alfonso Fasano. Asymmetric neuromodulation of motor circuits in Parkinson's disease: The role of subthalamic deep brain stimulation. 24-Oct-2017;8:261. Available from: http://surgicalneurologyint.com/surgicalint-articles/asymmetric-neuromodulation-of-motor-circuits-in-parkinsons-disease-the-role-of-subthalamic-deep-brain-stimulation/
Abstract
Whereas hemispheric dominance is well-established for appendicular motor control in humans, the evidence for dominance in axial motor control is still scarce. In Parkinson's disease (PD), unilateral (UL) onset of appendicular motor symptoms corresponds with asymmetric neurodegeneration predominantly affecting contralateral nigrostriatal circuits. Disease progression yields bilateral and axial motor symptoms but the initial appendicular asymmetry usually persists. Furthermore, there is evidence for hemispheric dominance for axial motor dysfunction in some of these patients. Dopaminergic medications improve appendicular symptoms but can also produce motor complications over time. Once these complications develop, bilateral (BL) deep brain stimulation (DBS) of the subthalamic nuclei (STN) can significantly improve appendicular symptoms while reducing medication doses and motor complications. Conversely, axial motor symptoms remain a significant source of disability, morbidity, and mortality for patients with PD. These axial symptoms do not necessarily improve with dopaminergic therapy, might not respond, and could even worsen after BL-DBS. In contrast to medications, DBS provides the opportunity to modify stimulation parameters for each cerebral hemisphere. Identical, BL-DBS of motor circuits with hemispheric dominance in PD might produce overstimulation on one side and/or understimulation on the other side, which could contribute to motor dysfunction. Several studies based on asymmetry of appendicular motor symptoms already support an initial UL rather than BL approach to DBS in some patients. The response of axial motor symptoms to UL versus BL-DBS remains unclear. Nonetheless, UL-DBS, staged BL-DBS, or asymmetric programming of BL-DBS could also be considered in patients with PD.
Keywords: Asymmetric neuromodulation, hemispheric dominance, Parkinson's disease, postural instability and gait dysfunction, subthalamic nucleus deep brain stimulation
INTRODUCTION
Parkinson's disease (PD) is a chronic neurodegenerative disorder associated with loss of dopaminergic neurons in the nigrostriatal pathways. In the U.S., approximately 1 million people have PD and additional 50,000 are diagnosed each year. The prevalence of PD significantly increases with age, ranging from 41 per 100,000 people in the 40–49 years group to 19 per 1,000 people older than 80 years worldwide.[
Appendicular motor dysfunction in early PD is usually unilateral (UL) and includes tremor, rigidity, and bradykinesia. Disease progression yields bilateral (BL) and axial motor symptoms, but the initial UL predominance usually persists. Dopaminergic agents can improve appendicular and some axial symptoms; however, they can also produce significant complications over time (fluctuations, dyskinesia). Once these complications develop, BL deep brain stimulation (DBS) of the subthalamic nuclei (STN) is a safe and effective intervention capable of improving appendicular symptoms while reducing medication requirements and motor complications. Axial motor dysfunction in PD includes dysarthria, dysphagia, postural instability, and gait dysfunction (PIGD) including freezing of gait (FOG). These symptoms remain a significant source of morbidity and mortality in PD. They do not necessarily improve with medications, might not respond, and could even worsen with BL STN-DBS.[
LATERALIZATION OF NORMAL MOTOR CONTROL
Certain brain functions are predominantly controlled by one hemisphere (i.e., hemispheric dominance or lateralization). For instance, the right (R) hemisphere is dominant for spatial cognition, body schema, proprioceptive control, and action inhibition,[
The mechanism of lateralization for motor control is unknown. Even though a genetic basis could be possible, heritability studies have not been conclusive.[
The L-sided lateralization for motor control is more evident for distal as opposed to proximal tasks, independent of the performing hand. Although motor dominance can be assessed in terms of preference (hand chosen to move) and/or performance (hand most proficient at the movement), it is also evident during bimanual movements. In this case, the dominant hand usually performs distal, fine movements, whereas the nondominant hand serves proximal, postural purposes.[
Though dominance for more proximal and axial motor functions such as posture, balance, and locomotion is not yet well-established, it has been proposed that the R hemisphere controls limb position and posture whereas the L hemisphere controls limb trajectory.[
Hemispheric functional differences for motor control have also been observed during learning. The progressive development of “motor expertise” has been associated with a transition from externally to internally generated movement control, along with a shift from R to L hemispheric activation. This phenomenon might be produced by a progressive reduction in the monitoring of global, spatial, and external features, as well as an increased representation of the local, internal motor program with learning.[
Even though locomotion is considered symmetric, functional gait asymmetries have been observed in normal humans.[
Because the functions preferentially carried out by the R hemisphere (visuospatial orientation, action inhibition, posture) are indispensable for movement,[
Figure 1
Graphic representation of the possible contributions of symmetric bilateral subthalamic stimulation to axial motor deterioration in the context of asymmetric circuits for axial motor control and Parkinson's disease progression. (L: left, R: right, BL: bilateral, PPN/MLR: pedunculopontine nucleus/mesencephalic locomotor region, PMRF: pontomedullary reticular formation)
LATERALIZATION OF MOTOR CONTROL IN PARKINSON'S DISEASE
Disease processes such as PD can also produce lateralized dysfunction. In fact, dopaminergic denervation of the striatum in PD begins asymmetrically and gradually becomes BL with disease progression.[
There is also evidence supporting lateralization of axial motor dysfunction in PD, which includes dysarthria, dysphagia, FOG, and PIGD.[
Patients with PD and FOG also appear to have abnormally reduced structural connectivity on diffusion tensor imaging (DTI) and functional MRI (fMRI) signals preferentially affecting R-sided motor circuits during gait imagery tasks.[
NEUROMODULATION OF LATERALIZED MOTOR CIRCUITS IN PARKINSON'S DISEASE
Dopaminergic agents can improve appendicular symptoms in PD; however, they can also produce motor fluctuations and/or dyskinesias over time. Once these complications develop, BL STN-DBS has emerged as a very effective and relatively safe treatment modality for these motor complications. It is especially effective in controlling appendicular symptoms in PD.[
The widespread BL as opposed to UL strategy for initial implantation of the STN is based on limited evidence. Identical DBS of potentially lateralized motor circuits might be unnecessary in all patients and could even contribute to the axial motor deterioration observed in some of them.[
Worsening of axial dysfunction after BL STN-DBS has been attributed to the variable combination of disease progression beyond dopaminergic systems and the unwanted spread of electrical fields beyond the STN.[
Interestingly, different patterns of local field potentials in motor networks have been associated with axial and appendicular symptoms. For instance, PIGD has been associated with decreased beta and increased gamma and alpha/theta bands. In contrast, bradykinesia has been associated with increased beta frequencies.[
In addition to PIGD, speech dysfunction can also be accelerated after BL STN-DBS in PD.[
In contrast to medications, DBS provides the opportunity to modify some stimulation parameters separately for each cerebral hemisphere. In some patients, both appendicular and axial motor improvements achieved with UL and BL STN-DBS are similar.[
Based on the asymmetry of appendicular motor symptoms in PD, several studies support an initial UL as opposed to BL approach to STN-DBS in some patients [
Previous studies have suggested that UL and BL DBS can produce similar effects on axial symptoms in PD; however, BL stimulation appears to yield the maximal benefits.[
Given the established efficacy of BL STN-DBS and the significant contribution of axial dysfunction to morbidity and mortality in PD patients, it is paramount to identify patients whose axial dysfunction could worsen with BL as opposed to UL or individualized asymmetric programming of BL STN-DBS. A comprehensive presurgical assessment of DBS candidates that includes evaluation of motor lateralization could identify patients who would benefit from an initial UL as opposed to BL DBS paradigm based on both appendicular, axial, and possibly nonmotor symptoms. Although contralateral implantation might be required with disease progression, the initial UL approach could be maintained by asymmetric programming of DBS parameters for each hemisphere (e.g., voltage).[
CONCLUSIONS
Whereas the L hemisphere appears to be dominant for appendicular movements, there is growing evidence supporting R hemispheric dominance for axial motor control. Recently, theories involving complex interhemispheric relationships are attempting to unify the established models of hemispheric lateralization. In PD, BL STN-DBS is an established treatment modality that can significantly improve appendicular symptoms. Given the usually persistent asymmetry of appendicular symptoms in PD, some patients benefit from an asymmetric approach favoring DBS of the STN contralateral to the worse symptomatic side. Axial symptoms are still a significant contributor to disability, morbidity, and mortality in PD. These symptoms might not respond and can even worsen with BL STN-DBS. The comparative effects of UL or asymmetric programming of BL STN-DBS for axial symptoms have not yet been systematically evaluated, although data consistent with R-sided hemispheric dominance for axial control suggests that both UL and BL STN-DBS could produce similar effects. Thus, an asymmetric approach to STN-DBS implantation or programming could also be considered in PD patients with predominant axial dysfunction to avoid over- or understimulation of potentially asymmetric circuits. The availability of new DBS technology could facilitate the design of individualized asymmetric stimulation parameters that minimize axial impairment while maintaining appendicular symptom control.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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