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Preserving cortico-striatal function: deep brain stimulation in Huntington's disease.

Nagel SJ, Machado AG, Gale JT, Lobel DA, Pandya M - Front Syst Neurosci (2015)

Bottom Line: Since the discovery of the HD gene, the pathogenesis has been outlined, but to date a cure has not been found.New insights into the mechanism of action of DBS suggest it may have the potential to circumvent other manifestations of HD including cognitive deterioration.Furthermore, because DBS is already widely used, reversible, and has a risk profile that is relatively low, new studies can be initiated.

View Article: PubMed Central - PubMed

Affiliation: Cleveland Clinic, Neurologic Institute, Center for Neurological Restoration Cleveland, Ohio, USA ; Department of Neurosurgery, Cleveland Clinic, Neurologic Institute Cleveland, Ohio, USA.

ABSTRACT
Huntington's disease (HD) is an incurable neurodegenerative disease characterized by the triad of chorea, cognitive dysfunction and psychiatric disturbances. Since the discovery of the HD gene, the pathogenesis has been outlined, but to date a cure has not been found. Disease modifying therapies are needed desperately to improve function, alleviate suffering, and provide hope for symptomatic patients. Deep brain stimulation (DBS), a proven therapy for managing the symptoms of some neurodegenerative movement disorders, including Parkinson's disease, has been reported as a palliative treatment in select cases of HD with debilitating chorea with variable success. New insights into the mechanism of action of DBS suggest it may have the potential to circumvent other manifestations of HD including cognitive deterioration. Furthermore, because DBS is already widely used, reversible, and has a risk profile that is relatively low, new studies can be initiated. In this article we contend that new clinical trials be considered to test the effects of DBS for HD.

No MeSH data available.


Related in: MedlinePlus

Therapeutic targets for deep brain stimulation in HD. The scale of the response could be modulated by using different stimulation paradigms in addition to the location of the lead(s). For example, increasing dopaminergic activity through SNc stimulation may improve non-specific striatal processing that governs learning. Similarly, thalamic stimulation at low frequencies may modulate multiple nested frequencies simultaneously to re-establish a normal frequency spectrum. High frequency, triggered focal, pulsed stimulation of the striatum paired to a specific task could augment learning of specific skills by boosting event sequencing.
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Figure 1: Therapeutic targets for deep brain stimulation in HD. The scale of the response could be modulated by using different stimulation paradigms in addition to the location of the lead(s). For example, increasing dopaminergic activity through SNc stimulation may improve non-specific striatal processing that governs learning. Similarly, thalamic stimulation at low frequencies may modulate multiple nested frequencies simultaneously to re-establish a normal frequency spectrum. High frequency, triggered focal, pulsed stimulation of the striatum paired to a specific task could augment learning of specific skills by boosting event sequencing.

Mentions: It is our opinion that DBS may hold promise in preserving brain function in patients with HD to maintain independence and reduce suffering. However, because the phenotypic expression of HD is heterogeneous, DBS may only benefit a select group of patients. Determining this subset is paramount to the success of any intervention. Fortunately, recent large-scale longitudinal studies (such as PREDICT-HD) that have identified specific functional imaging signals indicating early neuronal dysfunction in HD have exposed this window of opportunity. Targeted ES, early in the course of disease may be able to overcome limitations via several mechanisms including: (1) regulation of dopamine homeostasis, (2) focal inhibition or (3) activation of local brain regions, (4) task specific, triggered closed-loop stimulation or (5) diffuse modulation of multiple pathways with low frequency stimulation (Figure 1). Deciding when to initiate a disease modifying therapy in HD is challenging. Intervention in the prodromal stage exposes an individual to risk when they may be able to live and work independently for many more years. Similarly, initiating therapy after significant cell death, a precursor to end-stage disease, may be futile. The ethical considerations in delivering neuromodulation should therefore be taken very seriously before such an intervention is delivered to a desperate population (Ford and Kubu, 2006).


Preserving cortico-striatal function: deep brain stimulation in Huntington's disease.

Nagel SJ, Machado AG, Gale JT, Lobel DA, Pandya M - Front Syst Neurosci (2015)

Therapeutic targets for deep brain stimulation in HD. The scale of the response could be modulated by using different stimulation paradigms in addition to the location of the lead(s). For example, increasing dopaminergic activity through SNc stimulation may improve non-specific striatal processing that governs learning. Similarly, thalamic stimulation at low frequencies may modulate multiple nested frequencies simultaneously to re-establish a normal frequency spectrum. High frequency, triggered focal, pulsed stimulation of the striatum paired to a specific task could augment learning of specific skills by boosting event sequencing.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356075&req=5

Figure 1: Therapeutic targets for deep brain stimulation in HD. The scale of the response could be modulated by using different stimulation paradigms in addition to the location of the lead(s). For example, increasing dopaminergic activity through SNc stimulation may improve non-specific striatal processing that governs learning. Similarly, thalamic stimulation at low frequencies may modulate multiple nested frequencies simultaneously to re-establish a normal frequency spectrum. High frequency, triggered focal, pulsed stimulation of the striatum paired to a specific task could augment learning of specific skills by boosting event sequencing.
Mentions: It is our opinion that DBS may hold promise in preserving brain function in patients with HD to maintain independence and reduce suffering. However, because the phenotypic expression of HD is heterogeneous, DBS may only benefit a select group of patients. Determining this subset is paramount to the success of any intervention. Fortunately, recent large-scale longitudinal studies (such as PREDICT-HD) that have identified specific functional imaging signals indicating early neuronal dysfunction in HD have exposed this window of opportunity. Targeted ES, early in the course of disease may be able to overcome limitations via several mechanisms including: (1) regulation of dopamine homeostasis, (2) focal inhibition or (3) activation of local brain regions, (4) task specific, triggered closed-loop stimulation or (5) diffuse modulation of multiple pathways with low frequency stimulation (Figure 1). Deciding when to initiate a disease modifying therapy in HD is challenging. Intervention in the prodromal stage exposes an individual to risk when they may be able to live and work independently for many more years. Similarly, initiating therapy after significant cell death, a precursor to end-stage disease, may be futile. The ethical considerations in delivering neuromodulation should therefore be taken very seriously before such an intervention is delivered to a desperate population (Ford and Kubu, 2006).

Bottom Line: Since the discovery of the HD gene, the pathogenesis has been outlined, but to date a cure has not been found.New insights into the mechanism of action of DBS suggest it may have the potential to circumvent other manifestations of HD including cognitive deterioration.Furthermore, because DBS is already widely used, reversible, and has a risk profile that is relatively low, new studies can be initiated.

View Article: PubMed Central - PubMed

Affiliation: Cleveland Clinic, Neurologic Institute, Center for Neurological Restoration Cleveland, Ohio, USA ; Department of Neurosurgery, Cleveland Clinic, Neurologic Institute Cleveland, Ohio, USA.

ABSTRACT
Huntington's disease (HD) is an incurable neurodegenerative disease characterized by the triad of chorea, cognitive dysfunction and psychiatric disturbances. Since the discovery of the HD gene, the pathogenesis has been outlined, but to date a cure has not been found. Disease modifying therapies are needed desperately to improve function, alleviate suffering, and provide hope for symptomatic patients. Deep brain stimulation (DBS), a proven therapy for managing the symptoms of some neurodegenerative movement disorders, including Parkinson's disease, has been reported as a palliative treatment in select cases of HD with debilitating chorea with variable success. New insights into the mechanism of action of DBS suggest it may have the potential to circumvent other manifestations of HD including cognitive deterioration. Furthermore, because DBS is already widely used, reversible, and has a risk profile that is relatively low, new studies can be initiated. In this article we contend that new clinical trials be considered to test the effects of DBS for HD.

No MeSH data available.


Related in: MedlinePlus