Deep brain stimulation (DBS) improves debilitating symptoms of movement disorders when conventional medical therapies, cell transplant strategies, and the delivery of gene-delivered growth factors fail. Despite the remarkable efficacy of DBS, its therapeutic mechanism remains unclear. There is controversy regarding whether the therapeutic effects of DBS are associated with inhibition or excitation of target neurons, the introduction of new activity into the network, or a combination of these mechanisms. Additionally, it is unclear why stimulus frequency plays an important role in the clinical response to therapy. The fundamental hypothesis of this proposal is that unilateral subthalamic nucleus (STN) DBS in PD alters neuronal activity in the bilateral basal ganglia-thalamic-cortical motor system in a manner that is dependent on stimulation frequency. The following specific hypotheses will be tested in PD patients with unilateral STN DBS: (1) High frequency unilateral STN DBS in PD increases antidromic and orthodromic activation of contralateral STN neurons to a greater extent than low frequency stimulation. Preliminary findings of antidromic and orthodromic responses of STN neurons to contralateral DBS will be further explored using microelectrode recordings of STN neurons during contralateral high and low frequency STN DBS. Analyses will employ auto- and cross-correlograms and peristimulus rasters with histograms and Z-scores. (2) High frequency unilateral STN DBS in PD improves ipsilateral bradykinesia more than low frequency stimulation. Kinematic testing in the bilateral extremities of central and peripheral reaction time and movement time will be obtained at high and low stimulation frequencies during a wrist flexion/extension task and analyzed with ANOVA. (3) Unilateral STN DBS in PD alters activity in the ipsilateral premotor cortex. Magnetoencephalography (MEG) will measure the kinetics and localization of cortical magnetic fields evoked by high and low frequency STN DBS. Event detection, averaging, and peak detection will measure the kinetics of the evoked responses, and source localization will be calculated with single and two dipole models. As DBS is investigated for a wide variety of potential indications in neurology and psychiatry, there is a growing need to understand how it modulates brain activity to exert its clinical effects. Gaining such knowledge has the potential to improve the efficacy and safety of DBS in established indications and to guide future therapeutic innovations.

Public Health Relevance

Deep brain stimulation (DBS) improves debilitating symptoms of movement disorders when conventional therapies fail. As DBS is investigated for a wide variety of potential indications in neurology and psychiatry, there is a growing need to understand how it modulates brain activity to exert its clinical effects. Gaining such knowledge has the potential to improve the efficacy and safety of DBS in established indications and to guide future therapeutic innovations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS067053-03
Application #
8312600
Study Section
NST-2 Subcommittee (NST)
Program Officer
Galpern, Wendy R
Project Start
2010-06-15
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$186,251
Indirect Cost
$13,987
Name
University of Alabama Birmingham
Department
Neurology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Rawal, Pawan V; Almeida, Leonardo; Smelser, Luke B et al. (2014) Shorter pulse generator longevity and more frequent stimulator adjustments with pallidal DBS for dystonia versus other movement disorders. Brain Stimul 7:345-9
Amara, Amy W; Standaert, David G; Guthrie, Stephanie et al. (2012) Unilateral subthalamic nucleus deep brain stimulation improves sleep quality in Parkinson's disease. Parkinsonism Relat Disord 18:63-8
Walker, Harrison C; Watts, Ray L; Schrandt, Christian J et al. (2011) Activation of subthalamic neurons by contralateral subthalamic deep brain stimulation in Parkinson disease. J Neurophysiol 105:1112-21
Montgomery Jr, Erwin B; Huang, He; Walker, Harrison C et al. (2011) High-frequency deep brain stimulation of the putamen improves bradykinesia in Parkinson's disease. Mov Disord 26:2232-8