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Deep Brain Stimulation How does it work? Jerrold L. Vitek MD, PhD Director, Neuromodulation Research Center Department of Neuroscience Cleveland Clinic
Jerrold L. Vitek, M.D., Ph.D. Director, Neuromodulation Research Center Department of Neurosciences
Scott Cooper, MD, PhD (CNR) Jane Rein (Neurosciences) Debabrata Ghosh, MD (Pediatric Neurology) Donna Payerle (Neurosciences)
Erin Bynum (Neurosciences)
Lyn Elias (Neurosciences)
Matt Johnson, PhD (BioMed Eng)
Dawn Taylor, PhD (CASE BME)
Kim Gelbke, (Neurosciences)
Deep Brain Stimulation
How does it work? Why do we care? • Help to improve current applications – Have we perfected this technique?
• Aid the development of new applications • Provide the rationale for design of new technology – Different disease states may require different targets – Different targets require different lead shapes – This is not a “one size fits all” technology
Electrode Designs Current Design
Split Band Directional Electrode
3D Directional Electrode
Define the problem! • What is the underlying pathophysiology? • If you don’t know the problem, it is hard to find a solution! • Lesion and Look • Poke and Hope
Thalamus Basal Ganglia Cerebellum Brainstem
Basal Ganglia Cortex Glut.
GABA, enk. D2
GABA, subst P.
Brainstem and Spinal Cord
Adapted from Alexander, G.E. and Crutcher, M.E. (1990). Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci. 13: 266-271.
Mean Discharge Rates - Dystonia Mean Frequency GPe
Mean Frequency GPi
90 Mean Frequency (Hz)
80 70 60 50 40 30 20 10 0 JB
Neuronal Activity in GPi PD
Pathophysiology of PD
A Neuronal Model for Dystonia
Early Hypothesis for DBS Mechanism • Based on “Rate” hypothesis of Parkinson’s disease, i.e. motor symptoms occur as a result of excessive activity in the STN and GPi • Deep brain stimulation simulates a lesion – Behavioral effects of lesion same as stimulation – Early studies in anesthetized rats demonstrated decrease activity in the entopeduncular nucleus (GPi analogue in monkeys) after STN stimulation (Benazzouz and Hallett 2000) – Studies in humans undergoing implantation demonstrated a reduction of neuronal activity at the site of stimulation (Benazzouz and Hallett 2000; Dostrovsky et al.2000)
• Deep Brain stimulation improves clinical symptoms by suppressing output from the stimulated structure
“Because of the continuous interaction of all involved structures during STN-DBS, a precise allocation of effects in specific primary pathways may prove daunting” Li et al JNP 2007
trigger pulse conversion computer
Effective STN DBS (135 Hz) GPi (n = 38)
GPe (n = 21)
VA/VLo (n = 21)
VPLo (n = 19)
Effect of GPi‐DBS on VLo neuron
After DBS VLo Neuron Ne55‐280
Time after stimulus pulse (ms)
Effect of GPi‐DBS on VPLo neuron Before DBS
After DBS VPLo Neuron Ne39‐319
Time after stimulus pulse (ms)
Effect of GPi‐DBS on PPN Neuron 15 10
5 0 0
PPN Neuron Ne53‐368
Time after stimulus pulse (ms)
Effective GPe DBS (135 Hz)
STN (n = 50)
GPi (n = 58)
GPe (n = 23)
SN (n = 4)
VLo (n = 24)
Reticular (n = 14)
VPLo (n = 52)
GPe DBS – 135 Hz
Effective GPe DBS (135 Hz)
Very Therapeutic for Rigidity
Pattern Changes in Motor Cortex Activity during DBS
Motor Cortex Responses to DBS during Passive Limb Manipulation
Motor Cortex Responses to DBS during a Reaching Task
Motor Cortex Cell DBS off (n=11)
DBS on (n=9)
Conclusion • Net effect at effective stimulation parameters is activation of output from the stimulated structure • Pattern is changed from irregular bursty to one that is more regular and time locked to the stimulus • Shift in oscillatory activity to higher frequencies • Informational content of the signal is altered removing interference from subcortical structures allowing cortical areas to function more normally
Conclusion • Re-evaluation of models of movement disorders and incorporation of changes in pattern of neuronal activity – Pattern/regularity – Oscillatory activity – Synchronization – Changes in network dynamics » Informational content of the network is altered » Distribution of changes across populations of neurons
Future Studies • Multiunit recording across structures to assess population and network dynamics • Determine the relationship of changes in network dynamic to the development motor symptoms • Determine the effect of changing stimulation parameters on neuronal and network function • Define the relationship of these changes to changes in clinical symptomatology • Translate our understanding of DBS for movement disorders to other nervous system disorders