title: Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation.
abstract: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established treatment for the motor symptoms of Parkinson's disease (PD). However, the mechanisms of action of DBS are unknown. Random temporal patterns of DBS are less effective than regular DBS, but the neuronal basis for this dependence on temporal pattern of stimulation is unclear. Using a rat model of PD, we quantified the changes in behavior and single-unit activity in globus pallidus externa and substantia nigra pars reticulata during high-frequency STN DBS with different degrees of irregularity. Although all stimulus trains had the same average rate, 130-Hz regular DBS more effectively reversed motor symptoms, including circling and akinesia, than 130-Hz irregular DBS. A mixture of excitatory and inhibitory neuronal responses was present during all stimulation patterns, and mean firing rate did not change during DBS. Low-frequency (7-10 Hz) oscillations of single-unit firing times present in hemiparkinsonian rats were suppressed by regular DBS, and neuronal firing patterns were entrained to 130 Hz. Irregular patterns of DBS less effectively suppressed 7- to 10-Hz oscillations and did not regularize firing patterns. Random DBS resulted in a larger proportion of neuron pairs with increased coherence at 7-10 Hz compared with regular 130-Hz DBS, which suggested that long pauses (interpulse interval >50 ms) during random DBS facilitated abnormal low-frequency oscillations in the basal ganglia. These results suggest that the efficacy of high-frequency DBS stems from its ability to regularize patterns of neuronal firing and thereby suppress abnormal oscillatory neural activity within the basal ganglia.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina;
authors.forename: George C
authors.initials: GC
authors.lastname: McConnell
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina;
authors.forename: Rosa Q
authors.initials: RQ
authors.lastname: So
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina; Department of Electrical and Computer Engineering, Duke University, Durham, North Carolina; Department of Neurobiology, Duke University, Durham, North Carolina; and Department of Surgery, Duke University, Durham, North Carolina warren.grill@duke.edu.
authors.forename: Warren M
authors.initials: WM
authors.lastname: Grill
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D046690:Deep Brain Stimulation; D065127:Dopamine D2 Receptor Antagonists / Q000009:adverse effects / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D005260:Female; D005917:Globus Pallidus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology; D058542:Implantable Neurostimulators; D008694:Methamphetamine / Q000494:pharmacology; D008839:Microelectrodes; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D065841:Pars Reticulata / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D020318:Rats, Long-Evans; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
chemical_list: D000697:Central Nervous System Stimulants; D065127:Dopamine D2 Receptor Antagonists; D008694:Methamphetamine; D016627:Oxidopamine; D006220:Haloperidol
keywords: Parkinson's disease; deep brain stimulation; globus pallidus externa; substantia nigra pars reticulata; subthalamic nucleus