Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation.

Publisher: American Physiological Society Country of Publication: United States NLM ID: 0375404 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1598 (Electronic) Linking ISSN: 00223077 NLM ISO Abbreviation: J Neurophysiol Subsets: MEDLINE

Publication: Bethesda Md : American Physiological Society
Original Publication: Washington [etc.]

Deep Brain Stimulation*; Globus Pallidus/*physiopathology ; Parkinsonian Disorders/*physiopathology ; Parkinsonian Disorders/*therapy ; Pars Reticulata/*physiopathology ; Subthalamic Nucleus/*physiopathology; Action Potentials/drug effects ; Action Potentials/physiology ; Animals ; Central Nervous System Stimulants/pharmacology ; Dopamine D2 Receptor Antagonists/adverse effects ; Dopamine D2 Receptor Antagonists/pharmacology ; Dyskinesia, Drug-Induced/physiopathology ; Female ; Globus Pallidus/drug effects ; Globus Pallidus/pathology ; Haloperidol/adverse effects ; Haloperidol/pharmacology ; Implantable Neurostimulators ; Methamphetamine/pharmacology ; Microelectrodes ; Neural Inhibition/drug effects ; Neural Inhibition/physiology ; Neurons/drug effects ; Neurons/pathology ; Neurons/physiology ; Oxidopamine ; Parkinsonian Disorders/pathology ; Pars Reticulata/drug effects ; Pars Reticulata/pathology ; Rats, Long-Evans ; Subthalamic Nucleus/drug effects ; Subthalamic Nucleus/pathology

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.
(Copyright © 2016 the American Physiological Society.)

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R01 NS040894 United States NS NINDS NIH HHS; R37 NS040894 United States NS NINDS NIH HHS

Keywords: Parkinson's disease; deep brain stimulation; globus pallidus externa; substantia nigra pars reticulata; subthalamic nucleus

0 (Central Nervous System Stimulants)
0 (Dopamine D2 Receptor Antagonists)
44RAL3456C (Methamphetamine)
8HW4YBZ748 (Oxidopamine)
J6292F8L3D (Haloperidol)

Date Created: 20160311 Date Completed: 20170821 Latest Revision: 20181113

20231215

PMC4922603

10.1152/jn.00822.2015

26961105