Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms.
Inactivation of neurones in the subthalamic nucleus (STN) of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated monkey model of Parkinson's disease has been shown to relieve parkinsonian motor symptoms. In patients with Parkinson's disease, neurones in the STN display hyperactive firing rates and rhythmic discharge activity such as tremor-related oscillations (3-8 Hz) and synchronous high-frequency oscillations (15-30 Hz). In this study, microinjections of lidocaine (n = 4) and muscimol, a GABA(A) receptor agonist (n = 2), were performed in the STN of six patients with Parkinson's disease to determine whether the focal suppression of STN neuronal activity can lead to an improvement in tremor, bradykinesia and rigidity. We also report the first use of microelectrode recording of the effects of microinjections on neuronal activity in the human brain (n = 2). Microinjections of 10-23 microl of lidocaine produced striking improvements in bradykinesia, limb tremor and rigidity in three out of three patients. These improvements were correlated with good therapeutic effects of subsequent STN deep brain stimulation performed in the same microelectrode trajectories as these injections. The most dramatic observation following lidocaine injections was the appearance of dyskinetic limb movements. In one patient, simultaneous microelectrode recording during an injection of 3.5 microl of lidocaine demonstrated a suppression of neuronal activity at distances of < 0.9 mm from the injection site, but no suppression was observed at > or = 1.2 mm from the injection site. Microinjections of 5-10 microl of muscimol in a region with tremor-related activity resulted in suppression of limb tremor in two out of two patients. Interestingly, in one of these patients, 4 Hz oscillatory activity was diminished in a neurone recorded 1.3 mm from the injection site, but there was no reduction in the mean firing rate or 20 Hz oscillatory activity. These results demonstrate that inactivation of neuronal activity in the STN of patients with Parkinson's disease improves motor symptoms. These findings also suggest that a focal block of the STN might alter the oscillatory activity of neurones located beyond the inhibited region.
Levy
R
R
Department of Physiology, Faculty of Medicine, University of Toronto, Canada.
Lang
A E
AE
Dostrovsky
J O
JO
Pahapill
P
P
Romas
J
J
Saint-Cyr
J
J
Hutchison
W D
WD
Lozano
A M
AM
D000368:Aged; D000779:Anesthetics, Local / Q000008:administration & dosage*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D005260:Female; D018755:GABA Agonists / Q000008:administration & dosage*; D006801:Humans; D007276:Injections, Intraventricular; D008012:Lidocaine / Q000008:administration & dosage*; D008297:Male; D008839:Microelectrodes; D008845:Microinjections / Q000379:methods; D008875:Middle Aged; D009118:Muscimol / Q000008:administration & dosage*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D020531:Subthalamic Nucleus / Q000187:drug effects* / Q000502:physiology
D000779:Anesthetics, Local; D018755:GABA Agonists; D009118:Muscimol; D008012:Lidocaine