Lidocaine and muscimol microinjections in subthalamic nucleus reverse parkinsonian symptoms

Abstract

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.

Adenoviral clostridial light chain gene-based synaptic inhibition through neuronal synaptobrevin elimination

“…Electrolytic lesions, 39 electrical stimulation, 40 and chemical inhibition 41,42 of deep brain nuclei have all proven therapeutic in movement disorders. Since the effects of LC expression are reversible and tolerated by neurons, LC gene transfer to deep brain nuclei may be applied as an alternative to these approaches.…”

High Frequency Stimulation of the Subthalamic Nucleus Eliminates Pathological Thalamic Rhythmicity in a Computational Model

“…Several of these rely on the idea that DBS somehow silences STN firing Benabid et al, 2001c,d;Beurrier et al, 2001;Levy et al, 2001). Recordings have been done in the basal ganglia of rats and monkeys to assess how highfrequency stimulation (HFS) affects neuronal activity.…”

“…By analogy, one may expect that DBS of STN or GPi somehow has an inhibitory effect that reduces the increased activity of the GPi. This inhibitory effect may arise through a variety of mechanisms Benabid et al, 2001c,d;Beurrier et al, 2001;Levy et al, 2001;Wu et al, 2001).…”

Intraventricular and Intracerebral Delivery of Anti-epileptic Drugs in the Kindling Model

“…Catheter-driven infusion has been used both acutely and chronically in experimental and clinical settings. 21,22 One of the studied alternatives has been the intracerebral infusion of inactivating substances to reversibly block a chosen structure. 23 Local anaesthetics, divalent cations, or sodium channel blockers have been tried.…”