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Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is a surgical procedure for alleviating motor symptoms of Parkinson's Disease (PD). The pattern of DBS (e.g., the electrode pairs used and the intensity of stimulation) is usually optimized by trial and error based on a subjective evaluation of motor function. We tested the hypotheses that DBS releases glutamate in selected basal ganglia nuclei and that the creation of 6-hydroxydopamine (6-OHDA)-induced nigrostriatal lesions alters glutamate release during DBS in those basal ganglia nuclei. We studied the relationship between a pseudo-random binary sequence of DBS and glutamate levels in the STN itself or in the globus pallidus (GP) in anesthetized, control, and 6-OHDA-treated rats. We characterized the stimulus-response relationships between DBS and glutamate levels using a transfer function estimated using System Identification. Stimulation of the STN elevated glutamate levels in the GP and in the STN. Although the 6-OHDA treatment did not affect glutamate dynamics in the STN during DBS in the STN, the transfer function between DBS in the STN and glutamate levels in the GP was significantly altered by the presence or absence of 6-OHDA-induced lesions. Thus, glutamate responses in the GP in the 6-OHDA-treated animals (but not in the STN) depended on dopaminergic inputs. For this reason, measuring glutamate levels in the GP may provide a useful feedback target in a closed-loop DBS device in patients with PD since the dynamics of glutamate release in the GP during DBS seem to reflect the loss of dopaminergic neurons in the SNc. more...

Deep brain stimulation (DBS) of the thalamus has been demonstrated to be effective for the treatment of epilepsy. To investigate the mechanism of action of thalamic DBS, we examined the effects of high frequency stimulation (HFS) on spindle oscillations in thalamic brain slices from ferrets. We recorded intracellular and extracellular electrophysiological activity in the nucleus reticularis thalami (nRt) and in thalamocortical relay (TC) neurons in the lateral geniculate nucleus, stimulated the slice using a concentric bipolar electrode, and recorded the level of glutamate within the slice. HFS (100 Hz) of TC neurons generated excitatory post-synaptic potentials, increased the number of action potentials in both TC and nRt neurons, reduced the input resistance, increased the extracellular glutamate concentration, and abolished spindle wave oscillations. HFS of the nRt also suppressed spindle oscillations. In both locations, HFS was associated with significant and persistent elevation in extracellular glutamate levels and suppressed spindle oscillations for many seconds after the cessation of stimulation. We simulated HFS within a computational model of the thalamic network, and HFS also disrupted spindle wave activity, but the suppression of spindle activity was short-lived. Simulated HFS disrupted spindle activity for prolonged periods of time only after glutamate release and glutamate-mediated activation of a hyperpolarization-activated current (I(h)) was incorporated into the model. Our results suggest that the mechanism of action of thalamic DBS as used in epilepsy may involve the prolonged release of glutamate, which in turn modulates specific ion channels such as I(h), decreases neuronal input resistance, and abolishes thalamic network oscillatory activity. more...

Object: The authors tested the hypothesis that deep brain stimulation (DBS) in the nucleus accumbens (NAcc) decreases alcohol intake in alcohol-preferring (P) rats after each animal has established a stable, large alcohol intake and after P rats with an established intake have been deprived of alcohol for 4-6 weeks., Methods: Bipolar stimulating electrodes were bilaterally placed in the NAcc using stereotactic coordinates. In the first study, P rats (9 animals) were allowed to establish a stable pattern of alcohol intake (about 5-7 g/day) over approximately 2 weeks, and the acute effects of DBS in the NAcc (140-150 Hz, 60-microsec pulse width, and 200-microA current intensity) on alcohol intake and alcohol preference were studied. Each animal acted as its own control and received 1 hour of DBS followed by 1 hour of sham-DBS or vice versa on each of 2 sequential days. The order of testing (sham-DBS vs DBS) was randomized. In the second study, each animal was allowed to establish a stable alcohol intake and then the animal was deprived of alcohol for 4-6 weeks. Animals received DBS (6 rats) or sham-DBS (5 rats) in the NAcc for 24 hours starting when alcohol was reintroduced to each animal., Results: Deep brain stimulation in the NAcc, as compared with a period of sham-DBS treatment in the same animals, acutely decreased alcohol preference. Furthermore, alcohol consumption and preference were significantly reduced in the DBS group compared with the sham treatment group during the first 24 hours that alcohol was made available after a period of forced abstinence., Conclusions: The NAcc plays a key role in the rewarding and subsequent addictive properties of drugs of abuse in general and of alcohol in particular. Deep brain stimulation in the NAcc reduced alcohol consumption in P rats both acutely and after a period of alcohol deprivation. Therefore, DBS in the NAcc coupled with other neurophysiological measurements may be a useful tool in determining the role of the NAcc in the mesocorticolimbic reward circuit. Deep brain stimulation in the NAcc may also be an effective treatment for reducing alcohol consumption in patients who abuse alcohol and have not responded to other forms of therapy. more...

Background: Several neurological disorders are treated with deep brain stimulation; however, the mechanism underlying its ability to abolish oscillatory phenomena associated with diseases as diverse as Parkinson's disease and epilepsy remain largely unknown., Objective: To investigate the role of specific neurotransmitters in deep brain stimulation and determine the role of non-neuronal cells in its mechanism of action., Methods: We used the ferret thalamic slice preparation in vitro, which exhibits spontaneous spindle oscillations, to determine the effect of high-frequency stimulation on neurotransmitter release. We then performed experiments using an in vitro astrocyte culture to investigate the role of glial transmitter release in high-frequency stimulation-mediated abolishment of spindle oscillations., Results: In this series of experiments, we demonstrated that glutamate and adenosine release in ferret slices was able to abolish spontaneous spindle oscillations. The glutamate release was still evoked in the presence of the Na channel blocker tetrodotoxin, but was eliminated with the vesicular H-ATPase inhibitor bafilomycin and the calcium chelator 2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis acetoxymethyl ester. Furthermore, electrical stimulation of purified primary astrocytic cultures was able to evoke intracellular calcium transients and glutamate release, and bath application of 2-bis (2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis acetoxymethyl ester inhibited glutamate release in this setting., Conclusion: Vesicular astrocytic neurotransmitter release may be an important mechanism by which deep brain stimulation is able to achieve clinical benefits. more...

Object: The mechanism of action whereby high-frequency stimulation (HFS) in the thalamus ameliorates tremor and epilepsy is unknown. The authors studied the effects of HFS on thalamocortical relay neurons in a ferret in vitro slice preparation to test the hypothesis that HFS abolishes synchronized oscillations by neurotransmitter release., Methods: Intracellular and extracellular electrophysiological recordings were made in thalamic slices. The neurons in the thalamic slice spontaneously generated spindle oscillations, and treatment with picrotoxin, a gamma-aminobutyric acid A receptor antagonist, resulted in 3- to 4-Hz absence seizurelike activity. High-frequency stimulation (stimulation parameters: 10-1000-microA amplitude; l00-microsec pulse width; 100-Hz frequency; 1-60 seconds) was applied using a concentric bipolar stimulating electrode placed adjacent to the recording electrodes. High-frequency stimulation within the thalamus generated inhibitory and excitatory postsynaptic potentials, membrane depolarization, an increase in action potential firing during the stimulation period, and abolished the spindle oscillations in the thalamocortical relay neurons. High-frequency stimulation applied to 20-microM picrotoxin-treated slices eliminated the 3- to 4-Hz absence seizurelike activity., Conclusions: High-frequency stimulation eliminates spontaneous spindle oscillations and picrotoxin-induced absence seizurelike activity in thalamic slices by synaptic neurotransmitter release; thus, HFS may abolish synchronous oscillatory activities such as those that generate tremor and seizures. Paradoxically, HFS, which is excitatory, and surgical lesions of the ventrointermedius thalamus, which are presumably inhibitory, both suppress tremors. This paradox is resolved by recognizing that HFS-mediated neurotransmitter release and thalamic surgery both disrupt the circuit generating tremor or seizure, albeit by different mechanisms. more...

The precise mechanism whereby continuous high-frequency electrical stimulation of the subthalamic nucleus ameliorates motor symptoms of Parkinson's disease is unknown. We examined the effects of high-frequency stimulation of regions dorsal to and within the subthalamic nucleus on dopamine efflux in the striatum of urethane-anaesthetized rats using constant potential amperometry. Complementary extracellular electrophysiological studies determined the activity of subthalamic nucleus neurons in response to similar electrical stimulation of the subthalamic nucleus. High-frequency stimulation of the subthalamic nucleus increased action potential firing in the subthalamic nucleus only during the initial stimulation period and was followed by a cessation of firing over the remainder of stimulation. Electrical stimulation of the subthalamic nucleus with 15 pulses elicited stimulus-time-locked increases in striatal dopamine efflux with maximal peak effects occurring at 50 Hz frequency and 300 µA intensity. Extended subthalamic nucleus stimulation (1000 pulses at 50 Hz; 300 µA) elicited a similar peak increase in striatal dopamine efflux that was followed by a relatively lower steady-state elevation in extracellular dopamine over the course of stimulation. In contrast, extended stimulation immediately adjacent and dorsal to the subthalamic nucleus resulted in an 11-fold greater increase in dopamine efflux that remained elevated over the course of the stimulation. Immunohistochemical staining for tyrosine hydroxylase revealed catecholaminergic fibers running immediately dorsal to and through the subthalamic nucleus. Taken together, these results suggest that enhanced dopamine release within the basal ganglia may be an important mechanism whereby high-frequency stimulation of the subthalamic nucleus improves motor symptoms of Parkinson's disease. [ABSTRACT FROM AUTHOR] more...