Kendall H. Lee

Dopamine efflux in the rat striatum evoked by electrical stimulation of the subthalamic nucleus: potential mechanism of action in Parkinson's disease

The precise mechanism whereby continuous high‐frequency electrical stimulation of the subthalamic nucleus ameliorates motor symptoms of Parkinsons 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 15u2003pulses elicited stimulus‐time‐locked increases in striatal dopamine efflux with maximal peak effects occurring at 50u2003Hz frequency and 300u2003µA intensity. Extended subthalamic nucleus stimulation (1000u2003pulses at 50u2003Hz; 300u2003µA) 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 Parkinsons disease.

Abolition of Spindle Oscillations by Serotonin and Norepinephrine in the Ferret Lateral Geniculate and Perigeniculate Nuclei In Vitro

The transition from sleep to waking is associated with the abolition of spindle waves in thalamocortical neurons and the GABAergic cells of the thalamic reticular/perigeniculate nuclei. We tested the possibility that norepinephrine (NE) and serotonin (5-HT) may abolish spindle wave generation through an enhancement of the hyperpolarization-activated cation current Ih in thalamocortical neurons. Local application of agents known to enhance Ih, including 5-HT, NE, the adenylyl cyclase activator, forskolin, and the beta-adrenergic agonist, isoproterenol, to lamina A1 of the dorsal lateral geniculate nucleus resulted in an abolition of local spindle wave generation in thalamocortical neurons. The abolition of spindle waves was reversed by the local application of the Ih channel blocker, cesium. These results suggest that NE and 5-HT may abolish the generation of spindle waves through the modulation of Ih in thalamocortical neurons.

Effect of High-Frequency Stimulation of the Subthalamic Nucleus on Subthalamic Neurons: An Intracellular Study

Background/Aims: The precise mechanism of action of deep brain stimulation in the subthalamic nucleus (STN) for the treatment of Parkinson’s disease and epilepsy is unknown. In the present study, the intracellular effects on STN neurons following high-frequency stimulation (HFS) of STN were examined to test the hypothesis that HFS results in either an increase or a decrease in neuronal action potential generation. Methods: Intracellular electrophysiological recordings were made in the rat STN neurons in in vitro slice preparations. A concentric bipolar stimulating electrode was placed in the STN, and electrical stimulation (duration, 100–2000 ms; amplitude, 10–500 µA, and frequency, 10–200 Hz) was delivered while simultaneously recording intracellularly from a STN neuron using a sharp electrode. Results: HFS of STN resulted in the generation of excitatory postsynaptic potentials and an increase in action potential firing during the stimulation period followed by a period of poststimulation inhibition of firing in STN neurons. The degree of increase in action potentials from HFS was critically dependent on the frequency of electrical stimulation, i.e. at approximately 100–140 Hz, maximal increase was obtained, but at 200 Hz, the activity was blocked. Interestingly, the duration of poststimulation inhibition of firing was dependent on the duration of stimulation, i.e. the longer the HFS, the longer the inhibition. Conclusions: These results suggest that the mechanism of action of deep brain stimulation involves initial excitation followed by later inhibition of STN neurons at a cellular level rather than primary inhibition, as previously hypothesized.

Modulation of spindle oscillations by acetylcholine, cholecystokinin and 1S,3R-ACPD in the ferret lateral geniculate and perigeniculate nuclei in vitro

The transition from sleep to waking is associated with the abolition of spindle waves and the appearance of tonic activity in thalamocortical neurons and thalamic reticular/perigeniculate GABAergic cells. We tested the possibility that changes such as these may arise through modulation of the leak potassium current, IKL, by examining the effects of neurotransmitters known to modulate this current on spindle wave generation in the ferret geniculate slice maintained in vitro. Local application of agents that reduce IKL in thalamocortical neurons, including acetylcholine, DL-muscarine chloride and the glutamate metabotropic receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), to spontaneously spindling thalamocortical neurons resulted in a 5-10 mV membrane depolarization and the abolition of spindle waves. Local application of 1S,3R-ACPD and cholecystokinin-8-sulfate, both of which reduce IKL, to GABAergic neurons of the perigeniculate nucleus resulted in a 10-20 mV membrane depolarization, appearance of tonic discharge and the abolition of spindle wave generation. Local application of 1S,3R-ACPD and cholecystokinin to the perigeniculate nucleus while recording from thalamocortical neurons resulted in the abolition of spindle wave-associated inhibitory postsynaptic potentials and the occurrence of a continuous barrage of smaller amplitude inhibitory postsynaptic potentials, presumably in response to depolarization and tonic discharge of perigeniculate neurons. These results indicate that modulation of IKL in thalamocortical neurons and perigeniculate neurons is capable of abolishing the generation of spindle waves in thalamic networks. Through the modulation of IKL, ascending and descending activating systems may control the state of the thalamus such that the transition from slow wave sleep to waking is associated with the abolition of slow, synchronized rhythms and the facilitation of a state that is conducive to sensory receptor field analysis, arousal and perception.

Electrical Stimulation-Evoked Dopamine Release in the Primate Striatum

Background: Primate studies demonstrate that high-frequency electrical stimulation (HFS) of the caudate can enhance learning. Importantly, in these studies, stimulation was applied following the execution of behavior and the effect persisted into subsequent trials, suggesting a change in plasticity rather than a momentary facilitation of behavior. Objectives/Methods: Although the mechanism of HFS-enhanced learning is not understood, evidence suggests that dopamine plays a critical role. Therefore, we used in vivo amperometry to evaluate the effects of HFS on striatal dopamine release in the anesthetized primate. While this does not directly examine dopamine during learning, it provides insight with relation to dopamine dynamics during electrical stimulation and specifically between different stimulation parameters and striatal compartments. Results: We demonstrate that HFS results in significantly more dopamine release in the striatum compared to low-frequency stimulation. In addition, electrical stimulation operates differentially on specific neuronal elements, as the parameters for dopamine release are different for the caudate, putamen and medial forebrain bundle. Conclusions: While not direct evidence, these data suggest that HFS evokes significant dopamine release which may play a role in stimulation-enhanced learning. Moreover, these data suggest a means to modulate extracellular dopamine with a high degree of temporal and spatial precision for either research or clinical applications.

Mechanisms of Action of Deep Brain Stimulation

Publisher Summary nThis chapter focuses on the five mechanisms of action of deep brain simulation (DBS), which have gained widest acceptance form the scientific community. These hypothesis include depolarization block hypothesis, synaptic modulation hypothesis, synaptic depression hypothesis, neural jamming/modulation hypothesis, and synaptic facilitation hypothesis. Depolarization block hypothesis originated from the observation that the clinical effects of DBS are similar to those of a surgical lesion suggesting that this type of stimulation acts by silencing neurons of the stimulated structure. The synaptic modulation hypothesis states that DBS activates neuronal elements that are in close proximity to the stimulating electrode, which results in local synaptic inhibition via activation of axonal terminals within the stimulated nuclei that release inhibitory neurotransmitters such as GABA. The synaptic depression hypothesis is related to the synaptic modulation hypothesis and it states that a neuron that is activated by DBS is unable to sustain high frequency action on efferent targets due to depletion of terminal vesicular stores of neurotransmitters. The neural jamming or modulation hypothesis states that DBS regulates and corrects pathological activity in the basal ganglia network. Understanding the fundamental principles of neural jamming requires a detailed knowledge of neuronal ionic conductances, as well as normal firing patterns within the thalamocortical basal ganglia network. According to the synaptic facilitation hypothesis, DBS results in the release of dopamine from surviving dopaminergic neurons projecting to the basal ganglia to contribute to the therapeutic action of STN HFS in PD patients.Publisher Summary This chapter focuses on the five mechanisms of action of deep brain simulation (DBS), which have gained widest acceptance form the scientific community. These hypothesis include depolarization block hypothesis, synaptic modulation hypothesis, synaptic depression hypothesis, neural jamming/modulation hypothesis, and synaptic facilitation hypothesis. Depolarization block hypothesis originated from the observation that the clinical effects of DBS are similar to those of a surgical lesion suggesting that this type of stimulation acts by silencing neurons of the stimulated structure. The synaptic modulation hypothesis states that DBS activates neuronal elements that are in close proximity to the stimulating electrode, which results in local synaptic inhibition via activation of axonal terminals within the stimulated nuclei that release inhibitory neurotransmitters such as GABA. The synaptic depression hypothesis is related to the synaptic modulation hypothesis and it states that a neuron that is activated by DBS is unable to sustain high frequency action on efferent targets due to depletion of terminal vesicular stores of neurotransmitters. The neural jamming or modulation hypothesis states that DBS regulates and corrects pathological activity in the basal ganglia network. Understanding the fundamental principles of neural jamming requires a detailed knowledge of neuronal ionic conductances, as well as normal firing patterns within the thalamocortical basal ganglia network. According to the synaptic facilitation hypothesis, DBS results in the release of dopamine from surviving dopaminergic neurons projecting to the basal ganglia to contribute to the therapeutic action of STN HFS in PD patients.

Mechanisms of Action of Deep Brain Stimulation: A Review

Publisher Summary nThis chapter focuses on the five mechanisms of action of deep brain simulation (DBS), which have gained widest acceptance form the scientific community. These hypothesis include depolarization block hypothesis, synaptic modulation hypothesis, synaptic depression hypothesis, neural jamming/modulation hypothesis, and synaptic facilitation hypothesis. Depolarization block hypothesis originated from the observation that the clinical effects of DBS are similar to those of a surgical lesion suggesting that this type of stimulation acts by silencing neurons of the stimulated structure. The synaptic modulation hypothesis states that DBS activates neuronal elements that are in close proximity to the stimulating electrode, which results in local synaptic inhibition via activation of axonal terminals within the stimulated nuclei that release inhibitory neurotransmitters such as GABA. The synaptic depression hypothesis is related to the synaptic modulation hypothesis and it states that a neuron that is activated by DBS is unable to sustain high frequency action on efferent targets due to depletion of terminal vesicular stores of neurotransmitters. The neural jamming or modulation hypothesis states that DBS regulates and corrects pathological activity in the basal ganglia network. Understanding the fundamental principles of neural jamming requires a detailed knowledge of neuronal ionic conductances, as well as normal firing patterns within the thalamocortical basal ganglia network. According to the synaptic facilitation hypothesis, DBS results in the release of dopamine from surviving dopaminergic neurons projecting to the basal ganglia to contribute to the therapeutic action of STN HFS in PD patients.Publisher Summary This chapter focuses on the five mechanisms of action of deep brain simulation (DBS), which have gained widest acceptance form the scientific community. These hypothesis include depolarization block hypothesis, synaptic modulation hypothesis, synaptic depression hypothesis, neural jamming/modulation hypothesis, and synaptic facilitation hypothesis. Depolarization block hypothesis originated from the observation that the clinical effects of DBS are similar to those of a surgical lesion suggesting that this type of stimulation acts by silencing neurons of the stimulated structure. The synaptic modulation hypothesis states that DBS activates neuronal elements that are in close proximity to the stimulating electrode, which results in local synaptic inhibition via activation of axonal terminals within the stimulated nuclei that release inhibitory neurotransmitters such as GABA. The synaptic depression hypothesis is related to the synaptic modulation hypothesis and it states that a neuron that is activated by DBS is unable to sustain high frequency action on efferent targets due to depletion of terminal vesicular stores of neurotransmitters. The neural jamming or modulation hypothesis states that DBS regulates and corrects pathological activity in the basal ganglia network. Understanding the fundamental principles of neural jamming requires a detailed knowledge of neuronal ionic conductances, as well as normal firing patterns within the thalamocortical basal ganglia network. According to the synaptic facilitation hypothesis, DBS results in the release of dopamine from surviving dopaminergic neurons projecting to the basal ganglia to contribute to the therapeutic action of STN HFS in PD patients.