Cellular Effects of Deep Brain Stimulation: Model-Based Analysis of Activation and Inhibition

McIntyre, Cameron C.; Grill, Warren M.; Sherman, David; Thakor, Nitish V.

doi:10.1152/jn.00989.2003

Cited by 739 publications

(642 citation statements)

References 62 publications

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“…Although the results presented are insightful, the model is based on numerous assumptions (Rubin and Terman 2004;Pascual et al 2006). The therapeutic mechanisms that underlie DBS, however, most likely represent a combination of several phenomena (McIntyre et al 2004;Benabid et al 2002).…”

Section: Discussionmentioning

confidence: 96%

“…9(a), (c), and (e)], which is assumed to cause a release of the inhibitory GABAergic neurotransmitter, resulted in a decrease in STN activity. Increased axonal firing rate combined with a decrease in STN cell body firing rate is a realistic scenario due to the possibility of functional decoupling between the cell body and axon of a nucleus (McIntyre et al 2004). On the other hand, stimulation of the efferents [ Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the comparable effects of high frequency stimulation to a lesion of the nucleus, it appears that DBS of the STN induces a functional inhibition of the stimulated region, and thus to decreased neuronal activity. However, on the basis of physiological principles, one would expect that the effects of DBS are due to excitation of the neural elements (axons, soma) surrounding the tip of the electrode, and thus to increased firing of the axons projecting away from the stimulated region (Montgomery and Baker 2000;Benabid et al 2002;McIntyre et al 2004). DBS was investigated according to the following possible mechanisms:…”

Section: Deep Brain Stimulation (Dbs) Modelmentioning

confidence: 99%

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Increased bradykinesia in Parkinson’s disease with increased movement complexity: elbow flexion–extension movements

2008

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The present research investigates factors contributing to bradykinesia in the control of simple and complex voluntary limb movement in Parkinson's disease (PD) patients. The functional scheme of the basal ganglia (BG)-thalamocortical circuit was described by a mathematical model based on the mean firing rates of BG nuclei. PD was simulated as a reduction in dopamine levels, and a loss of functional segregation between two competing motor modules. In order to compare model simulations with performed movements, flexion and extension at the elbow joint is taken as a test case. Results indicated that loss of segregation contributed to bradykinesia due to interference between competing modules and a reduced ability to suppress unwanted movements. Additionally, excessive neurotransmitter depletion is predicted as a possible mechanism for the increased difficulty in performing complex movements. The simulation results showed that the model is in qualitative agreement with the results from movement experiments on PD patients and healthy subjects. Furthermore, based on changes in the firing rate of BG nuclei, the model demonstrated that the effective mechanism of Deep Brain Stimulation (DBS) in STN may result from stimulation induced inhibition of STN, partial synaptic failure of efferent projections, or excitation of inhibitory afferent axons even though the underlying methods of action may be quite different for the different mechanisms.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Deep Brain Stimulation (Dbs) Modelmentioning

confidence: 99%

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Increased bradykinesia in Parkinson’s disease with increased movement complexity: elbow flexion–extension movements

2008

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“…Converging theoretical (McIntyre et al, 2004a) and experimental (Hashimoto et al, 2003) results suggest that DBS generates an excitatory effect on axons surrounding the electrode. While correlations between axonal activation and the therapeutic mechanisms of DBS remain controversial, one leading hypothesis is that high frequency stimulation results in an override of the underlying pathological neural activity patterns (Grill et al, 2004;Hashimoto et al, 2003;McIntyre et al, 2004b;Montgomery and Baker, 2000).…”

Section: Introductionmentioning

confidence: 90%

Sources and effects of electrode impedance during deep brain stimulation

Butson

Maks

McIntyre

2006

Clinical Neurophysiology

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Objective-Clinical impedance measurements for deep brain stimulation (DBS) electrodes in human patients are normally in the range 500-1500 Ω. DBS devices utilize voltage-controlled stimulation; therefore, the current delivered to the tissue is inversely proportional to the impedance. The goals of this study were to evaluate the effects of various electrical properties of the tissue medium and electrode-tissue interface on the impedance and to determine the impact of clinically relevant impedance variability on the volume of tissue activated (VTA) during DBS.Methods-Axisymmetric finite-element models (FEM) of the DBS system were constructed with explicit representation of encapsulation layers around the electrode and implanted pulse generator. Impedance was calculated by dividing the stimulation voltage by the integrated current density along the active electrode contact. The models utilized a Fourier FEM solver that accounted for the capacitive components of the electrode-tissue interface during voltagecontrolled stimulation. The resulting time-and space-dependent voltage waveforms generated in the tissue medium were superimposed onto cable model axons to calculate the VTA.Results-The primary determinants of electrode impedance were the thickness and conductivity of the encapsulation layer around the electrode contact and the conductivity of the bulk tissue medium. The difference in the VTA between our low (790 Ω) and high (1244 Ω) impedance models with typical DBS settings (−3 V, 90 μs, 130 Hz pulse train) was 121 mm 3 , representing a 52% volume reduction.Conclusions-Electrode impedance has a substantial effect on the VTA and accurate representation of electrode impedance should be an explicit component of computational models of voltage-controlled DBS.Significance-Impedance is often used to identify broken leads (for values >2000 Ω) or short circuits in the hardware (for values <50 Ω); however, clinical impedance values also represent an important parameter in defining the spread of stimulation during DBS.

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“…A modeling study of thalamocortical neurons targeted by HFS found that the position of the neuron with respect to the electrode determined its output firing characteristics. 39 Neurons close to the stimulation electrode had their spontaneous activity suppressed by activation of inhibitory presynaptic terminals, and their axons were directly activated. Axonal spike output thus became time-locked to the stimulus frequency.…”

Section: Axonal Output Of the Stimulated Nucleusmentioning

confidence: 99%

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

et al. 2008

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Summary:Chronic electrical stimulation of the brain, known as deep brain stimulation (DBS), has become a preferred surgical treatment for medication-refractory movement disorders. Despite its remarkable clinical success, the therapeutic mechanisms of DBS are still not completely understood, limiting opportunities to improve treatment efficacy and simplify selection of stimulation parameters. This review addresses three questions essential to understanding the mechanisms of DBS. 1) How does DBS affect neuronal tissue in the vicinity of the active electrode or electrodes? 2) How do these changes translate into therapeutic benefit on motor symptoms? 3) How do these effects depend on the particular site of stimulation? Early hypotheses proposed that stimulation inhibited neuronal activity at the site of stimulation, mimicking the outcome of ablative surgeries. Recent studies have challenged that view, suggesting that although somatic activity near the DBS electrode may exhibit substantial inhibition or complex modulation patterns, the output from the stimulated nucleus follows the DBS pulse train by direct axonal excitation. The intrinsic activity is thus replaced by high-frequency activity that is time-locked to the stimulus and more regular in pattern. These changes in firing pattern are thought to prevent transmission of pathologic bursting and oscillatory activity, resulting in the reduction of disease symptoms through compensatory processing of sensorimotor information. Although promising, this theory does not entirely explain why DBS improves motor symptoms at different latencies. Understanding these processes on a physiological level will be critically important if we are to reach the full potential of this powerful tool.

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Cellular Effects of Deep Brain Stimulation: Model-Based Analysis of Activation and Inhibition

Cited by 739 publications

References 62 publications

Increased bradykinesia in Parkinson’s disease with increased movement complexity: elbow flexion–extension movements

Increased bradykinesia in Parkinson’s disease with increased movement complexity: elbow flexion–extension movements

Sources and effects of electrode impedance during deep brain stimulation

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

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