Pulse-to-Pulse Changes in the Frequency of Deep Brain Stimulation Affect Tremor and Modeled Neuronal Activity

Abstract

Birdno MJ, Cooper SE, Rezai AR, Grill WM. Pulse-to-pulse changes in the frequency of deep brain stimulation affect tremor and modeled neuronal activity. J Neurophysiol 98: [1675][1676][1677][1678][1679][1680][1681][1682][1683][1684] 2007. First published July 18, 2007; doi:10.1152/jn.00547.2007. The effectiveness of deep brain stimulation (DBS) in relieving the symptoms of movement disorders is dependent on the average frequency of stimulation. However, no one has yet examined whether the effectiveness of DBS in relieving tremor is dependent on the pulse-to-pulse (instantaneous) frequency of DBS. We examined the effects of pairedpulse thalamic DBS on tremor in subjects with essential tremor and on the firing of model neurons in a biophysically based computational model of DBS. DBS with an average rate of 130 Hz was more effective at reducing tremor when pulses were evenly spaced than when there were large differences between intrapair and interpair pulse intervals. Similar correlations were observed in the firing patterns of model neurons: increasing the difference between the intrapair and interpair intervals rendered model neurons more likely to fire synchronous bursts, more likely to fire irregularly, and less likely to entrain to the stimulus. The tremor responses provide evidence that the pulse-to-pulse frequency of DBS, not just its average rate, plays an important role in DBS function. Modeling results also suggest that effective DBS overrides oscillatory pathological activity and replaces it with more regularized neuronal firing patterns. I N T R O D U C T I O NChronic high-frequency stimulation of the brain, or deep brain stimulation (DBS), is an effective treatment for motor symptoms in Parkinson's disease, dystonia, and essential tremor (Benabid et al. 1991;Gross and Lozano 2000;Schuurman et al. 2000). DBS is also being investigated for treatment of epilepsy (Goodman 2004;Hodaie et al. 2002) and psychiatric disorders (Gross 2004), including obsessive-compulsive disorder (Nuttin et al. 2003) and depression (Carpenter 2006;Mayberg et al. 2005). Despite the clinical success of DBS, the underlying physiological mechanisms of action are unclear (Breit et al. 2004;Garcia et al. 2005;Grill and McIntyre 2001;McIntyre et al. 2004b). This lack of knowledge may limit the application of DBS for treating novel diseases; it also complicates the identification of optimal anatomical targets and the selection of appropriate stimulation parameters. The purposes of this investigation were to quantify the effects of paired-pulse DBS on tremor in subjects with essential tremor and to provide insight into the mechanisms responsible for these effects by analysis with a computational model.The effects of frequency of DBS within the ventral intermediate nucleus of the thalamus (Vim) on tremor in essential tremor subjects are well documented. Reductions in tremor are typically observed only when the frequency of stimulation is Ͼ90 Hz; conversely, low-frequency DBS (Ͻ50 Hz) often worsens symptoms (Benabid et al. 1991;Kuncel et ...

Mechanisms of Deep Brain Stimulation in Movement Disorders as Revealed by Changes in Stimulus Frequency

“…Further support for the link between regularization of neuronal activity and the clinical effects of DBS came from recent measurements of the effects of paired-pulse DBS on activity in bursting model thalamocortical neurons and on tremor in subjects with ET. 62 More regular stimuli (i.e., those with small differences between the intrapair and interpair pulse intervals) were more effective at regularizing neuronal firing patterns and suppressing tremor. Correlations between the burst index of neuronal firing and tremor were again very strong across variations in the pulse-to-pulse frequency of stimulation (R 2 ϭ 0.68; linear least squares fit) (FIG.…”

“…4). 16,18,62 As the frequency of stimulation increased, there was a decrease in both tremor and the CV of model neuron instantaneous firing rates, resulting in a strong correlation between model neuron CVs and tremor suppression (R 2 ϭ 0.92; linear least squares fit) (FIG. 4A).…”

“…26 Simulations of model thalamocortical relay neurons during 65 Hz and 130 Hz stimulation also indicate that intrinsic bursts were disrupted more by 130 Hz DBS than by 65 Hz DBS. 62 However, single-unit recordings in the STN of PD subjects suggest that the cell bodies in the STN may respond with more bursts during STN DBS. 19 Four out of 21 neurons switched from an irregular firing pattern before DBS to a burst firing pattern during 140 Hz DBS, and one neuron switched from a burst pattern to an irregular pattern.…”

“…4B). 62 In all of these cases, despite the fact that the simplified models did not include many of the features of the clinical experiments, there was an overarching correlation between the ability of stimulation to override intrinsic activity and its effectiveness at suppressing tremor.…”

“…B: There is likewise a positive correlation between the log tremor power measurements and the mean burst index across a population of 100 intrinsically bursting model thalamocortical neurons (R 2 ϭ 0.68). 62 Tremor and model neuron firing patterns were measured during paired-pulse stimulation as a function of the difference between the interpair and intrapair pulse intervals (IPI diff ). Paired-pulse trains had an average rate of 130 Hz.…”