Dynamic Stereotypic Responses of Basal Ganglia Neurons to Subthalamic Nucleus High-Frequency Stimulation in the Parkinsonian Primate

Moran, Anan; Stein, Edward; Tischler, Hadass; Belelovsky, Katya; Bar‐Gad, Izhar

doi:10.3389/fnsys.2011.00021

Cited by 68 publications

(87 citation statements)

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“…In contrast, beta oscillations and synchrony were reduced dramatically. Similar observations have been made by others during high-frequency microstimulation of the GPi (Bar-Gad et al 2004;Erez et al 2009;Chiken and Nambu 2013) or the STN (Meissner et al 2005;Moran et al 2011).…”

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confidence: 74%

Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex

McCairn

Turner

2015

Journal of Neurophysiology

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McCairn KW, Turner RS. Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex. J Neurophysiol 113: 2537-2548, 2015. First published February 4, 2015 doi:10.1152/jn.00701.2014.-Although there is general consensus that deep brain stimulation (DBS) yields substantial clinical benefit in patients with Parkinson's disease (PD), the therapeutic mechanism of DBS remains a matter of debate. Recent studies demonstrate that DBS targeting the globus pallidus internus (GPi-DBS) suppresses pathological oscillations in firing rate and between-cell spike synchrony in the vicinity of the electrode but has negligible effects on populationlevel firing rate or the prevalence of burst firing. The present investigation examines the downstream consequences of GPi-DBS at the level of the primary motor cortex (M1). Multielectrode, single cell recordings were conducted in the M1 of two parkinsonian nonhuman primates (Macaca fasicularis). GPi-DBS that induced significant reductions in muscular rigidity also reduced the prevalence of both beta (12-30 Hz) oscillations in single unit firing rates and of coherent spiking between pairs of M1 neurons. In individual neurons, GPi-DBS-induced increases in mean firing rate were three times more common than decreases; however, averaged across the population of M1 neurons, GPi-DBS induced no net change in mean firing rate. The population-level prevalence of burst firing was also not affected by GPi-DBS. The results are consistent with the hypothesis that suppression of both pathological, beta oscillations and synchronous activity throughout the cortico-basal ganglia network is a major therapeutic mechanism of GPi-DBS. deep brain stimulation; MPTP; nonhuman primate; Parkinson's disease; primary motor cortex; globus pallidus

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confidence: 74%

Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex

McCairn

Turner

2015

Journal of Neurophysiology

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“…There is persistent ambiguity regarding the effect of STN DBS on neuronal firing rates in nuclei downstream of the STN (GPe and SNr/GPi), and previous human and animal studies reported both decreases (Benazzouz et al 2000;Beurrier et al 2001;Magariños-Ascone 2002;Moran et al 2011;Welter et al 2004) and increases (Hahn et al 2008;Hashimoto et al 2003;Maurice et al 2003;Reese et al 2011) in firing rates during STN DBS. Our results show that regardless of the regularity of the stimulation pattern, highfrequency STN DBS generated both decreases and increases in firing rates, and changes in the mean firing rate did not correlate with behavioral effects.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies report a spectrum of firing rate changes in response to DBS resulting in no net change in the mean firing rate in rats (Bosch et al 2011;Chang et al 2006;McConnell et al 2012;Shi et al 2006), nonhuman primates Moran et al 2011), and humans (Reese et al 2011). This mixture of excitatory and inhibitory responses in GPe and SNr neurons during STN DBS differed during behaviorally effective high-frequency DBS compared with ineffective low-frequency DBS (McConnell et al 2012), suggesting that the mixture of firing rate responses may contribute to the mechanism of DBS.…”

Section: Discussionmentioning

confidence: 99%

“…Initial studies on the neuronal basis of high-frequency STN DBS focused on changes in neuronal firing rates and yielded contradictory results, with some indicating an inhibitory effect (Benazzouz et al 2000;Beurrier et al 2001;Magariños-Ascone 2002;Moran et al 2011;Welter et al 2004) and others supporting an excitatory effect of DBS (Hahn et al 2008;Hashimoto et al 2003;Maurice et al 2003;Reese et al 2011). This paradox may be explained by simultaneous somatic inhibition and axonal excitation in the same neuron (Johnson and McIntyre 2008;McIntyre et al 2004;Miocinovic et al 2006).…”

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confidence: 99%

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Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation

McConnell

Grill

2016

Journal of Neurophysiology

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McConnell GC, So RQ, Grill WM. Failure to suppress lowfrequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation. J Neurophysiol 115: 2791-2802, 2016. First published March 9, 2012 doi:10.1152/jn.00822.2015.-Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established treatment for the motor symptoms of Parkinson's disease (PD). However, the mechanisms of action of DBS are unknown. Random temporal patterns of DBS are less effective than regular DBS, but the neuronal basis for this dependence on temporal pattern of stimulation is unclear. Using a rat model of PD, we quantified the changes in behavior and single-unit activity in globus pallidus externa and substantia nigra pars reticulata during high-frequency STN DBS with different degrees of irregularity. Although all stimulus trains had the same average rate, 130-Hz regular DBS more effectively reversed motor symptoms, including circling and akinesia, than 130-Hz irregular DBS. A mixture of excitatory and inhibitory neuronal responses was present during all stimulation patterns, and mean firing rate did not change during DBS. Low-frequency (7-10 Hz) oscillations of single-unit firing times present in hemiparkinsonian rats were suppressed by regular DBS, and neuronal firing patterns were entrained to 130 Hz. Irregular patterns of DBS less effectively suppressed 7-to 10-Hz oscillations and did not regularize firing patterns. Random DBS resulted in a larger proportion of neuron pairs with increased coherence at 7-10 Hz compared with regular 130-Hz DBS, which suggested that long pauses (interpulse interval Ͼ50 ms) during random DBS facilitated abnormal low-frequency oscillations in the basal ganglia. These results suggest that the efficacy of high-frequency DBS stems from its ability to regularize patterns of neuronal firing and thereby suppress abnormal oscillatory neural activity within the basal ganglia. These observations led to the hypothesis that DBS disrupts pathological patterns of neuronal activity Garcia et al. 2005;Hashimoto et al. 2003) and that the resulting regularization of neuronal activity is critical to the mechanism of DBS McCairn and Turner 2009).The importance of the temporal pattern of neuronal activity was reinforced in clinical studies comparing the effects of irregular and regular patterns of DBS on motor symptoms (Gross and McDougal 2013;Hess et al. 2013). Stimulation that was periodically cycled on and off was less effective than continuous DBS (Montgomery 2005), and random patterns of stimulation, even when delivered at a high frequency, were less effective than regular stimulation at reducing tremor (Birdno et al. 2008(Birdno et al. , 2012 and bradykinesia (Dorval et al. 2010). However, these studies did not reveal why irregular high-frequency stimulation was not sufficient to treat symptoms.In the present study, we quantified behavior and single-unit neuronal activity in the globus pallidus externa (GPe) and substantia nigra pars reticulata (SNr) during differen...

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“…Despite all the importance placed on mechanisms, the mechanisms by which DBS affects the signs of MDs are still unknown despite decades of research using animals [239][240][241]. This is an important element in our analysis of animal models and DBS as one of the reasons animal models in general have been heralded as important, indeed vital, is for the search for mechanisms.…”

Section: Epistemology and Mechanismsmentioning

confidence: 99%

The Development of Deep Brain Stimulation for Movement Disorders

Greek¹

2012

J Clinic Res Bioeth

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The development of deep brain stimulation has revolutionized care for patients with movement disorders like Parkinson's disease. Many areas of science contributed to this technology but one area, the use of animal models, has been cited as vital. We review these claims as well as the history of the discoveries that eventually led to deep brain stimulation in an attempt to ascertain: 1) the contributions of animal models; 2) the contributions from humanbased research and observation; and the role of advances in the engineering, physics, and computer science. We distinguish between advances and discoveries that were, or at least appear to be, dependent on animal models and those where animals were involved but that could have occurred, and/or were occurring simultaneously, with humanbased research. We conclude that animal-based research played a role in defining gross anatomy in the 19 th and early 20 th centuries, but that essentially all subsequent advances were human-based or secondary to advances in the physical and applied sciences. This has historical, funding, and ethical implications as the development of deep brain stimulation is cited as an example of the importance of animal-based research and a reason for continued social and financial support of animal models in general as opposed to clinical research, other human-based research modalities, and the various disciplines of the physical and applied sciences.

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Dynamic Stereotypic Responses of Basal Ganglia Neurons to Subthalamic Nucleus High-Frequency Stimulation in the Parkinsonian Primate

Cited by 68 publications

References 60 publications

Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex

Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex

Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation

The Development of Deep Brain Stimulation for Movement Disorders

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