Neural targets for relieving parkinsonian rigidity and bradykinesia with pallidal deep brain stimulation

Johnson, Matthew D.; Zhang, Jianyu; Ghosh, Debabrata; Vitek, Jerrold L.

doi:10.1152/jn.00039.2012

Cited by 48 publications

(47 citation statements)

References 61 publications

(54 reference statements)

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“…Three adult rhesus monkey (Macaca mulatta; one male, monkey K, 11.0 kg, 12 yr old; and two females, monkey R, 4.9 kg, 9 yr old, and monkey F, 8 kg, 25 yr old) were used in this study. Monkey K received an intraputaminal infusion of 3-nitropropionic acid (Agnesi et al 2013), whereas monkeys R and F were rendered moderately parkinsonian with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, as described previously (Hashimoto et al 2003;Johnson et al 2012). The animals were housed with environmental enrichment, provided with water ad libitum, and given a range of food options including fresh fruit and vegetables.…”

Section: Methodsmentioning

confidence: 99%

“…In monkey K the contact used was the most ventral contact within VPLo (contact 1, Ϫ0.3 mA, 130 Hz, 90-s pulse width). In monkey R the two contacts below and above the lamina separating the external and internal segments of GP were used, as this location was found to be the most effective setting at reducing bradykinesia and rigidity (contact 0 or 1, Ϫ1 V or Ϫ1.5 V, 135 Hz, 90-s pulse width) (Johnson et al 2012). This stimulation location was likely to affect both excitatory GP (GPe) and inhibitory GOP (GPi) efferent pathways directly, especially because DBS targeted to the GPi volume likely stimulates GPe efferents projecting through GPi .…”

Section: Methodsmentioning

confidence: 99%

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Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS

Agnesi

Muralidharan

Baker

et al. 2015

Journal of Neurophysiology

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-High-frequency stimulation is known to entrain spike activity downstream and upstream of several clinical deep brain stimulation (DBS) targets, including the cerebellar-receiving area of thalamus (VPLo), subthalamic nucleus (STN), and globus pallidus (GP). Less understood are the fidelity of entrainment to each stimulus pulse, whether entrainment patterns are stationary over time, and how responses differ among DBS targets. In this study, three rhesus macaques were implanted with a single DBS lead in VPLo, STN, or GP. Single-unit spike activity was recorded in the resting state in motor cortex during VPLo DBS, in GP during STN DBS, and in STN and pallidal-receiving area of motor thalamus (VLo) during GP DBS. VPLo DBS induced timelocked spike activity in 25% (n ϭ 15/61) of motor cortex cells, with entrained cells following 7.5 Ϯ 7.4% of delivered pulses. STN DBS entrained spike activity in 26% (n ϭ 8/27) of GP cells, which yielded time-locked spike activity for 8.7 Ϯ 8.4% of stimulus pulses. GP DBS entrained 67% (n ϭ 14/21) of STN cells and 32% (n ϭ 19/59) of VLo cells, which showed a higher fraction of pulses effectively inhibiting spike activity (82.0 Ϯ 9.6% and 86.1 Ϯ 16.6%, respectively). Latency of phase-locked spike activity increased over time in motor cortex (58%, VPLo DBS) and to a lesser extent in GP (25%, STN DBS). In contrast, the initial inhibitory phase observed in VLo and STN during GP DBS remained stable following stimulation onset. Together, these data suggest that circuit-level entrainment is low-pass filtered during high-frequency stimulation, most notably for glutamatergic pathways. Moreover, phase entrainment is not stationary or consistent at the circuit level for all DBS targets. deep brain stimulation; mechanisms; entrainment; peri-stimulus time histogram; subthalamic nucleus; globus pallidus; thalamus; motor cortex HIGH-FREQUENCY STIMULATION of subcortical structures, known as deep brain stimulation (DBS), has emerged in the past decades as a highly effective surgical therapy for medicationrefractory movement disorders and a promising therapy for numerous other neurological and neuropsychiatric disorders (Wichmann and DeLong 2006). Despite the clinical success, refinement of DBS remains hampered by the lack of clear mechanistic understanding of how DBS affects brain areas distal to the stimulated electrode(s) and how to modulate this activity in a consistent way to appropriately ameliorate specific symptoms.Computational modeling studies have suggested that DBS preferentially activates axonal efferents, afferents, and fibers of passage near the active electrode(s) McIntyre et al. 2004;Miocinovic et al. 2006) because axons, compared with cell bodies, have a lower threshold for generating action potentials with typical DBS waveforms Ranck 1975). Accordingly, electrophysiological studies have shown that high-frequency stimulation can generate phase-locked antidromic spike activity (i.e., spike activity that occurs at a specific phase of the interpulse interval) in regions that project to or...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS

Agnesi

Muralidharan

Baker

et al. 2015

Journal of Neurophysiology

Self Cite

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“…First, it has been shown that deep brain stimulation (DBS) may antidromically activate afferent axons and fibers of passage (53)(54)(55)(56)(57)(58)(59), thus reaching structures not immediately downstream. Second, studies (57, 58) observed in 6-hydroxydopamine (6-OHDA)-intoxicated rats that the antidromic effects increase with the stimulation frequency and peak around 110-130 Hz.…”

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confidence: 99%

Therapeutic mechanisms of high-frequency stimulation in Parkinson’s disease and neural restoration via loop-based reinforcement

Santaniello¹,

McCarthy

Montgomery³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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High-frequency deep brain stimulation (HFS) is clinically recognized to treat parkinsonian movement disorders, but its mechanisms remain elusive. Current hypotheses suggest that the therapeutic merit of HFS stems from increasing the regularity of the firing patterns in the basal ganglia (BG). Although this is consistent with experiments in humans and animal models of Parkinsonism, it is unclear how the pattern regularization would originate from HFS. To address this question, we built a computational model of the cortico-BG-thalamo-cortical loop in normal and parkinsonian conditions. We simulated the effects of subthalamic deep brain stimulation both proximally to the stimulation site and distally through orthodromic and antidromic mechanisms for several stimulation frequencies and, correspondingly, we studied the evolution of the firing patterns in the loop. The model closely reproduced experimental evidence for each structure in the loop and showed that neither the proximal effects nor the distal effects individually account for the observed pattern changes, whereas the combined impact of these effects increases with the stimulation frequency and becomes significant for HFS. Perturbations evoked proximally and distally propagate along the loop, rendezvous in the striatum, and, for HFS, positively overlap (reinforcement), thus causing larger poststimulus activation and more regular patterns in striatum. Reinforcement is maximal for the clinically relevant 130-Hz stimulation and restores a more normal activity in the nuclei downstream. These results suggest that reinforcement may be pivotal to achieve pattern regularization and restore the neural activity in the nuclei downstream and may stem from frequency-selective resonant properties of the loop.igh-frequency (i.e., above 100 Hz) deep brain stimulation (HFS) of the basal ganglia (BG) and thalamus is clinically recognized to treat movement disorders in Parkinson's disease (PD) (1-4), but its therapeutic mechanisms remain unclear (5, 6).Early hypotheses about HFS were derived from the rate-based model of the BG function (7,8) and postulated the disruption of the output of the BG-thalamic system via either the inactivation of neurons in the stimulated site (target) (9-15), which would provide an effect similar to a surgical lesion, or the abnormal excitation of axons projecting out of the target (16-19), which would disrupt the neuronal activity in the structures downstream, including any pathophysiological activity (20).More recently, an ever-growing number of experiments in PD humans and animal models of Parkinsonism has indicated that HFS affects the firing patterns of the neurons rather than the mean firing rate both in the target and the structures downstream (18,19,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and it replaces repetitive low-frequency (i.e., ≤50 Hz) bursting patterns with regularized (i.e., more tonic) patterns at higher frequencies (25,26). It has been proposed that increased pattern regularity of neurons in the target may be therapeutic (...

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“…Motor behavioral effects of different stimulation parameters were also assessed using a semi-quantitative scoring system adapted from prior nonhuman primate, porcine and rodent studies [30][31][32][33][34]. Prior to these experiments, the maximal tolerable stimulation amplitude was determined for each DBS lead contact for each animal by a consensus of the veterinary and scientist team.…”

Section: Motor Behavior Assessmentsmentioning

confidence: 99%

Motor behaviors in the sheep evoked by electrical stimulation of the subthalamic nucleus

Lentz

Zhao

Kelly

et al. 2015

Experimental Neurology

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Neural targets for relieving parkinsonian rigidity and bradykinesia with pallidal deep brain stimulation

Cited by 48 publications

References 61 publications

Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS

Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS

Therapeutic mechanisms of high-frequency stimulation in Parkinson’s disease and neural restoration via loop-based reinforcement

Motor behaviors in the sheep evoked by electrical stimulation of the subthalamic nucleus

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