Effects of Transient Focal Inactivation of the Basal Ganglia in Parkinsonian Primates

Baron, Mark S.; Wichmann, Thomas; Ma, Dongrui; DeLong, Mahlon R.

doi:10.1523/jneurosci.22-02-00592.2002

Cited by 124 publications

(81 citation statements)

References 70 publications

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“…Striatal dopamine loss is postulated to result in increased striatal inhibition of GPe, which in turn results in disinhibition of STN and increased basal ganglia output from GPi. This concept is supported by the fact that STN inactivation results in a substantial reduction of the severity of parkinsonian motor signs in monkeys (Bergman et al, 1990;Guridi et al, 1993;Baron et al, 2002) and human patients (Sellal et al, 1992;Gill and Heywood, 1997;Alvarez et al, 2001).…”

Section: Global Neuronal Activity Changes In Parkinsonismmentioning

confidence: 96%

Role of External Pallidal Segment in Primate Parkinsonism: Comparison of the Effects of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism and Lesions of the External Pallidal Segment

Soares¹,

Kliem²,

Betarbet³

et al. 2004

J. Neurosci.

179

185

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These experiments re-examined the notion that reduced activity in the external pallidal segment (GPe) results in the abnormalities of neuronal discharge in the subthalamic nucleus (STN) and the internal pallidal segment (GPi) and in the development of parkinsonian motor signs. Extracellular recording in two rhesus monkeys, which had been rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed that the average neuronal discharge rate decreased in GPe but increased in STN and GPi. After MPTP, neurons in all three nuclei tended to discharge in oscillatory bursts. In addition, GABA release in STN (measured with microdialysis) was reduced, indicative of reduced activity along the GPe-STN pathway. Finally, the concentration of glutamic acid dehydrogenase (GAD; measured with autoimmunoradiography) was increased in GPe and GPi, likely reflecting increased striatal input and increased activity of local axon collaterals, respectively. Surprisingly, GAD protein in STN remained unchanged, indicating that the usual assumption that GAD levels are determined primarily by the overall activity of GABAergic elements may be too simplistic. The results from the MPTP-treated animals were compared with results obtained in a second group of three animals with ibotenic acid lesions of GPe. GPe lesions resulted in increased discharge in STN and GPi, comparable with the changes seen after MPTP but did not induce oscillatory bursting and had no behavioral effects. The results indicate that a mere reduction of GPe activity does not produce parkinsonism. Other changes, such as altered discharge patterns in STN and GPi, may play an important role in the generation of parkinsonism.

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Section: Global Neuronal Activity Changes In Parkinsonismmentioning

confidence: 96%

Role of External Pallidal Segment in Primate Parkinsonism: Comparison of the Effects of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism and Lesions of the External Pallidal Segment

Soares¹,

Kliem²,

Betarbet³

et al. 2004

J. Neurosci.

179

185

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“…2), again raising a paradoxical result. Indeed a decrease in STN neuronal activity should parallel an increased motor activity (Baron et al, 2002;Mehta and Chesselet, 2005). The known hypotensive action of prazosin could be ruled out, because it occurs at doses 10-fold higher than that used here (Sommermeyer et al, 1995).…”

Section: Effects Of ␣1 Noradrenergic Agents On Stn Neuronal Activitymentioning

confidence: 99%

“…The STN has been shown to play a key role in PD pathophysiology by the disorganization of its neuronal activity (Bergman et al, 1994;Hassani et al, 1996;Ni et al, 2001c). Because lesion (Bergman et al, 1990), high frequency stimulation (Benazzouz et al, 1993), and pharmacological inhibition (Baron et al, 2002) of the STN improved parkinsonian motor abnormalities in MPTP-treated monkey and in PD patients (for review, see Gross et al, 1999), we hypothesized that a part of the antiparkinsonian effects of ␣2-AR antagonists could be mediated by a direct action on STN neurons.…”

Section: Introductionmentioning

confidence: 99%

Noradrenergic Modulation of Subthalamic Nucleus Activity: Behavioral and Electrophysiological Evidence in Intact and 6-Hydroxydopamine-Lesioned Rats

Belujon¹,

Bézard²,

Taupignon³

et al. 2007

J. Neurosci.

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The subthalamic nucleus (STN) plays a key role in the pathophysiology of Parkinson's disease. The modulation of the STN by norepinephrine, however, is unknown. The present study aims at characterizing the effects of systemic administration of noradrenergic agents on locomotor activity and on in vivo extracellularly recorded STN neuronal activity in intact and 6-hydroxydopamine (6-OHDA)-lesioned rats. Using selective agonists and antagonists of ␣1 and ␣2 adrenergic receptors (ARs), we show that STN neurons have functional ␣1-and ␣2-AR controlling STN firing with an impact on locomotor activity. We further demonstrate that those systemic effects are supported, at least in part, by a direct modulation of STN neuronal activity, using patch-clamp recordings of STN neurons in brain slices. These findings support the premise that hypokinesia is associated with an increased STN neuronal activity, and that improvements of parkinsonian motor abnormalities are associated with a decrease in STN activity. Our data challenge assumptions about the role of ␣1-AR and ␣2-AR in the regulation of STN neurons in both intact and 6-OHDA-lesioned rats and further ground the rationale for using ␣2-AR noradrenergic antagonists in Parkinson's disease, albeit via an unexpected mechanism.

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“…Therefore the present results may not provide an accurate representation of pallidal efferent signaling during GPiDBS. Nevertheless, because GPi somata form a critical bottleneck for the pathologic neuronal activity associated with parkinsonism (Baron et al 2002;Lonser et al 1999), stimulation-induced reductions in abnormal somatic firing are likely to reflect true network-wide suppressions of those abnormalities. The effects of stimulation on nearby somata and fiber tracts are influenced by electrode geometry and stimulation parameters (Miocinovic et al 2006).…”

Section: Potential Confounds and Limitationsmentioning

confidence: 99%

Deep Brain Stimulation of the Globus Pallidus Internus in the Parkinsonian Primate: Local Entrainment and Suppression of Low-Frequency Oscillations

McCairn

Turner²

2009

Journal of Neurophysiology

118

114

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McCairn KW, Turner RS. Deep brain stimulation of the globus pallidus internus in the parkinsonian primate: local entrainment and suppression of low-frequency oscillations. J Neurophysiol 101: 1941-1960, 2009. First published January 21, 2009 doi:10.1152/jn.91092.2008. Competing theories seek to account for the therapeutic effects of high-frequency deep brain stimulation (DBS) of the internal globus pallidus (GPi) for medically intractable Parkinson's disease. To investigate this question, we studied the spontaneous activity of 102 pallidal neurons during GPiDBS in two macaques rendered parkinsonian by administration of MPTP. Stimulation through macroelectrodes in the GPi (Ն200 A at 150 Hz for 30 s) reduced rigidity in one animal and increased spontaneous movement in both. Novel artifact subtraction methods allowed uninterrupted single-unit recording during stimulation. GPiDBS induced phasic (78% of cells) or sustained (22%) peristimulus changes in firing in both pallidal segments. A subset of cells responded at short latency (Ͻ2 ms) in a manner consistent with antidromic driving. Later phasic increases clustered at 3-to 5-ms latency. Stimulation-induced decreases were either phasic, clustered at 1-3 ms, or sustained, showing no peristimulus modulation. Response latency and magnitude often evolved over 30 s of stimulation, but responses were relatively stable by the end of that time. GPiDBS reduced mean firing rates modestly and only in GPi (Ϫ6.9 spikes/s). Surprisingly, GPiDBS had no net effect on the prevalence or structure of burst firing. GPiDBS did reduce the prevalence of synchronized low-frequency oscillations. Some cell pairs became synchronized instead at the frequency of stimulation. Suppression of low-frequency oscillations did not require high-frequency synchronization, however, or even the presence of a significant peristimulus response. In summary, the therapeutic effects of GPiDBS may be mediated by an abolition of low-frequency synchronized oscillations as a result of phasic driving.

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Effects of Transient Focal Inactivation of the Basal Ganglia in Parkinsonian Primates

Cited by 124 publications

References 70 publications

Role of External Pallidal Segment in Primate Parkinsonism: Comparison of the Effects of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism and Lesions of the External Pallidal Segment

Role of External Pallidal Segment in Primate Parkinsonism: Comparison of the Effects of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism and Lesions of the External Pallidal Segment

Noradrenergic Modulation of Subthalamic Nucleus Activity: Behavioral and Electrophysiological Evidence in Intact and 6-Hydroxydopamine-Lesioned Rats

Deep Brain Stimulation of the Globus Pallidus Internus in the Parkinsonian Primate: Local Entrainment and Suppression of Low-Frequency Oscillations

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