Abstract
The pathophysiological mechanisms leading to dyskinesias in Parkinson’s disease (PD) after long-term treatment with levodopa remain unclear. This study investigates the neuronal firing characteristics of the entopeduncular nucleus (EPN), the rat equivalent of the human globus pallidus internus and output nucleus of the basal ganglia, and its coherence with the motor cortex (MCx) field potentials in the unilateral 6-OHDA rat model of PD with and without levodopa-induced dyskinesias (LID). 6-hydroxydopamine-lesioned hemiparkinsonian (HP) rats, 6-OHDA-lesioned HP rats with LID (HP-LID) rats, and naïve controls were used for recording of single-unit activity under urethane (1.4 g/kg, i.p) anesthesia in the EPN “on” and “off” levodopa. Over the MCx, the electrocorticogram output was recorded. Analysis of single-unit activity in the EPN showed enhanced firing rates, burst activity, and irregularity compared to naïve controls, which did not differ between drug-naïve HP and HP-LID rats. Analysis of EPN spike coherence and phase-locked ratio with MCx field potentials showed a shift of low (12–19 Hz) and high (19–30 Hz) beta oscillatory activity between HP and HP-LID groups. EPN theta phase-locked ratio was only enhanced in HP-LID compared to HP rats. Overall, levodopa injection had no stronger effect in HP-LID rats than in HP rats. Altered coherence and changes in the phase lock ratio of spike and local field potentials in the beta range may play a role for the development of LID.
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Alam M, Heissler HE, Schwabe K, Krauss JK (2012) Deep brain stimulation of the pedunculopontine tegmental nucleus modulates neuronal hyperactivity and enhanced beta oscillatory activity of the subthalamic nucleus in the rat 6-hydroxydopamine model. Exp Neurol 233:233–242. doi:10.1016/j.expneurol.2011.10.006
Alam M, Capelle HH, Schwabe K, Krauss JK (2014) Effect of deep brain stimulation on levodopa-induced dyskinesias and striatal oscillatory local field potentials in a rat model of Parkinson’s disease. Brain Stimul 7:13–20. doi:10.1016/j.brs.2013.09.001
Alonso-Frech F, Zamarbide I, Alegre M et al (2006) Slow oscillatory activity and levodopa-induced dyskinesias in Parkinson’s disease. Brain 129:1748–1757. doi:10.1093/brain/awl103
Benhamou L, Cohen D (2014) Electrophysiological characterization of entopeduncular nucleus neurons in anesthetized and freely moving rats. Front Syst Neurosci 8:7. doi:10.3389/fnsys.2014.00007
Boraud T, Bezard E, Guehl D et al (1998) Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey. Brain Res 787:157–160
Brazhnik E, Cruz AV, Avila I et al (2012) State-dependent spike and local field synchronization between motor cortex and substantia nigra in hemiparkinsonian rats. J Neurosci 32:7869–7880. doi:10.1523/JNEUROSCI.0943-12.2012
Brown P (2003) Oscillatory nature of human basal ganglia activity: relationship to the pathophysiology of Parkinson’s disease. Mov Disord 18:357–363. doi:10.1002/mds.10358
Chen CC, Litvak V, Gilbertson T et al (2007) Excessive synchronization of basal ganglia neurons at 20 Hz slows movement in Parkinson’s disease. Exp Neurol 205:214–221. doi:10.1016/j.expneurol.2007.01.027
Crowell AL, Ryapolova-Webb ES, Ostrem JL et al (2012) Oscillations in sensorimotor cortex in movement disorders: an electrocorticography study. Brain 135:615–630. doi:10.1093/brain/awr332
Filion M, Tremblay L (1991) Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 547:142–151
Fries P, Nikolić D, Singer W (2007) The gamma cycle. Trends Neurosci 30:309–316. doi:10.1016/j.tins.2007.05.005
Halliday DM, Rosenberg JR, Amjad AM et al (1995) A framework for the analysis of mixed time series/point process data–theory and application to the study of physiological tremor, single motor unit discharges and electromyograms. Prog Biophys Mol Biol 64:237–278
Hassani OK, Mouroux M, Feger J (1996) Increased subthalamic neuronal activity after nigral dopaminergic lesion independent of disinhibition via the globus pallidus. Neuroscience 72:105–115
Hollerman JR, Grace AA (1992) Subthalamic nucleus cell firing in the 6-OHDA-treated rat: basal activity and response to haloperidol. Brain Res 590:291–299
Hutchison WD, Lozano AM, Tasker RR et al (1997) Identification and characterization of neurons with tremor-frequency activity in human globus pallidus. Exp Brain Res 113:557–563
Kayser C, Montemurro MA, Logothetis NK, Panzeri S (2009) Spike-phase coding boosts and stabilizes information carried by spatial and temporal spike patterns. Neuron 61:597–608. doi:10.1016/j.neuron.2009.01.008
Kuhn AA, Kupsch A, Schneider GH, Brown P (2006) Reduction in subthalamic 8–35 Hz oscillatory activity correlates with clinical improvement in Parkinson’s disease. Eur J Neurosci 23:1956–1960. doi:10.1111/j.1460-9568.2006.04717.x
Kuhn AA, Brucke C, Schneider GH et al (2008) Increased beta activity in dystonia patients after drug-induced dopamine deficiency. Exp Neurol 214:140–143. doi:10.1016/j.expneurol.2008.07.023
Labarre D, Meissner W, Boraud T (2008) Measure of the regularity of events in stochastic point processes, application to neuron activity analysis. In: Acoustics, speech and signal processing, 2008. {ICASSP} 2008. {IEEE} International Conference on, pp 489–492
Lemaire N, Hernandez LF, Hu D et al (2012) Effects of dopamine depletion on LFP oscillations in striatum are task- and learning-dependent and selectively reversed by L-DOPA. Proc Natl Acad Sci U S A 109:18126–18131. doi:10.1073/pnas.1216403109
Levy R, Dostrovsky JO, Lang AE et al (2001) Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson’s disease. J Neurophysiol 86:249–260
Li Q, Ke Y, Chan DC et al (2012) Therapeutic deep brain stimulation in Parkinsonian rats directly influences motor cortex. Neuron 76:1030–1041. doi:10.1016/j.neuron.2012.09.032
Lindemann C, Alam M, Krauss JK, Schwabe K (2013) Neuronal activity in the medial associative-limbic and lateral motor part of the rat subthalamic nucleus and the effect of 6-hydroxydopamine-induced lesions of the dorsolateral striatum. J Comp Neurol 521:3226–3240. doi:10.1002/cne.23342
Lopez-Azcarate J, Tainta M, Rodriguez-Oroz MC et al (2010) Coupling between beta and high-frequency activity in the human subthalamic nucleus may be a pathophysiological mechanism in Parkinson’s disease. J Neurosci 30:6667–6677. doi:10.1523/jneurosci.5459-09.2010
Lourens MAJ, Meijer HGE, Contarino MF et al (2013) Functional neuronal activity and connectivity within the subthalamic nucleus in Parkinson’s disease. Clin Neurophysiol 124:967–981. doi:10.1016/j.clinph.2012.10.018
Lozano AM, Lang AE, Levy R et al (2000) Neuronal recordings in Parkinson’s disease patients with dyskinesias induced by apomorphine. Ann Neurol 47:S141–S146
Lundblad M, Andersson M, Winkler C et al (2002) Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. Eur J Neurosci 15:120–132
Magill PJ, Bolam JP, Bevan MD (2001) Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network. Neuroscience 106:313–330
Marceglia S, Foffani G, Bianchi AM et al (2006) Dopamine-dependent non-linear correlation between subthalamic rhythms in Parkinson’s disease. J Physiol 571:579–591. doi:10.1113/jphysiol.2005.100271
Marceglia S, Bianchi AM, Baselli G et al (2007) Interaction between rhythms in the human basal ganglia: application of bispectral analysis to local field potentials. IEEE Trans Neural Syst Rehabil Eng 15:483–492. doi:10.1109/tnsre.2007.907893
Marceglia S, Fiorio M, Foffani G et al (2009) Modulation of beta oscillations in the subthalamic area during action observation in Parkinson’s disease. Neuroscience 161:1027–1036. doi:10.1016/j.neuroscience.2009.04.018
Marin C, Aguilar E, Bonastre M (2008) Effect of locus coeruleus denervation on levodopa-induced motor fluctuations in hemiparkinsonian rats. J Neural Transm 115:1133–1139. doi:10.1007/s00702-008-0060-5
Marin C, Aguilar E, Mengod G et al (2009) Effects of early vs. late initiation of levodopa treatment in hemiparkinsonian rats. Eur J Neurosci 30:823–832. doi:10.1111/j.1460-9568.2009.06877.x
McCarthy MM, Moore-Kochlacs C, Gu X et al (2011) Striatal origin of the pathologic beta oscillations in Parkinson’s disease. Proc Natl Acad Sci U S A 108:11620–11625. doi:10.1073/pnas.1107748108
Meissner W, Ravenscroft P, Reese R et al (2006) Increased slow oscillatory activity in substantia nigra pars reticulata triggers abnormal involuntary movements in the 6-OHDA-lesioned rat in the presence of excessive extracellular striatal dopamine. Neurobiol Dis 22:586–598. doi:10.1016/j.nbd.2006.01.009
Merello M, Lees AJ, Balej J et al (1999) GPi firing rate modification during beginning-of-dose motor deterioration following acute administration of apomorphine. Mov Disord 14:481–483
Ni ZG, Bouali-Benazzouz R, Gao DM et al (2001) Time-course of changes in firing rates and firing patterns of subthalamic nucleus neuronal activity after 6-OHDA-induced dopamine depletion in rats. Brain Res 899:142–147
Obeso JA, Rodriguez-Oroz MC, Rodriguez M et al (2000) Pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease: problems with the current model. Ann Neurol 47:S22–S32 discussion S32–S34
Obeso JA, Rodriguez-Oroz MC, Javier Blesa F, Guridi J (2006) The globus pallidus pars externa and Parkinson’s disease. Ready for prime time? Exp Neurol 202:1–7. doi:10.1016/j.expneurol.2006.07.004
Papa SM, Desimone R, Fiorani M, Oldfield EH (1999) Internal globus pallidus discharge is nearly suppressed during levodopa-induced dyskinesias. Ann Neurol 46:732–738
Pavlides A, Hogan SJ, Bogacz R (2012) Improved conditions for the generation of beta oscillations in the subthalamic nucleus–globus pallidus network. Eur J Neurosci 36:2229–2239. doi:10.1111/j.1460-9568.2012.08105.x
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press Inc, San Diego
Picconi B, Pisani A, Barone I et al (2005) Pathological synaptic plasticity in the striatum: implications for Parkinson’s disease. Neurotoxicology 26:779–783. doi:10.1016/j.neuro.2005.02.002
Priori A, Foffani G, Pesenti A et al (2004) Rhythm-specific pharmacological modulation of subthalamic activity in Parkinson’s disease. Exp Neurol 189:369–379. doi:10.1016/j.expneurol.2004.06.001
Ray NJ, Jenkinson N, Wang S et al (2008) Local field potential beta activity in the subthalamic nucleus of patients with Parkinson’s disease is associated with improvements in bradykinesia after dopamine and deep brain stimulation. Exp Neurol 213:108–113. doi:10.1016/j.expneurol.2008.05.008
Rodriguez-Oroz MC, Rodriguez M, Guridi J et al (2001) The subthalamic nucleus in Parkinson’s disease: somatotopic organization and physiological characteristics. Brain 124:1777–1790
Rodriguez-Oroz MC, Lopez-Azcarate J, Garcia-Garcia D et al (2011) Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson’s disease. Brain 134:36–49. doi:10.1093/brain/awq301
Rumpel R, Alam M, Klein A et al (2013) Neuronal firing activity and gene expression changes in the subthalamic nucleus after transplantation of dopamine neurons in hemiparkinsonian rats. Neurobiol Dis 59:230–243
Sharott A, Magill PJ, Harnack D et al (2005) Dopamine depletion increases the power and coherence of beta-oscillations in the cerebral cortex and subthalamic nucleus of the awake rat. Eur J Neurosci 21:1413–1422. doi:10.1111/j.1460-9568.2005.03973.x
Shimamoto SA, Ryapolova-Webb ES, Ostrem JL et al (2013) Subthalamic nucleus neurons are synchronized to primary motor cortex local field potentials in Parkinson’s disease. J Neurosci 33:7220–7233. doi:10.1523/jneurosci.4676-12.2013
Thompson JA, Lanctin D, Ince NF, Abosch A (2014) Clinical implications of local field potentials for understanding and treating movement disorders. Stereotact Funct Neurosurg 92:251–263. doi:10.1159/000364913
Von Wrangel C, Schwabe K, John N et al (2015) The rotenone-induced rat model of Parkinson’s disease: behavioral and electrophysiological findings. Behav Brain Res 279:52–61. doi:10.1016/j.bbr.2014.11.002
Weinberger M, Mahant N, Hutchison WD et al (2006) Beta oscillatory activity in the subthalamic nucleus and its relation to dopaminergic response in Parkinson’s disease. J Neurophysiol 96:3248–3256. doi:10.1152/jn.00697.2006
Weinberger M, Hutchison WD, Alavi M et al (2012) Oscillatory activity in the globus pallidus internus: comparison between Parkinson’s disease and dystonia. Clin Neurophysiol 123:358–368. doi:10.1016/j.clinph.2011.07.029
Wichmann T, Dostrovsky JO (2011) Pathological basal ganglia activity in movement disorders. Neuroscience 198:232–244. doi:10.1016/j.neuroscience.2011.06.048
Wichmann T, Bergman H, DeLong MR (1994) The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism. J Neurophysiol 72:521–530
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The authors are thankful to China Scholarship Council (CNC), for their student fellowship to X. Jin.
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Jin, X., Schwabe, K., Krauss, J.K. et al. Coherence of neuronal firing of the entopeduncular nucleus with motor cortex oscillatory activity in the 6-OHDA rat model of Parkinson’s disease with levodopa-induced dyskinesias. Exp Brain Res 234, 1105–1118 (2016). https://doi.org/10.1007/s00221-015-4532-1
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DOI: https://doi.org/10.1007/s00221-015-4532-1