Local field potentials and neural activity in motor networks in levodopa-induced dykinesia in a model of Parkinson’s disease
- Authors: Brazhnik E.S.1, Mysin I.E.1, Novikov N.I.1
-
Affiliations:
- Federal State Budgetary Educational Institution, Institute of Theoretical and Experimental Biophysics
- Issue: Vol 74, No 5 (2024)
- Pages: 606-620
- Section: ФИЗИОЛОГИЯ ВЫСШЕЙ НЕРВНОЙ (КОГНИТИВНОЙ) ДЕЯТЕЛЬНОСТИ ЧЕЛОВЕКА
- URL: https://cardiosomatics.orscience.ru/0044-4677/article/view/652073
- DOI: https://doi.org/10.31857/S0044467724050058
- ID: 652073
Cite item
Abstract
Levodopa, a metabolic precursor of dopamine (DA), is used to treat movement disorders in Parkinson’s disease (PD). Long-term use of levodopa causes a serious side effect known as levodopa-induced dyskinesia (LID). With the development of LID, high-frequency gamma oscillations (80–120 Hz) are reported in recordings of local field potentials (LFPs) from the motor cortex (MCx) in rats with experimental PD and in patients with Parkinson’s disease. The mechanisms underlying the occurrence of these oscillations and their connection with LID are not entirely clear. The study of activity in divisions of the motor network can provide valuable information about the mechanisms of development of pathological gamma-oscillations and LID. Rats with experimental PD were treated with levodopa for 7 days. Local field potentials and neural activity were recorded from electrodes implanted in the motor cortex, ventromedial nucleus of the thalamus (Vm), and substantia nigra pars reticularis (SNpr). Dyskinesia was assessed using a standard abnormal involuntary movement scale. Administration of levodopa significantly reduced the power of beta-oscillations (30–36 Hz) in all 3 parts of the motor neural network associated with bradykinesia in PD and caused the appearance in Vm and MCx coherent LFP oscillations in the high gamma-frequency range. Their coherence increased during priming between days 1 and 7. This activity was strongly associated with the occurrence of dyskinesia. In LID, an increase in the frequency of neuronal activity in Vm and MCx was accompanied by increased synchronization of neuronal activity with cortical gamma-oscillations in VM (68%) and MCx (25%). In contrast to Vm and MCx, SNpr did not exhibit gamma-range oscillatory activity during LID, and its neural activity was not synchronized with LFPs in Vm or MCx. It is significant that during the LID period the frequency of SNpr spike activity in most recordings (76%) decreased significantly and was approximately three times lower than the initial one (before the administration of levodopa). Administration of the antidyskinetic drug, 8-OH-DPAT, restored the initial characteristics of LFPs (30–36 Hz oscillation), neuronal activity, and bradykinesia. Thus, repeated administration of levodopa leads to a decrease of the inhibitory control in motor neural networks due to a significant reduction in activity of SNpr. Obviously, Vm and SNpr can be considered as the most important components of the motor neural network, making the main contribution to the occurrence of high-frequency gamma oscillations and LID.
Full Text

About the authors
E. S. Brazhnik
Federal State Budgetary Educational Institution, Institute of Theoretical and Experimental Biophysics
Email: nikolay_novikov@hotmail.com
Russian Federation, Pushchino
I. E. Mysin
Federal State Budgetary Educational Institution, Institute of Theoretical and Experimental Biophysics
Email: nikolay_novikov@hotmail.com
Russian Federation, Pushchino
N. I. Novikov
Federal State Budgetary Educational Institution, Institute of Theoretical and Experimental Biophysics
Author for correspondence.
Email: nikolay_novikov@hotmail.com
Russian Federation, Pushchino
References
- Alegre M., Alonso-Frech F., Rodriguez-Oroz M.C., Guridi J, Zamaride I., Valencia M., Manrique M., Obeso J.A., Artieda J. Movement-related changes in oscillatory activity in the human subthalamic nucleus: ipsilateral vs. contralateral movements. Eur J Neurosci. 2005. 22(9): 2315–2324.
- Altwal F., Padovan-Neto F. E., Ritger A., Steiner H., West A.R. Role of 5-HT1A Receptor in Vilazodone-Mediated Suppression of L-DOPA-Induced Dyskinesia and Increased Responsiveness to Cortical Input in Striatal Medium Spiny Neurons in an Animal Model of Parkinson’s Disease Molecules. 2021 Oct; 26(19): 5790. Published online 2021 Sep 24. doi: 10.3390/molecules26195790.
- Avila I., Parr-Brownlie L.C., Brazhnik E., Castaneda E., Bergstrom D.A., Walters J.R. Beta frequency synchronization in basal ganglia output during rest and walk in a hemiparkinsonian rat. Exp Neurol. 2010; 221(2):307–319.
- Brazhnik E., Novikov N.I., Dupre K.B., Wahba M.I., McCow A.,Walters J.R. Dissociation of high frequency (100 Hz) oscillatory activity within the thalamocortical network from L-DOPA-induced dyskinesia in hemiparkinsonian rats. SfN Abstract, 2013 on-line
- Brazhnik E., Cruz A.V., Avila I., Wahba M.I., Novikov n., Ilieva N.M., McCoy A.J., Gerber C., Walters J.R. State-dependent spike and local field synchronization between motor cortex and substantia nigra in hemiparkinsonian rats. J Neurosci. 2012. 32 (23): 7869–7880.
- Brazhnik E., Novikov N., McCoy A.J., Cruz A.V., Walters J.R. Functional correlates of exaggerated oscillatory activity in basal ganglia output in hemiparkinsonian rats. Exp Neurol. 2014. 261: 563–577.
- Brazhnik E., McCoy A.J., Novikov N., Hatch C.E, Walters J.R. Ventral Medial Thalamic Nucleus Promotes Synchronization of Increased High Beta Oscillatory Activity in the Basal Ganglia-Thalamocortical Network of the Hemiparkinsonian Rat. J Neurosci. 2016. 36(15): 4196–208. doi: 10.1523/JNEUROSCI.3582-15.2016.
- Brazhnik E., Novikov N., McCoy A.J., Ilieva N.M., Ghraib M.W., Walters J.R. Early decreases in cortical mid-gamma peaks coincide with the onset of motor deficits and precede exaggerated beta build-up in rat models for Parkinson’s disease Neurobiol Dis. 2021 Jul: 155:105393. doi: 10.1016/j.nbd.2021.105393. Epub 2021 May 15.
- Brittain J.S., Brown P. Oscillations and the basal ganglia: motor control and beyond. NeuroImage. 2014. 2:637–647.
- Cavarretta F., Jaeger D. Modeling Synaptic Integration of Bursty and β Oscillatory Inputs in Ventromedial Motor Thalamic Neurons in Normal and Parkinsonian States. eNeuro 2023 Dec 12; 10 (12): ENEURO.0237-23.2023. doi: 10.1523/ENEURO.0237-23.2023.
- Cenci M.A., Kumar A. Cells, pathways, and models in dyskinesia research. Curr Opin Neurobiol. 2024 Feb. 84: 102833. doi: 10.1016/j.conb.2023.102833.
- Delaville C., McCoy A.J., Gerber C.M., Cruz A.V., Walters J.R. Subthalamic nucleus activity in the awake hemiparkinsonian rat: relationships with motor and cognitive networks. J Neurosci. 2015. 35(17): 6918–6930.
- di Biase L., Pecoraro P.M., Carbone S.P., Caminiti M.L., Di Lazzaro V. Levodopa-Induced Dyskinesias in Parkinson’s Disease: An Overview on Pathophysiology, Clinical Manifestations, Therapy Management Strategies and Future Directions J Clin Med. 2023 Jul.12 (13): 4427. doi: 10.3390/jcm12134427
- Dupre K.B., Cruz A.V., McCoy A.J., Delaville C., Gerber C.M., Eyring K.W., Walters J.R. Effects of L-dopa priming on cortical high beta and high gamma oscillatory activity in a rodent model of Parkinson’s disease. Neurobiol Dis. 2016. 1–15. doi: 10.1016/j.nbd.
- Güttler C., Altschüler J., Tanev K. Böckmann S., Haumesser J.K., Nikulin V.V., Kühn A.A., van Riesen C. Levodopa-Induced Dyskinesia Are Mediated by Cortical Gamma Oscillations in Experimental Parkinsonism. Mov Disord. 2021 Apr; 36 (4): 927–937. doi: 10.1002/mds.28403.
- Halje P., Tamte M., Richter U., Mohammed M., Cenci M.A., Petersson P. Levodopa-induced dyskinesia is strongly associated with resonant cortical oscillations. J Neurosci. 2012. 32 (47): 16541–16551.
- Jenkinson N., Kuhn A.A., Brown P. Gamma oscillations in the human basal ganglia. Exp Neurol. 2013. 245: 72–76.
- Kempf F., Brucke C., Salih F., Trottenberg T., Kupsch A., Schneider G.H., Doyle Gaynor L., Hoffmann K.T., Vesper J., Wohrle J., Altenmuller D.M., Krauss J.K., Mazzone P., Di Lazzano V., Yelnik J., Kuhn A., Brown P. Gamma activity and reactivity in human thalamic local field potentials. Eur J Neurosci. 2009. 29(5): 943–953.
- Kuhn A.A., Trottenberg T., Kivi A., Kupsch A., Schneider G.H., Brown P. The relationship between local field potential and neuronal discharge in the subthalamic nucleus of patients with Parkinson’s disease. Exp Neurol. 2005.194 (1): 212–220.
- Li M., Wang X., Yao X., Wang X., Chen F., Zhang X., Sun S., He F., Jia Q., Guo M., Chen D., Sun Y., Li Y., He Q., Zhu Z., Wang M. Roles of Motor Cortex Neuron Classes in Reach-Related Modulation for Hemiparkinsonian Rats. Front Neurosci. 2021 Apr 27. 15:645849. doi: 10.3389/fnins.2021.645849.
- Litvak V., Eusebio A., Jha A., Oostenveld R., Barnes G., Foltynie T., Limousin P., Zrinzo L., Hariz M.I., Friston K., Brown P. Movement-related changes in local and long-range synchronization in Parkinson’s disease revealed by simultaneous magnetoen-cephalography and intracranial recordings. J Neurosci. 2012. 32(31):10541–10553.
- Lundblad M., Andersson M., Winkler C., Kirik D., Wierup N., Cenci M.A. Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. Eur J Neurosci. 2002. 15 (1): 120–132.
- Meidahl A.C., Moll C.K.E., van Wijk B.C.M, Gulberti A., Tinkhauser G., Westphal M., Engel A.K., Hamel W., Brown P., Sharott A. Synchronized spiking activity underlies phase amplitude coupling in the subthalamic nucleus of Parkinson’s disease patients. Neurobiol Dis. 2019 Jul. 127:101–113. doi: 10.1016/j.nbd.2019.02.005.
- Mirabella G., Pilotto A., Rizzardi A., Montalti M., Olivola E., Zatti C., Di Caprio V., Ferrari E., Modugno N., Padovani A. Effects of dopaminergic treatment on inhibitory control differ across Hoehn and Yahr stages of Parkinson’s disease. Brain Commun. 2023 Dec; 20.6(1): fcad350.
- doi: 10.1093/braincomms/fcad350.
- Nakamura K.C., Sharott A., Tanaka T., Magill P.J.J. Input Zone-Selective Dysrhythmia in Motor Thalamus after Dopamine Depletion. J. Neurosci., 2021. 41(50):10382–10404. doi: 10.1523/JNEUROSCI.1753-21.2021.
- Ozturk M., Kaku H., Jimenez-Shahed J., Viswanathan A., Sheth S.A., Kumar S., Ince N.F. Subthalamic Single Cell and Oscillatory Neural Dynamics of a Dyskinetic Medicated Patient with Parkinson’s Disease. Front Neurosci. 2020 Apr 24. 14:391. doi: 10.3389/fnins.2020.00391.
- Pena R.F.O., Rotstein H.G. The voltage and spiking responses of subthreshold resonant neurons to structured and fluctuating inputs: persistence and loss of resonance and variability. Biol Cybern. 2022 Apr; 116 (2):163–190. doi: 10.1007/s00422-021-00919-0.
- Petersson P., Halje P., Cenci M.A. Significance and Translational Value of High-Frequency Cortico-Basal Ganglia Oscillations in Parkinson’s Disease. J Parkinsons Dis. 2019; 9(1): 183–196. doi: 10.3233/JPD-181480.
- Picazio S., Ponzo V., Caltagirone C., Brusa L., Koch G.J. Dysfunctional inhibitory control in Parkinson’s disease patients with levodopa-induced dyskinesias. Neurol. 2018 Sep; 265 (9): 2088–2096. doi: 10.1007/s00415-018-8945-1.
- Pinna A., Ko W.K., Costa G., Tronci E., Fidalgo C., Simola N., Li Q., Tabrizi M.A, Bezard E., Carta M., Morelli M. Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models of Parkinson’s disease. Mov Disord. 2016 Apr; 31 (4): 501–11. D
- Si Q., Gan C., Zhang H., Cao X., Sun H., Wang M., Wang L., Yuan Y., Zhang K. Altered dynamic functional network connectivity in levodopa-induced dyskinesia of Parkinson’s disease. CNS Neurosci Ther. 2023 Jan; 29(1): 192–201. doi: 10.1111/cns.13994.
- Skovgård K., Barrientos S.A., Petersson P., Halje P., Cenci M.A. Distinctive Effects of D1 and D2 Receptor Agonists on Cortico-Basal Ganglia Oscillations in a Rodent Model of L-DOPA-Induced Dyskinesia. Neurotherapeutics. 2023 Jan; 20 (1): 304–324. doi: 10.1007/s13311-022-01309-5.
- Stark E., Levi A., Rotstein H.G. Network resonance can be generated independently at distinct levels of neuronal organization. PLoS Comput Biol. 2022 Jul 18;18(7): e1010364. doi: 10.1371/journal.pcbi.1010364.
- Sun S., Wang X., Shi X., Fang H., Sun Y., Li M., Han H., He Q., Wang X., Zhang X., Zhu Z.W., Chen F., Wang M. Neural pathway connectivity and discharge changes between M1 and STN in hemiparkinsonian rats. Brain Res Bull. 2023 May; 196: 1–19. doi: 10.1016/j.brainresbull.2023.03.002.
- Swann N.C., de Hemptinne C., Miocinovic S. et al. Gamma oscillations in the hyperkinetic state detected with chronic human brain recordings in Parkinson’s disease. J Neurosci 2016; 36 (24): 6445–6458.
- Torrence C., Compo G. P. A Practical Guide to Wavelet Analysis. Bulletin of the American Meteorological Society, American Meteorological Society, 1998. 79: 61–78.
- Trottenberg T., Fogelson N., Kuhn A.A, A., Kupsch A., Schneider G-H., Brown P.. Subthalamic gamma activity in patients with Parkinson’s disease. Exp Neurol. 2006; 200(1): 56–65.
- Wiest C., Torrecillos F., Tinkhauser G. Pogosyan A., Morgante F., Pereira E.A., Tan H. Finely tuned gamma oscillations: Spectral characteristics and links to dyskinesia Exp Neurol. 2022 May; 351:113999. doi: 10.1016/j.expneurol.2022.113999.
- Yuewei B., Pengfei W., Jianshen Y., Zhuyong W., Hanjie Y., Yuhao D., Jianwei G., Wangming Z. Eltoprazine modulated gamma oscillations on ameliorating L-dopa-induced dyskinesia in rats CNS. Neurosci Ther. 2023 Oct; 29(10): 2998–3013. doi: 10.1111/cns.14241
Supplementary files
