Local field potentials and neural activity in motor networks in levodopa-induced dykinesia in a model of Parkinson’s disease

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

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

Restricted Access

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

  1. 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.
  2. 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.
  3. 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.
  4. 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
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Brittain J.S., Brown P. Oscillations and the basal ganglia: motor control and beyond. NeuroImage. 2014. 2:637–647.
  10. 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.
  11. 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.
  12. 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.
  13. 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
  14. 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.
  15. 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.
  16. 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.
  17. Jenkinson N., Kuhn A.A., Brown P. Gamma oscillations in the human basal ganglia. Exp Neurol. 2013. 245: 72–76.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. doi: 10.1093/braincomms/fcad350.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. Torrence C., Compo G. P. A Practical Guide to Wavelet Analysis. Bulletin of the American Meteorological Society, American Meteorological Society, 1998. 79: 61–78.
  38. 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.
  39. 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.
  40. 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

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Effects of serotonergic 5-HT1A-receptors agonist and antagonist on high-frequency gamma activity and dyskinesia. An example of a 3-hour recording from one animal. (а) – representative time-frequency wavelet scalograms of spectral power in LFP recordings from MCx (top), Vm (center) and SNpr (bottom) during walking, post-levodopa, post-DPAT (~85 min post-levodopa), and 5-HT1A receptor antagonist, WAY1006355 (WAY, 20 min after DPAT). The spectral power label is represented as a bar on the right as signal-to-noise ratio (dB), with higher power indicated by a darker color. (б) – coherence spectra in pairs MCx–Vm (top), Vm–SNpr (center), and MCx–SNpr (bottom). Graphs are plotted for the 60-second recording periods shown in (а), during walking before levodopa administration (solid line, thick), during LID (dashed line, thick), after DPAT administration (solid line, thin), after introduction of WAY (dashed line, thin). (в) – assessment of the intensity of dyskinesia in ALO AIM values. Note that DPAT reduced the power of gamma-oscillations in MCx and Vm, the coherence of oscillations between MCx and Vm, and eliminated dyskinesia, restoring beta frequency oscillations (30–36 Hz), and bradykinesia. While WAY restored gamma oscillatory activity and dyskinesia.

Download (448KB)
Indexing metadata
3. Fig. 2. High-frequency gamma oscillatory LFP activity in MCx, Vm of the thalamus and SNpr on the first and seventh days of levodopa administration. Columns in (а) represent the average total power of high-frequency gamma oscillations of the LFP MCx (middle), Vm (top), and SNpr (bottom). The bars in (б) represent the coherence values in the MCx–Vm (top) and MCx–SNpr (bottom) pairs on days 1 (white) and 7 (light gray) of levodopa priming. (в) – line graphs display ALO AIM scores on days 1 (open circles) and 7 (black squares) of priming. (г): line graphs represent the number of rotations in the cylinder on days 1 (open circles) and 7 (black squares). To construct graphs (а) and (б), 60-second epochs of LFP recordings were taken during walking before the administration of levodopa and six periods after the administration of levodopa, corresponding to the beginning (20 min), peak (60, 90 and 120 min) and end (150 and 180 min) dyskinesia. Note that the increase in the power and coherence of high-frequency LFP gamma activity and ALO AIM was greater on the 7th day than on the first day of levodopa administration. On (а) and (б) *difference in LFP power and coherence between days 1 and 7 of levodopa administration (p < 0.05); +the differences compared to the walking period in treadmills (p < 0.05). The dotted line in (б) indicates the threshold for the meaningful averaged coherence values. On (в) and (г) *difference in the ALO AIMs (p < 0.01) and the rotation score (p < 0.05) between LID1 and LID7.

Download (309KB)
Indexing metadata
4. Fig. 3. Changes in the frequencies of activity of neurons in the ventromedial nucleus of the thalamus during LID and the synchronization of their spikes with the MCx LFPs. (а) – oscillatory activity of LFP in MCx in 3 consecutive recordings before and after administration of levodopa and DPAT. Raw signals (2 s) are filtered in selected frequency ranges – beta (30–36 Hz) and gamma (80–120 Hz). LFP beta- and gamma-oscillations before levodopa administration (top inset); during the LID period (middle inset) and after DPAT administration (lower inset). (б) – changes in the frequencies of neuronal activity in 3 conditions at the population level. The left column represents changes in frequency during LID compared with walk before levodopa administration. The right column represents the frequency changes during transition from LID to DPAT. The color of the columns determines the direction of changes: increase (black), decrease (gray) or no change (light gray). (в) – frequency of neuronal activity (spike/s) before levodopa administration, during LID and after DPAT. (г–д) – synchronization of spikes with LFP in a motor neural network: (г) – average amplitude ratios of STWAs characterizing spike-LFP synchronization before levodopa administration, during LID and after DPAT administration; (д) – % of neurons having pronounced spike-LFP synchronization before levodopa administration, during LID and after DPAT administration. For (в), (г) and (д) two epochs (100 s each) are taken from the same identified neurons in three consecutive recordings – walking before levodopa administration (light gray bars), during LID (black bars) and after DPAT administration (gray bars). Values are presented as percentages or means ± SEM. # – significant differences with data obtained during walking before administration of levodopa, + – significant differences with data obtained after administration of DPAT.

Download (299KB)
Indexing metadata
5. Fig. 4. Changes in the frequencies of activity of cortical pyramidal neurons and the synchronization of their spikes with MCx LFP during LID. All designations in (а), (б), (в), (г) and (д) are the same as on Fig. 3.

Download (319KB)
Indexing metadata
6. Fig. 5. Changes in the activity frequencies of SNpr neurons and the synchronization of their spikes with the MCx and Vm LFP during LID. All designations in (а), (б), (в), (г) and (д) are the same as on Fig. 3. Inserts in Fig. 5 (г) – STWAs values for spike-LFP synchronization with Vm LFP; in Fig. 5д – % of SNpr neurons synchronized with Vm LFP.

Download (308KB)
Indexing metadata

Copyright (c) 2024 Russian Academy of Sciences