Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 7;148(7):2299-2305.
doi: 10.1093/brain/awaf103.

Modulating inhibitory synaptic plasticity to restore basal ganglia dynamics in Parkinson's disease

Kiah A Spencer  1   2 , Alexandra Boogers  1   3   4 , Srdjan Sumarac  1   2 , David B J Crompton  1   5 , Leon A Steiner  1   6 , Luka Zivkovic  1   2 , Yijinmide Buren  1   2 , Alexandre Boutet  1   7   8 , Andres M Lozano  1   8   9   10   11 , Suneil K Kalia  1   8   9   10   12 , William D Hutchison  1   5   8   9 , Alfonso Fasano  1   3   4   8   11 , Luka Milosevic  1   2   8   11   12
Affiliations

Modulating inhibitory synaptic plasticity to restore basal ganglia dynamics in Parkinson's disease

Kiah A Spencer et al. Brain. .

Abstract

Parkinson's disease is characterized, in part, by hypoactivity of direct pathway inhibitory projections from striatum to the globus pallidus internus (GPi) and indirect pathway inhibitory projections from globus pallidus externus (GPe) to the subthalamic nucleus (STN). In people with Parkinson's disease (n = 32), we explored the potential use of intracranial stimulation for eliciting long-term potentiation (LTP) of these underactive pathways to produce improvement of symptoms that persist beyond stimulation cessation. During GPi deep brain stimulation (DBS) surgery, we found strong evidence (P < 0.05; BF10 > 10) of increased amplitudes of hand movements and striato-GPi evoked potentials before versus after high-frequency microstimulation. In a small sample of outpatients with sensing-enabled GPi-DBS, we found anecdotal evidence (P < 0.10; BF10 > 1) of improved hand movements and attenuated beta frequency oscillations. In STN, enduring behavioural effects, potentiation of GPe-STN projections (intraoperative), and decreases to beta oscillations (extraoperative) were not observed. Our findings support that LTP-like effects in GPi may produce motor improvements that extend beyond stimulation cessation, while the lack of effects in STN suggests the need for optimizing stimulation paradigms for effective LTP induction. These findings nevertheless highlight the potential of LTP-based strategies for sustained therapeutic benefits, which may be useful for mitigating DBS side-effects and optimizing battery usage.

Keywords: Parkinson’s disease; basal ganglia; deep brain stimulation; globus pallidus internus; subthalamic nucleus; synaptic plasticity.

PubMed Disclaimer

Conflict of interest statement

L.M. and W.D.H. hold intellectual property related to predicting and modelling neuronal responses to DBS (patent publication number: 20220152396; application number: 17/527,042). All other authors declare no competing interests related to this work.

Figures

Figure 1
Figure 1
Potentiation of inhibitory projections within the basal ganglia circuitry. In Parkinson's disease, inhibitory striato-GPi (top; direct pathway) and GPe-STN (bottom; indirect pathway) projections are underactive. We propose that these fibre pathways can be potentiated by high-frequency GPi- or STN-DBS, respectively, which is expected to lead to improvements in motor symptoms that persist beyond stimulation cessation. GABA = blue; glutamate = red. DBS = deep brain stimulation; GPe = globus pallidus externus; GPi = globus pallidus internus; STN = subthalamic nucleus.
Figure 2
Figure 2
Intraoperative results. Strong evidence of increases in (A–C) evoked field potential (fEP) amplitude and (D–F) hand pronation-supination amplitude were found after a train of high-frequency microstimulation (40 s; 100 Hz; 100 μA; 150 μs pulse width) in GPi, but not (G–L) STN. GPi = globus pallidus internus; HFS = high frequency stimulation; STN = subthalamic nucleus.
Figure 3
Figure 3
Extraoperative results. Anecdotal evidence of (A–C) decreases in local field potential (LFP) beta power and (D–F) increases hand pronation-supination amplitude were found after a train of high-frequency stimulation (40 s; 125 Hz; 2 mA; 60 µs pulse width) in GPi, but not (G–L) STN (40 s; 180 Hz; 2 mA; 60 µs pulse width). GPi = globus pallidus internus; HFS = high frequency stimulation; PSD = power spectral density; STN = subthalamic nucleus.
See this image and copyright information in PMC

References

    1. McGregor MM, Nelson AB. Circuit mechanisms of Parkinson’s disease. Neuron. 2019;101:1042–1056. - PubMed
    1. Follett KA, Weaver FM, Stern M, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2010;362:2077–2091. - PubMed
    1. Bolam JP, Hanley JJ, Booth PAC, Bevan MD. Synaptic organisation of the basal ganglia. J Anat. 2000;196:527–542. - PMC - PubMed
    1. Milosevic L, Gramer R, Kim TH, et al. Modulation of inhibitory plasticity in basal ganglia output nuclei of patients with Parkinson’s disease. Neurobiol Dis. 2019;124:46–56. - PubMed
    1. Precht W, Yoshida M. Blockage of caudate-evoked inhibition of neurons in the substantia nigra by picrotoxin. Brain Res. 1971;32:229–233. - PubMed