The aperiodic exponent of subthalamic field potentials reflects excitation/inhibition balance in Parkinsonism
- University of Oxford, United Kingdom
- University Medical Center of the Johannes Gutenberg University Mainz, Germany
- King's College London, United Kingdom
- St. George's University, United Kingdom
- CNRS UMR5293, Université de Bordeaux, France
Abstract
Periodic features of neural time series data, such as local field potentials (LFP), are often quantified using power spectra. While the aperiodic exponent of spectra is typically disregarded, it is nevertheless modulated in a physiologically-relevant manner and was recently hypothesised to reflect excitation/inhibition (E/I) balance in neuronal populations. Here, we used a cross-species in vivo electrophysiological approach to test the E/I hypothesis in the context of experimental and idiopathic Parkinsonism. We demonstrate in dopamine-depleted rats that aperiodic exponents and power at 30-100 Hz in subthalamic nucleus (STN) LFPs reflect defined changes in basal ganglia network activity; higher aperiodic exponents tally with lower levels of STN neuron firing and a balance tipped towards inhibition. Using STN-LFPs recorded from awake Parkinson's patients, we show that higher exponents accompany dopaminergic medication and deep brain stimulation (DBS) of STN, consistent with untreated Parkinson's manifesting as reduced inhibition and hyperactivity of STN. These results suggest that the aperiodic exponent of STN-LFPs in Parkinsonism reflects E/I balance, and might be a candidate biomarker for adaptive DBS.
Data availability
The code was uploaded directly to eLife and in addition can be found here https://doi.org/10.5287/bodleian:rJ7jyjX97. The animal data (Mallet et al., 2022) used for this project is available at the Medical Research Council Brain Networks Dynamics Unit (MRC BNDU) Data Sharing Platform at the University of Oxford https://data.mrc.ox.ac.uk/stn-rat and DOI: https://doi.org/10.5287/bodleian:wx6D7oenk. The human data (Wiest et al., 2022) is also available at the MRC BNDU Data Sharing Platform https://data.mrc.ox.ac.uk/stn-lfp-on-off-and-dbs and DOI: https://doi.org/10.5287/bodleian:mzJ7YwXvo.
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Wideband recordings from silicon probes in the subthalamic nucleus of 6-OHDA hemi-lesioned rats during anaesthesiaOxford University Research Archive, doi:10.5287/bodleian:wx6D7oenk.
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STN local field potential recordings from awake patients with Parkinson's, ON and OFF meds, and during 130 Hz DBSOxford University Research Archive, doi:10.5287/bodleian:mzJ7YwXvo.
Article and author information
Author details
Muthuraman Muthuraman
Funding
Medical Research Council (MC_UU_00003/2)
- Huiling Tan
Medical Research Council (MC_UU_00003/5)
- Peter J Magill
Medical Research Council (MC_UU_00003/6)
- Andrew Sharott
National Institute for Health Research Oxford Biomedical Research Centre
- Huiling Tan
Rosetrees Trust
- Huiling Tan
Parkinson's UK (G-0806)
- Peter J Magill
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Experiments were performed on adult male Sprague Dawley rats (Charles River), and were conducted in accordance with the Animals (Scientific Procedures) Act, 1986 (UK) and the provisions of the Society for Neuroscience Policies on the Use of Animals in Neuroscience Research. Animal data that was analysed in this paper has been generated under the project licence numbers 30/2131 and 30/2629. All details on the 6-OHDA lesion and electrophysiological recordings were published before (Mallet et al., 2008a).
Human subjects: This protocol was approved by the Health Research Authority UK, the National Research Ethics Service local Research Ethics Committee (IRAS: 46576) and the local ethics committee at the University of Mainz (837.208.17(11042)). Patients were recruited at St. George's University Hospital NHS Foundation Trust, London, King's College Hospital NHS Foundation Trust, London, and the University Medical Center Mainz. Written informed consent, and consent to publish, was obtained before surgery in line with the Declaration of the Principles of Helsinki. We analysed data from 24 patients from these 3 centres.
Copyright
© 2023, Wiest et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The aperiodic exponent of subthalamic field potentials reflects excitation/inhibition balance in Parkinsonism
eLife 12:e82467.
https://doi.org/10.7554/eLife.82467
Further reading
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Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma, and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles in mice. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01–0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep, compared to that during wakefulness. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by Htr1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.
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The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models of familial Parkinsonism and conducted single-cell RNA sequencing on young brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells, and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinson’s disease patients confirms these findings. Indeed, the disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling in Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Hence, our research uncovers that one of the earliest indicators of disease in five different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons and this contributes to the development of hyposmia. Furthermore, the shared pathways of synaptic failure in these cholinergic neurons ultimately contribute to dopaminergic dysfunction later in life.
