Poster No:
302
Submission Type:
Abstract Submission
Authors:
Gabriel Costa1, Marjorie Metzger2, Stefan Dukic3, Orla Hardiman4, Bahman Nasseroleslami4
Institutions:
1Trinity Biomedical Sciences Institute, Coimbra, Portugal, 2Trinity College Dublin, Dublin, Dublin, 3UMC, Utrecht, Netherlands, 4Trinity College Dublin, Dublin, Ireland
First Author:
Gabriel Costa
Trinity Biomedical Sciences Institute
Coimbra, Portugal
Co-Author(s):
Introduction:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting primarily motor neurons, first described more than a century ago. While degeneration manifests mainly in upper and lower motor neurons there is a significant frontotemporal circuit involvement. It remains a disease with poor prognosis and no effective treatment. ALS displays clinical heterogeneity, and despite its predictable evolution the pathophysiology and triggers of the disease remain unknown. Evidence of impaired neuronal activity and network dysfunction has been identified in the spectral content of resting-state EEG in ALS when compared to healthy controls. More importantly, these EEG abnormalities have been shown to correlate with structural changes and clinical manifestations in ALS [1-3]. We have previously spatially localized this impaired neuroelectric activity, but the identity of the neuronal population and circuits affected remains unknown.
Here we aim to characterize the underlying molecular and cellular features of the brain areas where these early EEG biomarkers of ALS manifest. Using source localization of high-density resting-state EEG, we have spatially correlated spectral differences between healthy controls and ALS patients with normative mappings of neurotransmitter systems.
Methods:
We recorded high-density resting-state EEG from 94 individuals with ALS and 81 healthy controls. The time-series of 90 anatomically distinct brain regions (Automatic Anatomical Labelling, AAL) were obtained using LCMV beamformer for source localization in the time domain. Normalized spectral power was obtained for each region for the delta (2-4 Hz), theta (5-7 Hz), alpha (8-13 Hz), beta (14-30 Hz), low-gamma (31-47 Hz) and high-gamma (53-97 Hz) bands. Differences between controls and ALS patients were estimated as t-values which were correlated with several neurotransmitter brain mappings using a novel Python toolbox, neuromaps [4].
Results:
We had previously described a significant decrease in spectral power in the alpha and beta frequency bands in ALS patients [2]. A significant correlation between alpha power differences was found for the density of 5-HT1a and 5-HT2a serotonin receptors (Spearman correlation, ρ = 0.32, FDR-adjusted p < 0.05; ρ = 0.39, FDR-adjusted p < 0.01, respectively), while beta power differences show significant correlation with 5-HT1a and with the serotonin transporter 5-HTT (ρ = 0.50, FDR-adjusted p < 0.001; ρ = 0.46, FDR-adjusted p < 0.001, respectively). These receptors correspond mainly to presynaptic serotonin receptors that exert inhibitory feedback and postsynaptic receptors that can modulate motor neuron excitation. Moreover, the strong correlation with the 5-HTT/SERT serotonin transporter suggests that the spectral differences found in the ALS EEG might arise from an impairment of the dense innervations of the serotonergic system arising from the brainstem. We have further identified that areas with reduced beta power also showed a correlation with the density of dopamine receptors D1 and D2 (ρ = 0.38, FDR-adjusted p < 0.001; ρ = 0.44, FDR-adjusted p < 0.001, respectively), suggesting that the affected areas might be involved in the interplay between serotonergic and dopaminergic systems.
Conclusions:
Our study provides compelling evidence that the altered EEG signals can be a consequence of serotonergic dysfunction in ALS [5], which has been proposed as a cause of inhibitory motor control and excitotoxicity in ALS.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping 2
Keywords:
Degenerative Disease
Electroencephaolography (EEG)
Motor
Neurotransmitter
Seretonin
Source Localization
Other - Amyotrophic Lateral Sclerosis
1|2Indicates the priority used for review
Provide references using author date format
1. Dukic, S. et al (2022) Resting-state EEG reveals four subphenotypes of amyotrophic lateral sclerosis. Brain. 145(2):621-31. doi: 10.1093/brain/awab322.
2. Dukic, S. et al (2019) Patterned functional network disruption in amyotrophic lateral sclerosis. Human Brain Mapping. 40(16):4827-42. doi: 10.1002/hbm.24740.
3. Nasseroleslami, B. et al (2019) Characteristic Increases in EEG Connectivity Correlate With Changes of Structural MRI in Amyotrophic Lateral Sclerosis. Cerebral Cortex. 29(1):27-41. doi: 10.1093/cercor/bhx301.
4. Markello, R.D. et al (2022). neuromaps: structural and functional interpretation of brain maps. Nature Methods. doi: 10.1038/s41592-022-01625-w.
5. Vermeiren, Y. et al (2018) Serotonergic Dysfunction in Amyotrophic Lateral Sclerosis and Parkinson's Disease: Similar Mechanisms, Dissimilar Outcomes. Frontiers of Neuroscience. 12:185. doi: 10.3389/fnins.2018.00185.