Parkinson's disease (PD) is preceded by a prolonged prodromal phase during which subtle cognitive and behavioral alterations emerge before overt motor symptoms. Experimental models reproducing these early stages are essential for understanding disease mechanisms and identifying early biomarkers. In this study, we performed the multimodal characterization of two toxin-based rat models of prodromal PD induced by bilateral nigral injections of 6-hydroxydopamine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Animals were assessed over 2 months using behavioral testing, functional magnetic resonance imaging (fMRI), and histologic analyses. Both models produced moderate, heterogeneous dopaminergic degeneration within the nigrostriatal pathway, consistent with prodromal stages. Motor impairments remained limited whereas robust attentional deficits were detected. fMRI revealed region-specific connectivity alterations aligned with behavioral impairments, suggesting early circuit-level dysfunction despite the absence of widespread network disruption. To address inter-individual variability, a clinically inspired staging framework was implemented based on dopaminergic lesion severity, attentional performance, and sensorimotor impairment. This phenotype-based classification stratified animals into sham, asymptomatic, early, and advanced stages independent of the toxin used. Together, these findings demonstrate that moderate bilateral dopaminergic degeneration produces early cognitive and circuit-level alterations, and highlight the value of multimodal phenotyping for studying prodromal PD and identifying early functional biomarkers.

BACKGROUND:Levodopa is the gold-standard therapy for motor symptoms in Parkinson's disease (PD). However, individual responses vary substantially among patients, and the biological mechanisms underlying this heterogeneity remain incompletely understood. OBJECTIVE:This study aimed to investigate the neural substrates associated with variability in levodopa responsiveness using multimodal magnetic resonance imaging (MRI). METHODS:Data were retrieved for this ancillary study from the PREDISTIM cohort, that aims to define predictors for deep brain stimulation outcomes. Patients were stratified through a data-driven clustering approach according to their dopa responsiveness and disease duration. MRI analyses included T1-weighted imaging and multi-echo fast gradient-echo sequences. Structural and iron-sensitive MRI measures were compared across clusters within key regions. RESULTS:A three-phenotype response pattern previously reported in the Parkinson's Progression Markers Initiative dataset was identified, extending beyond the conventional binary classification of good (C3) and poor responders (C1). An intermediate phenotype (C2) showed preserved pharmacological responsiveness despite longer disease duration. Structural MRI revealed significant putaminal atrophy in this cluster. In contrast, patients in cluster C1 exhibited reduced grey matter in the temporo-parietal operculum and inferior frontal cortex as well as an increased iron deposition in the substantia nigra and globus pallidus internus. CONCLUSION:These findings, that should be validated in other populations, suggest that variability in levodopa responsiveness reflects distinct neurobiological substrates rather than a simple continuum of disease severity. Integrating markers of structural degeneration and iron-related microenvironmental changes within basal ganglia-cortical circuits may improve phenotypic stratification and support the development of precision therapeutic strategies in PD.

The study aims to establish histo-radiological correlates in a bilateral 6-OHDA rat model of Parkinson's disease. A total of 37 Wistar rats were included, distributed into a model group (n = 19) that received injection of low doses of the toxin into the substantia nigra (SN) while the remaining animals, considered as control group received saline injections. A protocol lasting 2 months was setup including motor and sensorimotor evaluations, multi-sequence magnetic resonance imaging with T2w images, echo gradient imaging (T2*w) used to compute R2* maps and resting-state functional imaging. Lastly, after animals' sacrifice, dopaminergic degeneration as well as ferritin quantification were done. While behavioural analyses did not reveal significant differences between the groups, dopaminergic degeneration showed neurons loss estimated at 53 % in the SN and 45 % in the striatum in the 6-OHDA group. In the same way, ferritin quantification showed an increase in this group. In terms of imaging, the results showed no structural changes but an increase of R2* values in the substantia nigra as well as an increase in functional connectivity involving this structure in the 6-OHDA group. The association analyses showed negative correlation between the dopaminergic neurons in the SN and the corresponding R2* values as well as with the functional connectivity involving this structure. Values from R2* maps were also positively correlated with ferritin quantification in the SN. Taken all together, the experimental design as well as the obtained results suggest that SN R2* and functional connectivity are potential biomarkers of early disease stages.

After successful applications in the oncology field to provide new in vivo diagnosis and prognosis imaging features, texture analysis and more generally radiomics were also reported as having the potential to provide markers of different neurodegenerative processes. Indeed, in neurodegenerative diseases such as Parkinson's disease (PD), there is a need for neuroprotective therapies, the development of which will be fundamentally aided by imaging biomarkers capable of inferring tissue changes such as loss of neurons in the nigro-striatal pathway or alpha synuclein aggregates that characterize PD. In this study, we therefore sought to decipher the relationship between signal changes measured using brain MRI texture features and histological changes in preclinical models of this disease. Three rodent models were used: two toxin-based models, one involving 6-hydroxydopamine injection and the other using methyl-phenyl-tetrahydropyridine, and a third model based on alpha-synuclein overexpression. Animals had MR imaging with a T2w sequence evaluation and were sacrificed for histological analyses of the brains. Texture features were measured in different brain structures. The association analyses revealed significant correlations between the imaging features measured in the substantia nigra and the striatum with dopaminergic degeneration, as well as significant correlations between texture features in key structures (substantia nigra, striatum, thalamus, hippocampus and associative and cingulate cortices), and alpha-synuclein quantified in these regions. These preliminary results suggest that MR signal changes captured using texture features reflect the underlying tissue changes occurring in the brain such as neuronal death and proteins accumulation.

Background and objectives: Focal epilepsies disrupt long-range networks with seizure recurrence driving both regional and global alterations in connectivity networks. While prior studies have focused on the interictal consequences, limited data exist on the direct aftermath of focal seizures. We hypothesize that mesial temporal lobe seizures lead to enduring cortical disorganization. The aim was to assess the effects of a mesial temporal lobe seizure on cortical activity and understand how the side of seizure onset influences these consequences. Methods: In this retrospective study, high-resolution EEG of patients with mesial temporal lobe epilepsy (mTLE) were analyzed. Groups of patients were identified based on the side of seizure onset. We compared relative powers in different frequency bands between interictal (prior to the seizure) and late postictal (one hour following the seizure) periods. Network-based statistics were employed to compare functional connectivity at source level between periods. Results: Twenty-three patients were included (13 left and 10 right mesial temporal lobe seizures). In patients with left mTLE, we observed a post-seizure increase in the relative spectral power in the delta band (p = 0.001) and a decrease in the relative spectral power in the alpha band (p = 0.013) over the left temporofrontal regions. We isolated a subnetwork that presented a decrease in connectivity strength in alpha band, primarily involving long-range left hemisphere connections (p = 0.042). We also identified a subnetwork that presented a decrease in connectivity strength in theta band, primarily involving interhemispheric connections (p = 0.039). No significant post-seizure changes were found in patients with right mTLE. Discussion: Left mesial temporal lobe seizures appear to be associated with lasting and widespread disorganization of cortical activity. We propose that the postictal state is associated with a prolonged functional deafferentation of the affected region in patients with left mTLE. This leads to a widespread disorganization of the functional networks, which may be associated with cognitive impairments and promote the progression of epilepsy. Further studies are required to fully understand the functional repercussions.

Introduction L’évolution de l’électroencéphalogramme continu (EEGc) à la levée de sédation des états de mal épileptiques généralisés convulsifs (EMEGC) semble hétérogène en pratique clinique et pourrait constituer un marqueur pronostique. Objectifs Notre objectif était de décrire l’évolution qualitative et quantitative de l’EEG à la levée de sédation des EMEGC et de déterminer des profils évolutifs distincts. Méthodes Étude rétrospective monocentrique. Patients admis pour un EMECG sédatés par propofol avec EEGc à la levée de sédation. Caractérisation de l’évolution de paramètres qualitatifs (fréquence et réactivité) et quantitatifs (puissance spectrale et entropie). Identification de clusters par méthode k-means. Description de l’évolution des paramètres et du devenir fonctionnel (score de Rankin à la sortie et à 3 mois) selon les groupes identifiés. Résultats L’arrêt du propofol s’associait à une augmentation de la fréquence, réactivité et complexité du signal. Seulement 45 % des patients avait récupéré un rythme alpha. Deux groupes ont pu être identifiés. Un premier (n=5, 25 %) retrouvant une récupération du rythme alpha, associé à une entropie et une puissance dans les bandes alpha/thêta/bêta supérieures au deuxième groupe (n=15, 75 %). Ce dernier comportait une puissance supérieure en bande delta. Il n’y avait pas de différence de pronostic fonctionnel. Discussion L’évolution de l’EEGc à l’arrêt du propofol des EMEGC est hétérogène. Nous avons isolé deux groupes : un dont le tracé se normalise à l’arrêt du propofol et l’autre chez qui persiste une activité anormale, lente et moins complexe. Ces anomalies sont présentes avant l’arrêt du propofol et pourraient refléter une désorganisation de l’activité corticale par l’EMEGC et/ou la sédation. Conclusion Plus de la moitié des patients ne récupèrent pas une activité normale. Deux profils EEG semblent émerger et pourraient refléter l’impact de l’EMEGC et/ou de la sédation sur l’activité cérébrale.

Objective: The study aimed to address the challenge of early assessment of neonatal hypoxic-ischemic encephalopathy (HIE) severity to identify candidates for therapeutic hypothermia (TH). The objective was to develop an automated classification model for neonatal EEGs, enabling accurate HIE severity assessment 24/7. Methods: EEGs recorded within 6 h of life after perinatal anoxia were visually graded into 3 severity groups (HIE French Classification) and quantified using 6 qEEG markers measuring amplitude, continuity and frequency content. Machine learning models were developed on a dataset of 90 EEGs and validated on an independent dataset of 60 EEGs. Results: The selected model achieved an overall accuracy of 80.6% in the development phase and 80% in the validation phase. Notably, the model accurately identified 28 out of 30 children for whom TH was indicated after visual EEG analysis, with only 2 cases (moderate EEG abnormalities) not recommended for cooling. Conclusions: The combination of clinically relevant qEEG markers led to the development of an effective automated EEG classification model, particularly suited for the post-anoxic latency phase. This model successfully discriminated neonates requiring TH. Significance: The proposed model has potential as a bedside clinical decision support tool for TH. (c) 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

This study aimed to compare the diagnostic performance of visual assessment of electroencephalography (EEG) using the Grand Total EEG (GTE) score and quantitative EEG (QEEG) using spectral analysis in the context of cognitive impairment. This was a retrospective study of patients with mild cognitive impairment, with (MCI+V) or without (MCI) vascular dysfunction, and patients with dementia including Alzheimer's disease, Lewy Body Dementia and vascular dementia. The results showed that the GTE is a simple scoring system with some potential applications, but limited ability to distinguish between dementia subtypes, while spectral analysis appeared to be a powerful tool, but its clinical development requires the use of artificial intelligence tools.

Background Freezing of gait (FoG) is among the most disabling gait disorders of Parkinson's disease. The full understanding of its mechanisms requires a network study approach. So far, FoG was mainly studied using magnetic resonance imaging, and especially using the resting state functional sequence, which does not completely reflect the brain actual modifications. Objective This study aims to investigate metabolic networks using position emission tomography (PET) imaging. Exploration after a rest or gait session combined with a delayed tracer's uptake are assumed to reflect the actual metabolism modifications. Methods Twenty-six patients in the off-drug state underwent two PET imaging sessions using [18F]- fluorodeoxyglucose, the first after 30 min of rest (rest condition) and the second after 30 min of real gait (gait condition). Twelve patients presented real FoG during cerebral glucose uptake. Brain connectivity matrices were measured for each group and condition, and then compared. Results In the rest condition, the freezing group showed globally reduced metabolic connectivity between brain regions compared to the non-freezing group. During gait, enhanced connectivity was observed in the cerebellum, cerebello-cortical loops and parieto-frontal regions, with high recruitment of the visual cortex in the freezing group. However, connectivity inside cerebellar networks remained lower in the freezing group than in the non-freezing group, while occipito-frontal connectivity was higher in the freezing group. Conclusions Studying real freezing of gait in a vertical position emphasized the role of the visual cortex and cerebellum in gait problems.

Parkinson's disease (PD) is primarily characterized by three histological hallmarks: dopaminergic neuronal degeneration, α-synuclein accumulation and iron deposition. Over the last years, neuroimaging, particularly magnetic resonance imaging (MRI) has provided invaluable insights into the mechanisms underlying the disease. However, no imaging method has yet been able to translate α-synuclein protein accumulation and spreading. Amongst the animal models mimicking the disease, the α-synuclein rat, generated through the injection of human α-synuclein, has been characterized in terms of behavioural and histological aspects but not thoroughly explored in MRI. The aim of this study is, therefore, to identify the radiological signature from several MRI sequences, while controlling for histological and behavioural characteristics. Rats were assessed for motor and cognitive functions over a 4-month period. During this time, three MRI sessions, including both morphological and functional sequences, were conducted. Histological studies evaluated the three main hallmarks of PD. The progressive dopaminergic neurodegeneration and the spread of human α-synuclein corresponded to the level of sensorimotor, attentional and learning deficits observed in this PD model. MRI analyses showed progressive structural abnormalities in the midbrain, diencephalon and several cortical structures, as well as a pattern of hyperconnectivity in the basal ganglia and cortical networks. The regions affected in imaging demonstrated the highest load of human α-synuclein. This model's structural and functional MRI changes could serve as indirect indicators of α-synuclein accumulation and its association with impaired non-motor functions.

Background Freezing of gait (FoG) is among the most disabling gait disorders of Parkinson's disease. The full understanding of its mechanisms requires a network study approach. So far, FoG was mainly studied using magnetic resonance imaging, and especially using the resting state functional sequence, which does not completely reflect the brain actual modifications. Objective This study aims to investigate metabolic networks using position emission tomography (PET) imaging. Exploration after a rest or gait session combined with a delayed tracer's uptake are assumed to reflect the actual metabolism modifications. Methods Twenty-six patients in the off-drug state underwent two PET imaging sessions using [18F]- fluorodeoxyglucose, the first after 30 min of rest (rest condition) and the second after 30 min of real gait (gait condition). Twelve patients presented real FoG during cerebral glucose uptake. Brain connectivity matrices were measured for each group and condition, and then compared. Results In the rest condition, the freezing group showed globally reduced metabolic connectivity between brain regions compared to the non-freezing group. During gait, enhanced connectivity was observed in the cerebellum, cerebello-cortical loops and parieto-frontal regions, with high recruitment of the visual cortex in the freezing group. However, connectivity inside cerebellar networks remained lower in the freezing group than in the non-freezing group, while occipito-frontal connectivity was higher in the freezing group. Conclusions Studying real freezing of gait in a vertical position emphasized the role of the visual cortex and cerebellum in gait problems.

Objective: An executive dysfunction is supposed to contribute to freezing of gait (FoG) in Parkinson's dis-ease. We aimed to investigate at a behavioral and cortical levels whether an attentional load (particularly, a conflicting situation) can specifically impact preparation and execution phases of step initiation in parkinsonian patients with FoG.Methods: Fifteen patients with FoG, 16 without and 15 controls performed an adapted version of the Attention Network Test, with step initiation as response instead of the standard manual keypress. Kinetic and kinematic features of gait initiation as well as high-resolution electroencephalography were recorded during the task. Results: Patients with FoG presented an impaired executive control. Step execution time was longer in parkinsonian patients. However, the executive control effect on step execution time was not different between all groups. Compared to patients, controls showed a shorter step initiation-locked alpha desyn-chronization, and an earlier, more intense and shorter beta desynchronization over the sensorimotor cor-tex. Even though controls were faster, the induced alpha and beta activity associated with the effect of executive control didn't differ between patients and controls.Conclusions: Tasks of conflict resolution lead to a comparable alteration of step initiation and its under-lying brain activity in all groups. Links between executive control, gait initiation and FoG seem more complex than expected.Significance: This study questions the cognitive hypothesis in the pathophysiology of freezing of gait. Executive dysfunction is associated with FoG but is not the main causal mechanism since the interaction between attention and motor preparation didn't provoke FoG.& COPY; 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Electroencephalography's (EEG) sensitivity in discriminating dementia syndromes remains unclear. This study aimed to investigate EEG markers in patients with major cognitive disorders. The studied population included 4 groups of patients: Alzheimer's disease with associated vascular lesions, Alzheimer's disease without vascular lesions (AD-V), Lewy body disease and vascular dementia (VaD); and completed by a control group composed by cognitively unimpaired patients. EEGs were analysed quantitatively using spectral analysis, functional connectivity and micro-states. By comparison to the controls, expected slowing and alterations of functional connectivity were detected in patients with dementia. Among these patients, an overall increase in power in the alpha band was observed in the VaD group, mainly when compared to the 2 AD groups, while the Alzheimer's disease without vascular lesions group exhibited increased power in the beta-2 band and higher functional connectivity in the same frequency band. Micro-state analyses revealed differences in temporal dynamics for the VaD group. A number of EEG modifications reported as markers of some syndromes were found, but others were not reproduced.

Cryogenic magnetoencephalography (MEG) enhances the presurgical assessment of refractory focal epilepsy (RFE). Optically pumped magnetometers (OPMs) are cryogen-free sensors that enable on-scalp MEG recordings. Here, we investigate the application of tri-axial OPMs [87Rb (Rb-OPM) and 4He gas (He-OPM)] for the detection of interictal epileptiform discharges (IEDs). IEDs were recorded simultaneously with 4 tri-axial Rb- and 4 tri-axial He-OPMs in a child with RFE. IEDs were identified visually, isolated from magnetic background noise using independent component analysis (ICA) and were studied following their optimal magnetic field orientation thanks to virtual sensors. Most IEDs (>1,000) were detectable by both He- and Rb-OPM recordings. IEDs were isolated by ICA and the resulting magnetic field oriented mostly tangential to the scalp in Rb-OPMs and radial in He-OPMs. Likely due to differences in sensor locations, the IED amplitude was higher with Rb-OPMs. This case study shows comparable ability of Rb-OPMs and He-OPMs to detect IEDs and the substantial benefits of triaxial OPMs to detect IEDs from different sensor locations. Tri-axial OPMs allow to maximize spatial brain sampling for IEDs detection with a limited number of sensors.