6 Jun

Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson's Disease

Assessing imaging biomarker in the prodromal and early phases of Parkinson's disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation will gain significance.

Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system.

Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD.

6 Jun

Prenatal exposure to alcohol and its impact on reward processing and substance use in adulthood

Heavy maternal alcohol drinking during pregnancy has been associated with altered neurodevelopment in the child but the effects of low-dose alcohol drinking are less clear and any potential safe level of alcohol use during pregnancy is not known. We evaluated the effects of prenatal alcohol on reward-related behavior and substance use in young adulthood and the potential sex differences therein. Participants were members of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort who participated in its neuroimaging follow-up in young adulthood. A total of 191 participants (28-30 years; 51% men) had complete data on prenatal exposure to alcohol, current substance use, and fMRI data from young adulthood. Maternal alcohol drinking was assessed during mid-pregnancy and pre-conception. Brain response to reward anticipation and reward feedback was measured using the Monetary Incentive Delay task and substance use in young adulthood was assessed using a self-report questionnaire. We showed that even a moderate exposure to alcohol in mid-pregnancy but not pre-conception was associated with robust effects on brain response to reward feedback (six frontal, one parietal, one temporal, and one occipital cluster) and with greater cannabis use in both men and women 30 years later. Moreover, mid-pregnancy but not pre-conception exposure to alcohol was associated with greater cannabis use in young adulthood and these effects were independent of maternal education and maternal depression during pregnancy.

15 May

Timing matters for accurate identification of the epileptogenic zone

Objective: Interictal biomarkers of the epileptogenic zone (EZ) and their use in machine learning models open promising avenues for improvement of epilepsy surgery evaluation. Currently, most studies restrict their analysis to short segments of intracranial EEG (iEEG).

Methods: We used 2381 hours of iEEG data from 25 patients to systematically select 5-minute segments across various interictal conditions. Then, we tested machine learning models for EZ localization using iEEG features calculated within these individual segments or across them and evaluated the performance by the area under the precision-recall curve (PRAUC).

Results: On average, models achieved a score of 0.421 (the result of the chance classifier was 0.062). However, the PRAUC varied significantly across the segments (0.323-0.493). Overall, NREM sleep achieved the highest scores, with the best results of 0.493 in N2. When using data from all segments, the model performed significantly better than single segments, except NREM sleep segments.

Conclusions: The model based on a short segment of iEEG recording can achieve similar results as a model based on prolonged recordings. The analyzed segment should, however, be carefully and systematically selected, preferably from NREM sleep.

24 Apr

Inhibition of CD40L with Frexalimab in Multiple Sclerosis

Background: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis.

Methods: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab.

Results: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. 

17 Apr

Striato-cortical functional connectivity changes in mild cognitive impairment with Lewy bodies

Background: Functional connectivity changes in clinically overt neurodegenerative diseases such as dementia with Lewy bodies have been described, but studies on connectivity changes in the pre-dementia phase are scarce.

Objectives: We concentrated on evaluating striato-cortical functional connectivity differences between patients with Mild Cognitive Impairment with Lewy bodies and healthy controls and on assessing the relation to cognition.

Methods: Altogether, we enrolled 77 participants (47 patients, of which 35 met all the inclusion criteria for the final analysis, and 30 age- and gender-matched healthy controls, of which 28 met all the inclusion criteria for the final analysis) to study the seed-based connectivity of the dorsal, middle, and ventral striatum. We assessed correlations between functional connectivity in the regions of between-group differences and neuropsychological scores of interest (visuospatial and executive domains z-scores).

Results: Subjects with Mild Cognitive Impairment with Lewy Bodies, as compared to healthy controls, showed increased connectivity from the dorsal part of the striatum particularly to the bilateral anterior part of the temporal cortex with an association with executive functions.

17 Apr

Blind deconvolution decreases requirements on temporal resolution of DCE-MRI: Application to 2nd generation pharmacokinetic modeling

Purpose: Dynamic Contrast-Enhanced (DCE) MRI with 2nd generation pharmacokinetic models provides estimates of plasma flow and permeability surface-area product in contrast to the broadly used 1st generation models (e.g. the Tofts models). However, the use of 2nd generation models requires higher frequency with which the dynamic images are acquired (around 1.5 s per image). Blind deconvolution can decrease the demands on temporal resolution as shown previously for one of the 1st generation models. Here, the temporal-resolution requirements achievable for blind deconvolution with a 2nd generation model are studied.

Methods: The 2nd generation model is formulated as the distributed-capillary adiabatic-tissue-homogeneity (DCATH) model. Blind deconvolution is based on Parker's model of the arterial input function. The accuracy and precision of the estimated arterial input functions and the perfusion parameters is evaluated on synthetic and real clinical datasets with different levels of the temporal resolution.

Results: The estimated arterial input functions remained unchanged from their reference high-temporal-resolution estimates (obtained with the sampling interval around 1 s) when increasing the sampling interval up to about 5 s for synthetic data and up to 3.6-4.8 s for real data. 

17 Apr

Weak coupling of neurons enables very high-frequency and ultra-fast oscillations through the interplay of synchronized phase shifts

Recently, in the past decade, high-frequency oscillations (HFOs), very high-frequency oscillations (VHFOs), and ultra-fast oscillations (UFOs) were reported in epileptic patients with drug-resistant epilepsy. However, to this day, the physiological origin of these events has yet to be understood. Our study establishes a mathematical framework based on bifurcation theory for investigating the occurrence of VHFOs and UFOs in depth EEG signals of patients with focal epilepsy, focusing on the potential role of reduced connection strength between neurons in an epileptic focus. We demonstrate that synchronization of a weakly coupled network can generate very and ultra high-frequency signals detectable by nearby microelectrodes. In particular, we show that a bistability region enables the persistence of phase-shift synchronized clusters of neurons. This phenomenon is observed for different hippocampal neuron models, including Morris-Lecar, Destexhe-Paré, and an interneuron model. The mechanism seems to be robust for small coupling, and it also persists with random noise affecting the external current. Our findings suggest that weakened neuronal connections could contribute to the production of oscillations with frequencies above 1000 Hz, which could advance our understanding of epilepsy pathology and potentially improve treatment strategies. 

17 Apr

Short-term effects of transcranial direct current stimulation on motor speech in Parkinson's disease: a pilot study

Introduction: Hypokinetic dysarthria (HD) is a common motor speech symptom of Parkinson's disease (PD) which does not respond well to PD treatments. We investigated short-term effects of transcranial direct current stimulation (tDCS) on HD in PD using acoustic analysis of speech. Based on our previous studies we focused on stimulation of the right superior temporal gyrus (STG) - an auditory feedback area.

Methods: In 14 PD patients with HD, we applied anodal, cathodal and sham tDCS to the right STG using a cross-over design. A protocol consisting of speech tasks was performed prior to and immediately after each stimulation session. Linear mixed models were used for the evaluation of the effects of each stimulation condition on the relative change of acoustic parameters. We also performed a simulation of the mean electric field induced by tDCS.

Results: Linear mixed model showed a statistically significant effect of the stimulation condition on the relative change of median duration of silences longer than 50 ms (p = 0.015). The relative change after the anodal stimulation (mean = -5.9) was significantly lower as compared to the relative change after the sham stimulation (mean = 12.8), p = 0.014.