SDI-118, a novel procognitive SV2A modulator: First-in-human randomized controlled trial including PET/fMRI assessment of target engagement

Background: Current treatments for progressive neurodegenerative disorders characterized by cognitive impairment either have limited efficacy or are lacking altogether. SDI-118 is a small molecule which modulates the activity of synaptic vesicle glycoprotein 2A (SV2A) in the brain and shows cognitive enhancing effects in a range of animal models of cognitive deficit.Methods: This first-in-human study evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics of SDI-118 in single ascending oral doses up to 80 mg administered to 32 healthy male subjects. Brain target occupancy was measured in eight subjects using positron emission tomography with PET-ligand [11C]-UCB-J. Food effect was assessed in seven subjects. Mood state was regularly evaluated using standardized questionnaires, and resting state fMRI data were analyzed as exploratory objectives.Key Results: At all doses tested, SDI-118 was well tolerated and appeared safe. Adverse events were mainly dizziness, hypersomnia, and somnolence. All were mild in intensity and increased in frequency with increasing administered dose. No dose-limiting adverse reactions were observed at any dose. SDI-118 displayed a linear pharmacokinetic profile with no significant food effect. Brain penetration and target engagement were demonstrated by a dose-proportional SV2A occupancy.Conclusion: Single oral doses of SDI-118 up to 80 mg were very well tolerated in healthy male subjects. Dose-proportional SV2A occupancy in the brain was demonstrated with brain imaging. Adverse effects in humans mainly occurred in higher dose ranges, with high occupancy levels, and were all mild and self-limiting. These data support further clinical exploration of the compound in patients with cognitive disorders.Clinical Trial Registration:https://clinicaltrials.gov/, identifier NCT0548619

Brain correlates of single trial visual evoked potentials in migraine: more than meets the eye.

Background: Using conventional visual evoked potentials (VEPs), migraine patients were found to be hyperresponsive to visual stimulus. Considering that a significant portion of neuronal activity is lost for analysis in the averaging process of conventional VEPs, in this study we investigated visual evoked responses of migraine patients and healthy volunteers using a different approach: single trial analysis. This method permits to preserve all stimulus-induced neuronal activations, whether they are synchronized or not. In addition, we used MRI voxel-based morphometry to search for cortical regions where gray matter volume correlated with single trial (st) VEP amplitude. Finally, using resting-state functional MRI, we explored the connectivity between these regions. Results: stVEP amplitude was greater in episodic migraine patients than in healthy volunteers. Moreover, in migraine patients it correlated positively with gray matter volume of several brain areas likely involved in visual processing, mostly belonging to the ventral attention network. Finally, resting state functional connectivity corroborated the existence of functional interactions between these areas and helped delineating their directions. Conclusions: st-VEPs appear to be a reliable measure of cerebral responsiveness to visual stimuli. Mean st-VEP amplitude is higher in episodic migraine patients compared to controls. Visual hyper-responsiveness in migraine involves several functionally-interconnected brain regions, suggesting that it is the result of a complex multi-regional process coupled to stimulus driven attention systems rather than a localized alteration

Behavioral results.

<p><b>a.</b> Group mean RTs in compatible and incompatible trials showed the expected pattern with a PCE at ISI-0 followed by a NCE at ISI-100 and ISI-150. At ISI-200, the size of the NCE decreased and did not reach the level of significance anymore. At ISI-250, there was a tendency toward a PCE. <b>b.</b> Group mean compatibility effects (i.e. mean RT in incompatible trials – mean RT in compatible trials) across all ISIs. Vertical bars represent standard errors.</p

Sunlight irradiance and habituation of visual evoked potentials in migraine: The environment makes its mark

peer reviewedBackground Migraine is a complex multifactorial disease that arises from the interaction between a genetic predisposition and an enabling environment. Habituation is considered as a fundamental adaptive behaviour of the nervous system that is often impaired in migraine populations. Given that migraineurs are hypersensitive to light, and that light deprivation is able to induce functional changes in the visual cortex recognizable through visual evoked potentials habituation testing, we hypothesized that regional sunlight irradiance levels could influence the results of visual evoked potentials habituation studies performed in different locations worldwide. Methods We searched the literature for visual evoked potentials habituation studies comparing healthy volunteers and episodic migraine patients and correlated their results with levels of local solar radiation. Results After reviewing the literature, 26 studies involving 1291 participants matched our inclusion criteria. Deficient visual evoked potentials habituation in episodic migraine patients was reported in 19 studies. Mean yearly sunlight irradiance was significantly higher in locations of studies reporting deficient habituation. Correlation analyses suggested that visual evoked potentials habituation decreases with increasing sunlight irradiance in migraine without aura patients. Conclusion Results from this hypothesis generating analysis suggest that variations in sunlight irradiance may induce adaptive modifications in visual processing systems that could be reflected in visual evoked potentials habituation, and thus partially account for the difference in results between studies performed in geographically distant centers. Other causal factors such as genetic differences could also play a role, and therefore well-designed prospective trials are warranted

fMRI results for the conjunction analysis.

<p>Common activation in the left hemisphere between incongruent trials in the MI versus neutral trials in the MN context (blue) and incongruent trials in the MC versus neutral trials in the MC context (red) (statistical threshold at <i>p</i><.001 uncorrected for the present display). Bar graphs illustrate the mean parameter estimates for brain areas that emerged in the conjunction analysis (DLPFC, insula, and superior parietal cortex), and are displayed for the different item types (incongruent, congruent, and neutral) in the three contexts. Error bars represent standard errors.</p

General interference effect (incongruent vs. neutral in MI, MC, and MN context).

<p>L/R = left or right; x, y, z: coordinates (mm) in the stereotactic space defined by the Montreal Neurological Institute (MNI). This analysis was conducted with a <i>p</i> value <.05 FWE corrected.</p

Accuracy data (percentage of errors and no responses) in the MI, MC, and MN contexts for incongruent, congruent and neutral items.

<p><i>Note</i>: Numbers in parentheses correspond to standard deviations.</p

Interference effect (incongruent vs. neutral items) in MI, MC and MN contexts.

<p>L/R = left or right; x, y, z: coordinates (mm) in the stereotactic space defined by the Montreal Neurological Institute (MNI). This analysis was conducted with a <i>p</i> value <.05 FWE corrected.</p>a<p>P<.05 FWE corrected with SVC using a 10-mm sphere radius centered on the DLPFC’s MNI coordinates [−48 15 20] <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041513#pone.0041513-Roberts1" target="_blank">[22]</a>.</p

Comparison of incongruent trials in the MC and MI contexts with neutral trials in the MN context.

<p>L/R = left or right; x, y, z: coordinates (mm) in the stereotactic space defined by the Montreal Neurological Institute (MNI). This analysis was conducted with a <i>p</i> value <.05 FWE corrected.</p