CN-105 in Participants with Acute SupraTentorial IntraCerebral Hemorrhage (CATCH) Trial

BackgroundEndogenous apoliloprotein E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apolipoprotein E-mimetic peptides can effectively penetrate the brain and down-regulate acute inflammation. CN-105 is a novel apolipoprotein E-mimetic pentapeptide with excellent preclinical evidence as an acute intracerebral hemorrhage (ICH) therapeutic. The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state, multi-center, open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH.MethodsEligible patients were age 30-80 years, had confirmed primary supratentorial ICH, and able to intiate CN-105 administration (1.0 mg/kg every 6 hours for 72 hours) within 12 hours of symptom onset. A priori defined safety endpoints, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes were analyzed. For comparisons, CATCH participants were matched 1:1 with a contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on Days 0, 1, 2, and 5 and ordinal modified Rankin Score at 30 days after ICH were compared.ResultsIn 39 participants enrolled across six study sites in the United States, adverse events occurred at expected rate without increase in hematoma expansion or neurological deterioration or significant serum accumulation. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31–5.51) for lower 30-day mRS, after adjustment for ICH Score, sex, and race/ethnicity, compared to matched contemporary cohort.ConclusionCN-105 administration represents an excellent translational candidate as an actue ICH therapeutic due to its safety, dosing feasibility, favorable pharmacokinetics, and evidence of improved neurological recovery.

Augmenting cognitive load during split-belt walking increases the generalization of motor memories across walking contexts

Cognitive load plays a role on the movement recalibration induced by sensorimotor adaptation, but little is known about its impact on the generalization of movements from trained to untrained situations. We hypothesized that altering cognitive load by distracting subjects during sensorimotor adaptation would facilitate the generalization of recalibrated movements beyond the training condition. We reasoned that awareness of the novel condition inducing adaptation could be used to consciously contextualize movements to that particular situation. To test this hypothesis, young adults adapted their gait on a split-belt treadmill (moving their legs at different speeds) while they observed visual information that either distracted them or made them aware of the speed difference between their feet. We assessed the adaptation and aftereffects of spatial and temporal gait features known to adapt and generalize differently when walking on the treadmill or overground. We found similar adaptation and aftereffects on the treadmill across all groups. In contrast, both groups with altered cognitive load (i.e., distraction and awareness groups) generalized their movements from the treadmill to overground more than controls, who walked without altered cognitive load. Of note, this effect was only observed in temporal gait features, which are less susceptible to online motor adjustments, and were eliminated upon experiencing large errors by briefly removing the split perturbation during adaptation (i.e., catch trial). Taken together, increasing cognitive demands during sensorimotor adaptation facilitates the generalization of movement recalibration, but this cognitive-mediated effect cannot eliminate the specificity of actions due to context-specific errors.New and NoteworthyLittle is known about how cognition affects the generalization of motor recalibration induced by sensorimotor adaptation paradigms. We showed that augmenting cognitive load during adaptation on a split-belt treadmill led to greater recalibration of movements without the training device. However, this effect was eliminated when unusual motor errors were experienced on the treadmill. Thus, cognition can influence the generalization of sensorimotor adaptation, but it cannot suppress the context-specificity originated by the errors that one feels.

Different Error Size During Locomotor Adaptation Affects Transfer to Overground Walking Poststroke

Background. Studies in neurologically intact subjects suggest that the gradual presentation of small perturbations (errors) during learning results in better transfer of a newly learned walking pattern to overground walking. Whether the same result would be true after stroke is not known. Objective. To determine whether introducing gradual perturbations, during locomotor learning using a split-belt treadmill influences learning the novel walking pattern or transfer to overground walking poststroke. Methods. Twenty-six chronic stroke survivors participated and completed the following walking testing paradigm: baseline overground walking; baseline treadmill walking; split-belt treadmill/adaptation period (belts moving at different speeds); catch trial (belts at same speed); post overground walking. Subjects were randomly assigned to the Gradual group (gradual changes in treadmill belts speed during adaptation) or the Abrupt group (a single, large, abrupt change during adaptation). Step length asymmetry adaptation response on the treadmill and transfer of learning to overground walking was assessed. Results. Step length asymmetry during the catch trial was the same between groups ( P = .195) confirming that both groups learned a similar amount. The magnitude of transfer to overground walking was greater in the Gradual than in the Abrupt group ( P = .041). Conclusions. The introduction of gradual perturbations (small errors), compared with abrupt (larger errors), during a locomotor adaptation task seems to improve transfer of the newly learned walking pattern to overground walking poststroke. However, given the limited magnitude of transfer, future studies should examine other factors that could impact locomotor learning and transfer poststroke.

Evaluating the Mind’s Eye

Can people evaluate phenomenal qualities of internally generated experiences, such as whether a mental image is vivid or detailed? This question exemplifies a problem of metacognition: How well do people know their own thoughts? In the study reported here, participants were instructed to imagine a specific visual pattern and rate its vividness, after which they were presented with an ambiguous rivalry display that consisted of the previously imagined pattern plus an orthogonal pattern. On individual trials, higher ratings of vividness predicted a greater likelihood that the imagined pattern would appear dominant when the participant was subsequently presented with the binocular rivalry display. Off-line self-report questionnaires measuring imagery vividness also predicted individual differences in the strength of imagery bias over the entire study. Perceptual bias due to mental imagery could not be attributed to demand characteristics, as no bias was observed on catch-trial presentations of mock rivalry displays. Our findings provide novel evidence that people have a good metacognitive understanding of their own mental imagery and can reliably evaluate the vividness of single episodes of imagination.