Up to date, the functional gains obtained after robot-aided gait rehabilitation training are limited. Error augmenting strategies have a great potential to enhance motor learning of simple motor tasks. However, little is known about the effect of these error modulating strategies on complex tasks, such as relearning to walk after a neurologic accident. Additionally, neuroimaging evaluation of brain regions involved in learning processes could provide valuable information on behavioral outcomes. We investigated the effect of robotic training strategies that augment errors—error amplification and random force disturbance—and training without perturbations on brain activation and motor learning of a complex locomotor task. Thirty-four healthy subjects performed the experiment with a robotic stepper (MARCOS) in a 1.5 T MR scanner. The task consisted in tracking a Lissajous figure presented on a display by coordinating the legs in a gait-like movement pattern. Behavioral results showed that training without perturbations enhanced motor learning in initially less skilled subjects, while error amplification benefited better-skilled subjects. Training with error amplification, however, hampered transfer of learning. Randomly disturbing forces induced learning and promoted transfer in all subjects, probably because the unexpected forces increased subjects' attention. Functional MRI revealed main effects of training strategy and skill level during training. A main effect of training strategy was seen in brain regions typically associated with motor control and learning, such as, the basal ganglia, cerebellum, intraparietal sulcus, and angular gyrus. Especially, random disturbance and no perturbation lead to stronger brain activation in similar brain regions than error amplification. Skill-level related effects were observed in the IPS, in parts of the superior parietal lobe (SPL), i.e., precuneus, and temporal cortex. These neuroimaging findings indicate that gait-like motor learning depends on interplay between subcortical, cerebellar, and fronto-parietal brain regions. An interesting observation was the low activation observed in the brain's reward system after training with error amplification compared to training without perturbations. Our results suggest that to enhance learning of a locomotor task, errors should be augmented based on subjects' skill level. The impacts of these strategies on motor learning, brain activation, and motivation in neurological patients need further investigation.

Background: Risk factors for vascular cognitive impairment (VCI) are the same as traditional risk factors for cerebrovascular disease (CVD). Early identification of subjects at higher risk of VCI is important for the development of effective preventive strategies. In addition to traditional vascular risk factors (VRF), circulating biomarkers have emerged as potential tools for early diagnoses, as they could provide in vivo measures of the underlying pathophysiology. While VRF have been consistently linked to a VCI profile (i.e., deficits in executive functions and processing speed), the cognitive correlates of CVD biomarkers remain unclear. In this population-based study, the aim was to study and compare cognitive patterns in relation to VRF and circulating biomarkers of CVD. Methods: TheBarcelona-AsIA Neuropsychology Study included 747 subjects older than 50, without a prior history of stroke or coronary disease and with a moderate to high vascular risk (mean age, 66 years; 34.1% women). Three cognitive domains were derived from factoral analysis: visuospatial skills/speed, verbal memory and verbal fluency. Multiple linear regression was used to assess relationships between cognitive performance (multiple domains) and a panel of circulating biomarkers, including indicators of inflammation, C-reactive protein (CRP) and resistin, endothelial dysfunction, asymmetric dimethylarginine (ADMA), thrombosis, plasminogen activator inhibitor 1 (PAI-1), as well as traditional VRF, metabolic syndrome and insulin resistance (homeostatic model assessment for insulin resistance index). Analyses were adjusted for age, gender, years of education and depressive symptoms. Results: Traditional VRF were related to lower performance in verbal fluency, insulin resistance accounted for lower performance in visuospatial skills/speed and the metabolic syndrome predicted lower performance in both cognitive domains. From the biomarkers of CVD, CRP was negatively related to verbal fluency performance and increasing ADMA levels were associated with lower performance in verbal memory. Resistin and PAI-1 did not relate to cognitive function performance. Conclusion: Vascular risk factors, and markers of inflammation and endothelial dysfunction predicted lower performance in several cognitive domains. Specifically, cognitive functions associated with CRP are typically affected in VCI and overlap those related to VRF. ADMA indicated a dissociation in the cognitive profile involving verbal memory. These findings suggest that inflammation and endothelial dysfunction might play a role in the predementia cognitive impairment stages.

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Research on motor learning has emphasized that errors drive motor adaptation. Thereby, several researchers have proposed robotic training strategies that amplify movement errors rather than decrease them. In this study, the effect of different robotic training strategies that amplify errors on learning a complex locomotor task was investigated. The experiment was conducted with a one degree-of freedom robotic stepper (MARCOS). Subjects were requested to actively coordinate their legs in a desired gait-like pattern in order to track a Lissajous figure presented on a visual display. Learning with three different training strategies was evaluated: (i) No perturbation: the robot follows the subjects' movement without applying any perturbation, (ii) Error amplification: existing errors were amplified with repulsive forces proportional to errors, (iii) Noise disturbance: errors were evoked with a randomly-varying force disturbance. Results showed that training without perturbations was especially suitable for a subset of initially less-skilled subjects, while error amplification seemed to benefit more skilled subjects. Training with error amplification, however, limited transfer of learning. Random disturbing forces benefited learning and promoted transfer in all subjects, probably because it increased attention. These results suggest that learning a locomotor task can be optimized when errors are randomly evoked or amplified based on subjects' initial skill level.

Apolipoprotein E (APOE) has an important role in the multiple trajectories of cognitive aging. However, environmental variables and other genes mediate the impact of APOE on cognition. Our main objective was to analyze the effect of APOE genotype on cognition and its interactions and relationships with sex, age, lipid profile, C-reactive protein (CRP) and Brain derived neurotrophic factor (BDNF) genotype in a sample of 648 healthy subjects over 50 years of age with a comprehensive neuropsychological assessment. Our results showed that APOE ε2 carriers performed better in the Verbal Memory (p = 0.002) and Fluency Domains (p = 0.001). When we studied the effect of sex, we observed that the beneficial effect of APOE ε2 on the normalized values of these cognitive domains occurred only in females (β = 0.735; 95% CI, 0.396-1.074; p = 3.167·10 -5 and β = 0.568; 95% CI, 0.276-0.861; p = 1.853·10 -4, respectively). Similarly, the sex-specific effects of APOE ε2 were further observed on lipidic and inflammation biomarkers. In the whole sample, APOE ε2 carriers showed significantly lower levels of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and CRP. These differences were found only among females. Furthermore, TC and LDL-C mediated the protective effect of APOE ε2 on cognition in the whole sample and TC in females, providing candidate physiological mechanisms for the observed genetic effects. Our results show that the neuroprotective role of APOE ε2 in cognition varies with sex and that the lipidic profile partially mediates this protection.