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INTRODUCTION: Impairments in bottom-up perceptual processing have been associated to the age-related cognitive decline. Digital cognitive training focusing on bottom-up and/or top-down processes have been studied as a tool to remediate age-related cognitive decline. However, the most effective training type and order of application remain unclear. METHODS: One hundred and fifteen older adults were randomly assigned to 40 h of bottom-up then top-down or top-down then bottom-up digital cognitive training or an active control group. We evaluated cognition at baseline, after 20 h and 40 h of training and at follow-up using a mixed-model analysis. RESULTS: Global cognition improved, for the top-down group, after 20 h of training (p = 0.04; d = 0.7) and for all three groups after 40 h. The improvement in global cognition remained five months after the bottom-up/ top-down training (p = 0.009; d = 4.0). There were also improvements in the recall cognitive domain, after 20 h of training, for the bottom-up group and, after 40 h, for all three groups. Gains were observed in verbal fluency after 40 h of training for both therapeutic groups. Processing speed was significantly slower, after 20 h of training, for the control and bottom-up groups and, after 40 h, only for the control group. Emotion recognition improved, after 20 h, for the control group as compared to the therapeutic groups. CONCLUSIONS: These results indicate that the bottom-up/top-down training has the most endurable effects, which reveals the importance of the order of application of the exercises for gains in cognition in older adults.

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Introduction: The locus coeruleus-noradrenaline (LC-NA) system is involved in a wide range of cognitive functions and may be altered in schizophrenia. A non-invasive method to indirectly measure LC activity is task-evoked pupillary response. Individuals with schizophrenia present reduced pupil dilation compared to healthy subjects, particularly when task demand increases. However, the extent to which alteration in LC activity contributes to schizophrenia symptomatology remains largely unexplored. We aimed to investigate the association between symptomatology, cognition, and noradrenergic response in individuals with schizophrenia. Methods: We assessed task-evoked pupil dilation during a pro- and antisaccade task in 23 individuals with schizophrenia and 28 healthy subjects. Results: Both groups showed similar preparatory pupil dilation during prosaccade trials, but individuals with schizophrenia showed significantly lower pupil dilation compared to healthy subjects in antisaccade trials. Importantly, reduced preparatory pupil dilation for antisaccade trials was associated with worse general symptomatology in individuals with schizophrenia. Discussion: Our findings suggest that changes in LC-NA activity - measured by task-evoked pupil dilation - when task demand increases is associated with schizophrenia symptoms. Interventions targeting the modulation of noradrenergic responses may be suitable candidates to reduce schizophrenia symptomatology.

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BACKGROUND: Digital cognitive training can remediate cognitive deficits present in schizophrenia. However, limited motivation and engagement may impact adherence to training. Therefore, identifying factors that may enhance (facilitators) or decrease (barriers) engagement in digital cognitive training and possibly modulate its effects are of great clinical relevance. METHODS: We measured cognition, symptom severity, motivation (semi-structured interview), and engagement (adapted Utrecht Work Engagement Scale - UWES) of 27 patients with schizophrenia after a 40-h digital cognitive training. The interview transcript quotes were coded and categorized into facilitators and barriers. Thereafter, we tested the association of motivation and engagement with changes in cognition and symptoms after training. RESULTS: The facilitator 'good performance' and the barrier 'difficult exercise' were associated with larger gains in attention (p = 0.03) and reasoning and problem solving (p = 0.02), respectively. 'Poor performance' was associated with smaller gains in global cognition (p < 0.01), attention (p = 0.03), and working memory (p = 0.02). The facilitator 'welcoming setting' was associated with larger reductions in the negative (p = 0.01) and total (p = 0.01) symptoms measured by the Positive and Negative Syndrome Scale. The UWES engagement scale was associated with different facilitators and barriers that emerged from the interview, an indication of consistency among both qualitative and quantitative assessments. DISCUSSION: Using a mixed quantitative and qualitative research design, we showed associations between motivation and engagement and the response to digital cognitive training in schizophrenia. Facilitators and barriers were associated with engagement, gains in cognition, and reduced symptoms after the intervention, providing insights on how to increase engagement in the digital cognitive training delivered to subjects with schizophrenia.

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Studies indicate that neuroscience-informed digital cognitive training can remediate cognitive impairments in schizophrenia, but the factors contributing to these deficits and response to treatment remain unclear. Toxoplasma gondii is a neuroinvasive parasite linked to cognitive decline that also presents a higher prevalence in schizophrenia. Here, we compared the cognition and symptom severity of IgG seropositive (TOXO+; n = 25) and seronegative (TOXO-; n = 35) patients who participated in a randomized controlled trial of digital cognitive training. At baseline, TOXO+ subjects presented lower global cognition than TOXO- (F = 3.78, p = 0.05). Specifically, TOXO+ subjects showed worse verbal memory and learning (F = 4.48, p = 0.03), social cognition (F = 5.71, p = 0.02), and higher antibody concentrations were associated with increased negative (r = 0.42, p = 0.04) and total (r = 0.40, p = 0.04) schizophrenia symptoms. After training, the TOXO+ group showed higher adherence to the intervention (X2 = 9.31, p = 0.03), but there were no differences in changes in cognition and symptoms between groups. These findings highlight the association between seropositivity to T. gondii and deteriorated cognition and symptoms in schizophrenia. Further research is needed to assess the specific efficacy of digital cognitive training on this population.

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BACKGROUND: D-serine is an endogenous co-agonist of the N-Methyl D-Aspartate Receptor (NMDAR) that plays a crucial role in cognition including learning processes and memory. Decreased D-serine levels have been associated with age-related decline in mechanisms of learning and memory in animal studies. Here, we asked whether D-serine administration in older adults improves cognition. RESULTS: D-serine administration improved performance in the Groton Maze learning test of spatial memory and learning and problem solving (F(3, 38)= 4.74, p = 0.03). Subjects that achieved higher increases in plasma D-serine levels after administration improved more in test performance (r2=-0.19 p = 0.009). D-serine administration was not associated with any significant changes in the other cognitive tests or in the mood of older adults (p > 0.05). METHODS: Fifty healthy older adults received D-serine and placebo in a randomized, double blind, placebo-controlled, crossover design study. We studied the effect of D-serine administration on the performance of cognitive tests and an analogue mood scale. We also collected blood samples to measure D-serine, L-serine, glutamate and glutamine levels. CONCLUSIONS: D-serine administration may be a strategy to improve spatial memory, learning and problem solving in healthy older adults. Future studies should evaluate the impact of long-term D-serine administration on cognition in older adults.

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In this review, we present the main findings of the 6th Symposium for the Search for the Causes of Schizophrenia, which took place between 3 and 6 February 2009, in Sao Paulo, Brazil. In a few short years, the landscape of the causes of schizophrenia has changed dramatically. The flat and featureless epidemiological horizon has developed undulating contours, which promise new avenues for research, particularly if we are able to integrate such findings with tantalising new findings from genetics as novel methods for identifying genuine sites of genetic risk emerge. The Search highlighted and fostered the emerging acknowledgement that we will need to integrate knowledge across traditionally disparate disciplines in psychiatry in order to develop complex, testable hypotheses in the search for the causes of schizophrenia. Such challenges are beginning to be addressed. From epidemiology, gene-environment studies are becoming more sophisticated, while neuroscience is increasingly concerned about social organisation and how social factors impinge upon biological pathways to potentially lead to psychosis. Tantalising new insights from genome-wide association studies offer new clues about rare genetic mutations, which have large effect sizes for schizophrenia, including copy number variants and de novo mutations. It is only through forums such as the 6th Symposium for the Search for the Causes of Schizophrenia that the seeds of integrated collaborations across disciplines can be sown to address the complex polyfactorial basis of schizophrenia.

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