Problem-solving training modifies cognitive functioning and related functional connectivity in healthy adults.

Cognitive functioning evolves throughout life. Regular practice of stimulating activities maintains or even strengthens cognitive skills. This study investigated the effects of a cognitive training programme based on complex closed-ended problem solving on innovative thinking. To this end, using partial least squares variance-based structural equation modeling, we first evaluated in 83 healthy adults how inhibition, cognitive flexibility, and reasoning were related to the distinct dimensions of innovative thinking. Second, we assessed how these interactions were modified after cognitive training based on problem solving in a subgroup of 16 subjects compared to leisure activity based on crossword solving in another subgroup of 15 subjects. Third, in a pilot fMRI study, we evaluated changes in brain connectivity at rest as a result of training in the problem solving group. Data on cognitive measures showed that innovative thinking was influenced by reasoning in control subjects, whereas it was influenced by cognitive flexibility following problem-solving training. These findings highlight that a cognitive intervention based on complex closed-ended problem solving promotes innovative thinking by changing the way subjects recruit and use relevant cognitive processes. Modifications in the resting-state connectivity of attention, default mode and visual networks were observed in the problem solving group.

A comprehensive approach to study the resting-state brain network related to creative potential.

Studies related to creativity generally investigate cognition and brain functioning linked to creative achievement. However, this approach does not allow characterization of creative potential. To better define creative potential, we studied cognitive function related to creative processes and the associated brain resting functional connectivity. Therefore, in this pilot study, we constructed a cognitive functioning model via structural equation modeling assuming an influence of working memory (WM) and analytical thinking on creativity assessed by the Torrance Tests of Creative Thinking. On the basis of this model, we differentiated two groups with different functioning levels on the basis of their creative score. We identified one group as the high-creative potential group, with a positive correlation between WM and creativity and a negative correlation between analytical thinking and creativity. The other group was the low-creative potential group, with no correlation between WM and creativity and a negative correlation between analytical thinking and creativity. Then, we examined brain functional connectivity at rest and found that the high-creative potential group had increased connectivity in the attentional network (AN) and default-mode network (DMN) and decreased connectivity in the salience network (SN). Our findings highlight the involvement of the AN. We, therefore, linked this network to creative potential, which is consistent with cognitive theories suggesting that creativity is underpinned by attentional processes.

Ageing stereotypes and prodromal Alzheimer's disease (AGING): study protocol for an ongoing randomised clinical study.

INTRODUCTION: The number of older people diagnosed with amnestic mild cognitive impairment (aMCI), the prodromal state of Alzheimer's disease (AD), is increasing worldwide. However, some patients with aMCI never convert to the AD type of dementia, with some remaining stable and others reverting to normal. This overdiagnosis bias has been largely overlooked and gone unexplained. There is ample evidence in the laboratory that negative ageing stereotypes (eg, the culturally shared belief that ageing inescapably causes severe cognitive decline) contribute to the deteriorating cognitive performances of healthy older adults, leading them to perform below their true abilities. The study described here is intended to test for the first time whether such stereotypes also impair patients' cognitive performances during neuropsychological examinations in memory clinics, resulting in overdiagnosis of aMCI. METHODS AND ANALYSIS: The ongoing study is a 4-year randomised clinical trial comparing patients' physiological stress and cognitive performances during neuropsychological testing in memory clinics. A total of 260 patients attending their first cognitive evaluation will be randomised to either a standard condition of test administration, assumed here to implicitly activate negative ageing stereotypes or a reduced-threat instruction condition designed to alleviate the anxiety arising from these stereotypes. Both groups will be tested with the same test battery and stress biomarkers. For 30 patients diagnosed with aMCI in each group (n=60), biomarkers of neurodegeneration and amyloidopathy will be used to distinguish between aMCI with normal versus abnormal AD biomarkers. A 9-month follow-up will be performed on all patients to identify those whose cognitive performances remain stable, deteriorate or improve. ETHICS AND DISSEMINATION: This protocol has been approved by the French National Agency for Medicines and Health Products Safety and the Sud-Est I French Ethics Committee (2017-A00946-47). Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03138018.

Resting Brain Functional Networks and Trait Coping.

This study aims to investigate the effects of individual differences in trait coping on brain networks at rest using electroencephalography (EEG) data. EEG recordings were processed using graph theory analysis. Active and passive coping styles were determined according to the factor structure of the Brief Coping Orientation to Problems Experienced questionnaire. A structural equation modeling analysis indicated that the influence of coping strategies on quality of life varies in strength and direction. In particular, active coping strategies were positively correlated with the psychological dimension. Graph measures, at both global and nodal levels, were used to identify the brain network properties in accordance with passive versus active coping styles. Preliminary evidence showed that both the global and nodal graph metrics were affected by the coping strategy in the delta band. During resting state, passive coping strategy participants had network topology characterized by a high global efficiency, indicating an important level of integration between distant brain areas and a high local efficiency and transitivity, suggesting a high local communication between adjacent regions. Various regions, such as the paracentral lobule, posterior cingulate, and other frontal or parietal areas, seemed to play a key role, suggesting that processes such as emotional load are highly solicited in passive coping individuals. In active coping participants, the superior temporal gyrus seemed to be of importance when neurons oscillated in the theta and alpha frequencies.

Omics analysis of mouse brain models of human diseases.

The identification of common gene/protein profiles related to brain alterations, if they exist, may indicate the convergence of the pathogenic mechanisms driving brain disorders. Six genetically engineered mouse lines modelling neurodegenerative diseases and neuropsychiatric disorders were considered. Omics approaches, including transcriptomic and proteomic methods, were used. The gene/protein lists were used for inter-disease comparisons and further functional and network investigations. When the inter-disease comparison was performed using the gene symbol identifiers, the number of genes/proteins involved in multiple diseases decreased rapidly. Thus, no genes/proteins were shared by all 6 mouse models. Only one gene/protein (Gfap) was shared among 4 disorders, providing strong evidence that a common molecular signature does not exist among brain diseases. The inter-disease comparison of functional processes showed the involvement of a few major biological processes indicating that brain diseases of diverse aetiologies might utilize common biological pathways in the nervous system, without necessarily involving similar molecules.

Aging Stereotypes Must be Taken Into Account for the Diagnosis of Prodromal and Early Alzheimer Disease.

Because of a dramatic increase of older people worldwide, screening for prodromal state of Alzheimer disease (AD) is a major societal challenge. Many individuals diagnosed with prodromal AD, do not convert to AD, some remaining stable and others reversing back to normal. We argue that an important source of this overdiagnosis comes from negative aging stereotypes (eg, the culturally shared beliefs that aging inescapably causes severe cognitive decline and diseases). Many laboratory studies show that such stereotypes impair memory performance in healthy older adults, producing inflated age differences. Research is needed to examine how aging stereotypes implicitly permeate neuropsychological testing and contribute to false positives.

[Subjective cognitive impairment and Alzheimer's disease: a two year follow up of 51 subjects during two years]. / Subjective cognitive impairment et maladie d'Alzheimer : étude d'une cohorte de 51 sujets suivis sur deux ans.

Subjective cognitive impairment (SCI) is defined by a state of subjective complaint, without objective cognitive deterioration. Amnestic mild cognitive impairment (A-MCI), which characterizes a syndrome between normal cognitive aging and early Alzheimer's disease (E-AD), is preceded by A-MCI from many years. SCI expresses a metacognitive impairment. A cohort of 51 subjects [7 normal controls (NC), 28 SCI, 12 A-MCI and 5 E-AD] was followed up during 24 months, with a neuropsychological evaluation each 6 months during 1 year (V1, V2, V3), then 1 year later (V4). Among the 28 SCI, 6 converted to A-MCI at V4 (21.42%), 1 to A-MCI-A at V3, then to E-AD at V4. These results suggest a continuum from SCI to A-MCI, and E-AD. Progressive SCI differed from non-progressive SCI on verbal episodic memory and executive functions tests at the initial examination. MRI showed anterior cingular atrophy in all SCI patients but hippocampal atrophy was only observed in 20 patients. Our results suggest that metacognition impairment is the expression of a dysfunction in the anterior pre-frontal cortex, in correlation with a syndrome of hyper-attention.

Benefits of computer-based memory and attention training in healthy older adults.

Multifactorial cognitive training programs have a positive effect on cognition in healthy older adults. Among the age-sensitive cognitive domains, episodic memory is the most affected. In the present study, we evaluated the benefits on episodic memory of a computer-based memory and attention training. We targeted consciously controlled processes at encoding and minimizing processing at retrieval, by using more familiarity than recollection during recognition. Such an approach emphasizes processing at encoding and prevents subjects from reinforcing their own errors. Results showed that the training improved recognition performances and induced near transfer to recall. The largest benefits, however, were for tasks with high mental load. Improvement in free recall depended on the modality to recall; semantic recall was improved but not spatial recall. In addition, a far transfer was also observed with better memory self-perception and self-esteem of the participants. Finally, at 6-month follow up, maintenance of benefits was observed only for semantic free recall. The challenge now is to corroborate far transfer by objective measures of everyday life executive functioning.

Genomic transcriptional profiling in LOU/C/Jall rats identifies genes for successful aging.

Inbred LOU/C/Jall rats are currently described as a model of successful aging. These rats have a longer healthy median lifespan than many other strains, do not develop obesity, diabetes, or tumor and more importantly they do not show cognitive decline with aging. This is the first study to examine gene expression changes in the inbred LOU/C/Jall rat hippocampus and frontal cortex. Microarray data from animals aged 5 and 26 months were compared to that obtained from the classical Wistar rat strain to potentially identify only the genes associated with successful aging. We have thus identified a set of 15 genes in the hippocampus and 70 genes in the frontal cortex that could be grouped into several clearly delineated clusters of highly correlated genes associated with a diversity of biological processes, including regulation of plasticity, inflammatory response, metabolic, catabolic and homeostatic processes, and transcription. Such a multiplicity of gene networks and diversity of biological functions were not observed in the Wistar rat strain. The gene expression profiles identified in aged the LOU/C/Jall rats' hippocampus and frontal cortex should be related to their intact cognitive abilities, such as those assessed through spontaneous alternation.

Neuroanatomical, sensorimotor and cognitive deficits in adult rats with white matter injury following prenatal ischemia.

Perinatal brain injury including white matter damage (WMD) is highly related to sensory, motor or cognitive impairments in humans born prematurely. Our aim was to examine the neuroanatomical, functional and behavioral changes in adult rats that experienced prenatal ischemia (PI), thereby inducing WMD. PI was induced by unilateral uterine artery ligation at E17 in pregnant rats. We assessed performances in gait, cognitive abilities and topographical organization of maps, and neuronal and glial density in primary motor and somatosensory cortices, the hippocampus and prefrontal cortex, as well as axonal degeneration and astrogliosis in white matter tracts. We found WMD in corpus callosum and brainstem, and associated with the hippocampus and somatosensory cortex, but not the motor cortex after PI. PI rats exhibited mild locomotor impairments associated with minor signs of spasticity. Motor map organization and neuronal density were normal in PI rats, contrasting with major somatosensory map disorganization, reduced neuronal density, and a marked reduction of inhibitory interneurons. PI rats exhibited spontaneous hyperactivity in open-field test and short-term memory deficits associated with abnormal neuronal density in related brain areas. Thus, this model reproduces in adult PI rats the main deficits observed in infants with a perinatal history of hypoxia-ischemia and WMD.

Gene regulation in the rat prefrontal cortex after learning with or without cholinergic insult.

The prefrontal cortex is essential for a wide variety of higher functions, including attention and memory. Cholinergic neurons are thought to be of prime importance in the modulation of these processes. Degeneration of forebrain cholinergic neurons has been linked to several neurological disorders. The present study was designed to identify genes and networks in rat prefrontal cortex that are associated with learning and cholinergic-loss-memory deficit. Affymetrix microarray technology was used to screen gene expression changes in rats submitted or not to 192 IgG-saporin immunolesion of cholinergic basal forebrain and trained in spatial/object novelty tasks. Results showed learning processes were associated with significant expression of genes, which were organized in several clusters of highly correlated genes and would be involved in biological processes such as intracellular signaling process, transcription regulation, and filament organization and axon guidance. Memory loss following cortical cholinergic deafferentation was associated with significant expression of genes belonging to only one clearly delineated cluster and would be involved in biological processes related to cytoskeleton organization and proliferation, and glial and vascular remodeling, i.e., in processes associated with brain repair after injury.

Neurotrophic signaling molecules associated with cholinergic damage in young and aged rats: environmental enrichment as potential therapeutic agent.

The aim of this study was to determine the neurobiological bases of behavioral deficits associated with cholinergic damage and the potential of long-term environmental enrichment as a therapeutic agent. Rats were submitted to intra-structures injection of 192 IgG-saporin and then behaviorally tested 1 month and 1 year post-lesion in a nonmatching-to-position task. The gene expression changes were assessed by cDNA macroarray technology using the GE array Q series designed to profile the expression of neurotrophic signaling molecules. Results showed that (1) cholinergic injury modulated the expression of genes such as brain-derived neurotrophin factor but also genes associated with inflammatory response, neuron apoptosis, regulation of angiogenesis, and synaptic plasticity, (2) aging is associated with regulation of glial proliferation and apoptosis, and (3) long-term enriched environment housing enhanced behavioral performance in lesioned and non-lesioned rats and upregulated gene expression. This therapeutic role of the enriched environment seemed to be associated with a suppression of expression of genes involved in apoptosis, glial cell differentiation, and cell cycle, but also with an enhanced expression of a subset of genes involved in signal transduction.

Age-related changes in metabolic profiles of rat hippocampus and cortices.

The time course of metabolic changes was investigated in the hippocampus and the parietal, rhinal and frontal cortices of rats from 4 to 30 months old. Samples were analysed by the solid-state high-resolution magic angle spinning nuclear magnetic resonance method. Quantification was performed with the quest procedure of jMRUI software. Eighteen metabolites were identified and separated in the spectrum. Six of them were not age sensitive, in particular alanine, glutamine and lactate. In contrast, choline, glycerophosphocholine, myo-inositol, N-acetylaspartate, scyllo-inositol (s-Ins) and taurine (Tau) were notably altered over aging. Interestingly, each age group showed a specific metabolic profile. The concentration of metabolites such as Tau was altered in middle-aged rats only, whereas the s-Ins level decreased in old rats only. Most metabolites showed progressive alteration during the process of aging, which was initiated during the middle-aged period (18 months). Taken together, these results suggest that cell membrane integrity is perturbed with age. Each brain region investigated had distinctive qualitative and/or quantitative metabolic age-related features. These age-related changes would affect network connectivities and then cognitive functions.

Gene expression profile in rat hippocampus with and without memory deficit.

The cholinergic neuronal system, through its projections to the hippocampus, plays an important role in learning and memory. The aim of the study was to identify genes and networks in rat hippocampus with and without memory deficit. Genome-scale screening was used to analyze gene expression changes in rats submitted or not to intraparenchymal injection of 192 IgG-saporin and trained in spatial/object novelty tasks. Results showed learning processes were associated with significant expression of genes that could be grouped into several clusters of similar expression profiles and that are involved in biological functions, namely lipid metabolism, signal transduction, protein metabolism and modification, and transcription regulation. Memory loss following hippocampal cholinergic deafferentation was associated with significant expression of genes that did not show similar cluster organization. Only one cluster of genes could be identified; it included genes that would be involved in tissue remodeling. More important, most of the genes significantly altered in lesioned rats were down-regulated.

Behavioral effects of basal forebrain cholinergic lesions in young adult and aging rats.

The interactive effects of age and cholinergic damage were assessed behaviorally in young and middle-aged rats. Rats were lesioned at either 3 or 17 months of age by injection of 192 IgG-saporin immunotoxin into the medial septum and the nucleus basalis magnocellularis, and they were then tested on a range of behavioral tasks: a nonmatching-to-position task in a T-maze, an object-recognition task, an object-location task, and an open-field activity test. Depending on the task used, only an age or a lesion effect was observed, but there was no Age X Lesion interaction. Middle-aged and young rats responded to the cholinergic lesions in the same manner. These results show that in the middle-aged rats in which cholinergic transmission was affected, additional injury to the system was not always accompanied by major cognitive dysfunctions.

Behavioral effects of arginine8-vasopressin in the Hebb-Williams maze.

Arginine(8)-vasopressin (AVP) has been shown to improve memory consolidation in various mnemonic tasks. Our previous studies have pointed out the involvement of the hippocampus (with higher sensitivity of its ventral part) in memory consolidation and retrieval processes during discriminative learning in mice. The present study was designed to extend our knowledge, firstly, of the range of tasks and consequently the types of information for which the peptide improves consolidation processes, and secondly, the effects of AVP on information treatment processes such an information transfer. To this end, the effects of AVP were analyzed in the Hebb-Williams closed-field maze. Mice were initially trained on one of the mazes in the Hebb-Williams series (Maze 7) and subsequently tested on either that maze or another maze in the series (Maze 11). The effects of the peptide on both memory consolidation and information transfer processes were analyzed in relation to the route of administration: peripheral (subcutaneous, s.c.), central (intracerebroventricular, i.c.v.), and in situ (dorsal or ventral hippocampus). The results showed that AVP facilitated spatial memory consolidation following s.c., i.c.v, and dorsal, but not ventral hippocampal administration. This differential effect of AVP following injection into the hippocampus can be interpreted in regards to this structure's functions. In line with the involvement of the dorsal hippocampus in spatial memory, the effectiveness of the peptide in the Hebb-Williams maze, which contains spatial components, was better when the treatment was performed in this part of the structure. In contrast, whatever the route of administration, AVP had no effect on processes related to the transfer from one learning situation to another.