Relação entre nível de atividade física, cognição, processamento da informação e funcionalidade motora de idosos no estágio leve da doença de Alzheimer

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Funções cognitivas frontais e controle postural na doença de Alzheimer: efeitos do programa de intervenção motora com tarefa dupla

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Efeito do treinamento aeróbio nos níveis plasmáticos do fator neurotrófico derivado do cérebro, variáveis metabólicas e funções cognitivas em idosos com a doença de Alzheimer

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Respiratory training as strategy to prevent cognitive decline in aging: a randomized controlled trial

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Mathematical models of cognitive processes

The research activity carried out during the PhD course was focused on the development of mathematical models of some cognitive processes and their validation by means of data present in literature, with a double aim: i) to achieve a better interpretation and explanation of the great amount of data obtained on these processes from different methodologies (electrophysiological recordings on animals, neuropsychological, psychophysical and neuroimaging studies in humans), ii) to exploit model predictions and results to guide future research and experiments. In particular, the research activity has been focused on two different projects: 1) the first one concerns the development of neural oscillators networks, in order to investigate the mechanisms of synchronization of the neural oscillatory activity during cognitive processes, such as object recognition, memory, language, attention; 2) the second one concerns the mathematical modelling of multisensory integration processes (e.g. visual-acoustic), which occur in several cortical and subcortical regions (in particular in a subcortical structure named Superior Colliculus (SC)), and which are fundamental for orienting motor and attentive responses to external world stimuli. This activity has been realized in collaboration with the Center for Studies and Researches in Cognitive Neuroscience of the University of Bologna (in Cesena) and the Department of Neurobiology and Anatomy of the Wake Forest University School of Medicine (NC, USA). PART 1. Objects representation in a number of cognitive functions, like perception and recognition, foresees distribute processes in different cortical areas. One of the main neurophysiological question concerns how the correlation between these disparate areas is realized, in order to succeed in grouping together the characteristics of the same object (binding problem) and in maintaining segregated the properties belonging to different objects simultaneously present (segmentation problem). Different theories have been proposed to address these questions (Barlow, 1972). One of the most influential theory is the so called “assembly coding”, postulated by Singer (2003), according to which 1) an object is well described by a few fundamental properties, processing in different and distributed cortical areas; 2) the recognition of the object would be realized by means of the simultaneously activation of the cortical areas representing its different features; 3) groups of properties belonging to different objects would be kept separated in the time domain. In Chapter 1.1 and in Chapter 1.2 we present two neural network models for object recognition, based on the “assembly coding” hypothesis. These models are networks of Wilson-Cowan oscillators which exploit: i) two high-level “Gestalt Rules” (the similarity and previous knowledge rules), to realize the functional link between elements of different cortical areas representing properties of the same object (binding problem); 2) the synchronization of the neural oscillatory activity in the γ-band (30-100Hz), to segregate in time the representations of different objects simultaneously present (segmentation problem). These models are able to recognize and reconstruct multiple simultaneous external objects, even in difficult case (some wrong or lacking features, shared features, superimposed noise). In Chapter 1.3 the previous models are extended to realize a semantic memory, in which sensory-motor representations of objects are linked with words. To this aim, the network, previously developed, devoted to the representation of objects as a collection of sensory-motor features, is reciprocally linked with a second network devoted to the representation of words (lexical network) Synapses linking the two networks are trained via a time-dependent Hebbian rule, during a training period in which individual objects are presented together with the corresponding words. Simulation results demonstrate that, during the retrieval phase, the network can deal with the simultaneous presence of objects (from sensory-motor inputs) and words (from linguistic inputs), can correctly associate objects with words and segment objects even in the presence of incomplete information. Moreover, the network can realize some semantic links among words representing objects with some shared features. These results support the idea that semantic memory can be described as an integrated process, whose content is retrieved by the co-activation of different multimodal regions. In perspective, extended versions of this model may be used to test conceptual theories, and to provide a quantitative assessment of existing data (for instance concerning patients with neural deficits). PART 2. The ability of the brain to integrate information from different sensory channels is fundamental to perception of the external world (Stein et al, 1993). It is well documented that a number of extraprimary areas have neurons capable of such a task; one of the best known of these is the superior colliculus (SC). This midbrain structure receives auditory, visual and somatosensory inputs from different subcortical and cortical areas, and is involved in the control of orientation to external events (Wallace et al, 1993). SC neurons respond to each of these sensory inputs separately, but is also capable of integrating them (Stein et al, 1993) so that the response to the combined multisensory stimuli is greater than that to the individual component stimuli (enhancement). This enhancement is proportionately greater if the modality-specific paired stimuli are weaker (the principle of inverse effectiveness). Several studies have shown that the capability of SC neurons to engage in multisensory integration requires inputs from cortex; primarily the anterior ectosylvian sulcus (AES), but also the rostral lateral suprasylvian sulcus (rLS). If these cortical inputs are deactivated the response of SC neurons to cross-modal stimulation is no different from that evoked by the most effective of its individual component stimuli (Jiang et al 2001). This phenomenon can be better understood through mathematical models. The use of mathematical models and neural networks can place the mass of data that has been accumulated about this phenomenon and its underlying circuitry into a coherent theoretical structure. In Chapter 2.1 a simple neural network model of this structure is presented; this model is able to reproduce a large number of SC behaviours like multisensory enhancement, multisensory and unisensory depression, inverse effectiveness. In Chapter 2.2 this model was improved by incorporating more neurophysiological knowledge about the neural circuitry underlying SC multisensory integration, in order to suggest possible physiological mechanisms through which it is effected. This endeavour was realized in collaboration with Professor B.E. Stein and Doctor B. Rowland during the 6 months-period spent at the Department of Neurobiology and Anatomy of the Wake Forest University School of Medicine (NC, USA), within the Marco Polo Project. The model includes four distinct unisensory areas that are devoted to a topological representation of external stimuli. Two of them represent subregions of the AES (i.e., FAES, an auditory area, and AEV, a visual area) and send descending inputs to the ipsilateral SC; the other two represent subcortical areas (one auditory and one visual) projecting ascending inputs to the same SC. Different competitive mechanisms, realized by means of population of interneurons, are used in the model to reproduce the different behaviour of SC neurons in conditions of cortical activation and deactivation. The model, with a single set of parameters, is able to mimic the behaviour of SC multisensory neurons in response to very different stimulus conditions (multisensory enhancement, inverse effectiveness, within- and cross-modal suppression of spatially disparate stimuli), with cortex functional and cortex deactivated, and with a particular type of membrane receptors (NMDA receptors) active or inhibited. All these results agree with the data reported in Jiang et al. (2001) and in Binns and Salt (1996). The model suggests that non-linearities in neural responses and synaptic (excitatory and inhibitory) connections can explain the fundamental aspects of multisensory integration, and provides a biologically plausible hypothesis about the underlying circuitry.

Genetic and environmental factors associated with the risk of cognitive decline and dementia

AD is the most common age related neurodegenerative disease in the industrialized world. Clinically AD is defined as a progressing decline of cognitive functions. Neuropathologically, AD is characterized by the aggregation of b-amyloid (Ab) peptide in the form of extracellular senile plaques, and hyperphosphorlylated tau protein in the form of intracellular neurofibrillary tangles. These neuropathological hallmarks are often accompanied by abundant microvascular damage and pronounced inflammation of the affected brain regions. In this thesis we investigated several aspects of AD focusing on the genetic aspect. We confirmed that Alpha 1 antichymotrypsin (ACT), an acute phase protein, was associated to AD subjects, being plasma levels higher in AD cases than controls. In addition, in a GWA study we demonstrated that two different gene, Clusterin and CR1 were strongly associated to AD. A single gene association not explain such a complex disease like AD. The goal should be to created a network of genetic, phenotypic and clinical data associated to AD. We used a new algorithm, the ANNs, aimed to map variables and search for connectivity among variables. We found specific variables associated to AD like cholesterol levels, the presence of variation in HMGCR enzyme and the age. Other factors such as the BMI, the amount of HDL and blood folate levels were also associated with AD. Pathogen infections, above all viral infections, have been previously associated to AD. The hypothesis suggests that virus and in particular herpes virus could enter the brain when an individual becomes older, perhaps because of a decline in the immune system. Our new hypothesis is that the presence of SNPs in our GWA gene study results in a genetic signature that might affect individual brain susceptibility to infection by herpes virus family during aging.

The future in action: neurophysiological and behavioral evidence of anticipatory motor simulation.

The motor system can no longer be considered as a mere passive executive system of motor commands generated elsewhere in the brain. On the contrary, it is deeply involved in perceptual and cognitive functions and acts as an “anticipation device”. The present thesis investigates the anticipatory motor mechanisms occurring in two particular instances: i) when processing sensory events occurring within the peripersonal space (PPS); and ii) when perceiving and predicting others’actions. The first study provides evidence that PPS representation in humans modulates neural activity within the motor system, while the second demonstrates that the motor mapping of sensory events occurring within the PPS critically relies on the activity of the premotor cortex. The third study provides direct evidence that the anticipatory motor simulation of others’ actions critically relies on the activity of the anterior node of the action observation network (AON), namely the inferior frontal cortex (IFC). The fourth study, sheds light on the pivotal role of the left IFC in predicting the future end state of observed right-hand actions. Finally, the fifth study examines how the ability to predict others’ actions could be influenced by a reduction of sensorimotor experience due to the traumatic or congenital loss of a limb. Overall, the present work provides new insights on: i) the anticipatory mechanisms of the basic reactivity of the motor system when processing sensory events occurring within the PPS, and the same anticipatory motor mechanisms when perceiving others’ implied actions; ii) the functional connectivity and plasticity of premotor-motor circuits both during the motor mapping of sensory events occurring within the PPS and when perceiving others’ actions; and iii) the anticipatory mechanisms related to others’ actions prediction.

Brain metabolite composition in relation to cognitive function and dystrophin mutations in boys with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a hereditary X-linked recessive disorder affecting the synthesis of dystrophin, a protein essential for structural stability in muscle. Dystrophin also occurs in the central nervous system, particularly in the neocortex, hippocampus and cerebellum. Quantitative metabolic analysis by localized (1) H MRS was performed in the cerebellum (12 patients and 15 controls) and a temporo-parietal location (eight patients and 15 controls) in patients with DMD and healthy controls to investigate possible metabolic differences. In addition, the site of individual mutations on the dystrophin gene was analyzed and neuropsychological cognitive functions were examined. Cognitive deficits in the patient group were found in line with earlier investigations, mainly concerning verbal short-term memory, visuo-spatial long-term memory and verbal fluency, but also the full-scale IQ. Causal mutations were identified in all patients with DMD. Quantitative MRS showed consistent choline deficits, in both cerebellar white matter and temporo-parietal cortex, as well as small, but significant, metabolic abnormalities for glutamate and total N-acetyl compounds in the temporo-parietal region. Compartment water analysis did not reveal any abnormalities. In healthy subjects, choline levels were age related in the cerebellum. The choline deficit contrasts with earlier findings in DMD, where a surplus of choline was postulated for the cerebellum. In patients, total N-acetyl compounds in the temporo-parietal region were related to verbal IQ and verbal short-term memory. However, choline, the putative main metabolic abnormality, was not found to be associated with cognitive deficits. Furthermore, in contrast with the cognitive performance, the metabolic brain composition did not depend significantly on whether or not gene mutations concerned the expression of the dystrophin isoform Dp140, leading to the conclusion that the effect of the missing Dp140 isoform on cognitive performance is not mediated through the observed metabolite composition, or is caused by local effects beyond the resolution accessible to MRS investigations.

Developmental changes of BOLD signal correlations with global human EEG power and synchronization during working memory

In humans, theta band (5-7 Hz) power typically increases when performing cognitively demanding working memory (WM) tasks, and simultaneous EEG-fMRI recordings have revealed an inverse relationship between theta power and the BOLD (blood oxygen level dependent) signal in the default mode network during WM. However, synchronization also plays a fundamental role in cognitive processing, and the level of theta and higher frequency band synchronization is modulated during WM. Yet, little is known about the link between BOLD, EEG power, and EEG synchronization during WM, and how these measures develop with human brain maturation or relate to behavioral changes. We examined EEG-BOLD signal correlations from 18 young adults and 15 school-aged children for age-dependent effects during a load-modulated Sternberg WM task. Frontal load (in-)dependent EEG theta power was significantly enhanced in children compared to adults, while adults showed stronger fMRI load effects. Children demonstrated a stronger negative correlation between global theta power and the BOLD signal in the default mode network relative to adults. Therefore, we conclude that theta power mediates the suppression of a task-irrelevant network. We further conclude that children suppress this network even more than adults, probably from an increased level of task-preparedness to compensate for not fully mature cognitive functions, reflected in lower response accuracy and increased reaction time. In contrast to power, correlations between instantaneous theta global field synchronization and the BOLD signal were exclusively positive in both age groups but only significant in adults in the frontal-parietal and posterior cingulate cortices. Furthermore, theta synchronization was weaker in children and was--in contrast to EEG power--positively correlated with response accuracy in both age groups. In summary we conclude that theta EEG-BOLD signal correlations differ between spectral power and synchronization and that these opposite correlations with different distributions undergo similar and significant neuronal developments with brain maturation.

The experimental combination of rTMS and fMRI reveals the functional relevance of parietal cortex for visuospatial functions

We combined repetitive transcranial magnetic stimulation (rTMS) and functional magnetic resonance imaging (fMRI) to investigate the functional relevance of parietal cortex activation during the performance of visuospatial tasks. fMRI provides information about local transient changes in neuronal activation during behavioural or cognitive tasks. Information on the functional relevance of this activation was obtained by using rTMS to induce temporary regional deactivations. We thereby turned the physiological parameter of brain activity into an independent variable controlled and manipulated by the experimenter and investigated its effect on the performance of the cognitive tasks within a controlled experimental design. We investigated cognitive tasks that were performed on the same visual material but differed in the demand on visuospatial functions. For the visuospatial tasks we found a selective enhancement of fMRI signal in the superior parietal lobule (SPL) and a selective impairment of performance after rTMS to this region in comparison to a control group. We could thus show that the parietal cortex is functionally important for the execution of spatial judgements on visually presented material and that TMS as an experimental tool has the potential to interfere with higher cognitive functions such as visuospatial information processing.

Cerebellar disorders in childhood: cognitive problems

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions, and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome, William's syndrome, and autism. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also, focal lesions during childhood or adolescence such as cerebellar tumor or stroke are related with neuropsychological abnormalities, which are most pronounced in visuospatial, language, and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal intelligence quotient and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions, especially in learning. There is a suggestion that the earlier the incorrect influence, the more pronounced the problems.

Cognitive deficits after recovery from thrombotic thrombocytopenic purpura

BACKGROUND: Patients with apparent complete recovery from thrombotic thrombocytopenic purpura (TTP) often complain of problems with memory, concentration, and fatigue. STUDY DESIGN AND METHODS: Twenty-four patients who were enrolled in the Oklahoma TTP-HUS Registry for their initial episode of TTP, 1995-2006, and who had ADAMTS13 activity of less than 10 percent were evaluated for a broad range of cognitive functions 0.1 to 10.6 years (median, 4.0 years) after their most recent episode. At the time of their evaluation, they had normal physical and Mini-Mental State Examinations and no evidence of TTP. RESULTS: The patients, as a group, performed significantly worse on 4 of the 11 cognitive domains tested than standardized US data from neurologically normal individuals adjusted for age, sex, and education (p < 0.05). These four domains measured complex attention and concentration skills, information processing speed, rapid language generation, and rote memorization. Twenty-one (88%) patients performed below expectations on at least 1 of the 11 domains. No clear patterns were observed between cognitive test results and patients' characteristics or features of the preceding TTP, including age, occurrence of severe neurologic abnormalities, multiple episodes, and interval from an acute episode. CONCLUSION: Patients who have recovered from TTP may have persistent cognitive abnormalities. The abnormalities observed in these patients are characteristic of disorders associated with diffuse subcortical microvascular disease. Studies of larger patient groups will be required to confirm these preliminary observations and to determine patient characteristics that may contribute to persistent cognitive abnormalities.

Cognitive response control in writer's cramp

Disturbances of the motor and sensory system as well as an alteration of the preparation of movements have been reported to play a role in the pathogenesis of dystonias. However, it is unclear whether higher aspects of cortical – like cognitive – functions are also involved. Recently, the NoGo-anteriorization (NGA) elicited with a visual continuous performance test (CPT) during recording of a 21-channel electroencephalogram has been proposed as an electrophysiological standard-index for cognitive response control. The NGA consists of a more anterior location of the positive area of the brain electrical field associated with the inhibition (NoGo-condition) compared with that of the execution (Go-condition) of a prepared motor response in the CPT. This response control paradigm was applied in 16 patients with writer’s cramp (WC) and 14 age matched healthy controls. Topographical analysis of the associated event-related potentials revealed a significant (P < 0.05) NGA effect for both patients and controls. Moreover, patients with WC showed a significantly higher global field power value (P < 0.05) in the Go-condition and a significantly higher difference-amplitude (P < 0.05) in the NoGo-condition. A source location analysis with the low resolution electromagnetic tomography (LORETA) method demonstrated a hypoactivity for the Go-condition in the parietal cortex of the right hemisphere and a hyperactivity in the NoGo-condition in the left parietal cortex in patients with WC compared with healthy controls. These results indicate an altered response control in patients with WC in widespread cortical brain areas and therefore support the hypothesis that the pathogenesis of WC is not restricted to a pure sensory-motor dysfunction.

Cognitive Remediation in early psychosis and in at-risk mental states – Approaches and efficacy

Cognitive Remediation approaches have proven to be effective in enhancing cognitive functions and psychosocial outcomes in multi-episode schizophrenia patients. However, there is a paucity of studies evaluating Cognitive Remediation in first-episode psychosis patients and in those symptomatically at-risk for psychosis. This is despite the growing evidence that impairments in neuro- and social-cognitive functions are already present in early psychosis and even in at-risk mental states and are important predictors of poor outcome, including transition to psychosis. Moreover, Cognitive Remediation applied at younger ages and at earlier stages of schizophrenia yielded greater cognitive and functional gains. Therefore, Cognitive Remediation may be especially appropriate for early intervention. Against this background, we will review and discuss the efficacy of current Cognitive Remediation approaches in early psychosis and in at-risk mental states. Furthermore, we will present novel interventions that are tailored to the specific needs and developmental tasks of patients at-risk for psychosis and aim at improving social and self-referential cognitions as well as interpersonal skills

Effectiveness of integrated cognitive remediartion therapy for schizophrenia outpatients: Early versus long-term course of illness – results from an international RCT

Background Nowadays there is extensive evidence available showing the efficacy of cognitive remediation therapies. Integrative approaches seem superior regarding the maintenance of proximal outcome at follow-up as well as generalization to other areas of functioning. To date, only limited evidence about the efficacy of CRT is available concerning elder schizophrenia patients. The Integrated Neurocognitive Therapy (INT) represents a new developed cognitive remediation approach. It is a manualized group therapy approach targeting all 11 NIMH-MATRICS dimensions within one therapy concept. In this study we compared the effects of INT on an early course group (duration of disease<5 years) to a long-term group of schizophrenia outpatients (duration of disease>15 years). Methods An international multicenter study carried out in Germany, Switzerland and Austria with a total of 90 outpatients diagnosed with Schizophrenia (DSM-IV-TR) were randomly assigned either to an INT-Therapy or to Treatment-As-Usual (TAU). 50 of the 90 Patients were an Early-Course (EC) group, suffering from schizophrenia for less than 5 years (Mean age=29 years, Mean duration of illness=3.3 years). The other 40 were a Long-term Course (LC) group, suffering from schizophrenia longer than 15 years (Mean age= 45 years, Mean duration of illness=22 years). Treatment comprised of 15 biweekly sessions. An extensive assessment battery was conducted before and after treatment and at follow up (1 year). Multivariate General Linear Models (GLM) (duration of illness x treatment x time) examined our hypothesis, if an EC group of schizophrenia outpatients differ in proximal and distal outcome from a LC group. Results Irrespective of the duration of illness, both groups (EC & LC) were able to benefit from the INT. INT was superior compared to TAU in most of the assessed domains. Dropout rate of EC group was much higher (21.4%) than LC group (8%) during therapy phase. However, interaction effects show that the LC group revealed significantly higher effects in the neurocognitive domains of speed of processing (F>3.6) and vigilance (F>2.4). In social cognition the EC group showed significantly higher effects in social schema (F>2.5) and social attribution (blame; F>6.0) compared to the LC group. Regarding more distal outcome, patients treated with INT obtained reduced general symptoms unaffected by the duration of illness during therapy phase and at follow-up (F>4.3). Discussion Results suggest that INT is a valid goal-oriented treatment to improve cognitive functions in schizophrenia outpatients. Irrespective of the duration of illness significant treatment, effects were evident. Against common expectations, long-term, more chronic patients showed higher effects in basal cognitive functions compared to younger patients and patients without any active therapy (TAU). Consequently, more integrated therapy offers are also recommended for long-term course schizophrenia patients.