Down Syndrome: Neuropsychological phenotype and mitochondrial DNA

Introduction. Down Syndrome (DS) is the most known autosomal trisomy, due to the presence in three copies of chromosome 21. Many studies were designed to identify phenotypic and clinical consequences related to the triple gene dosage. However, the general conclusion is a senescent phenotype; in particular, the most features of physiological aging, such as skin and hair changes, vision and hearing impairments, thyroid dysfunction, Alzheimer-like dementia, congenital heart defects, gastrointestinal malformations, immune system changes, appear in DS earlier than in normal age-matched subjects. The only established risk factor for the DS is advanced maternal age, responsible for changes in the meiosis of oocytes, in particular the meiotic nondisjunction of chromosome 21. In this process mitochondria play an important role since mitochondrial dysfunction, due to a variety of extrinsic and intrinsic influences, can profoundly influence the level of ATP generation in oocytes, required for a correct chromosomal segregation. Aim. The aim of this study is to investigate an integrated set of molecular genetic parameters (sequencing of complete mtDNA, heteroplasmy of the mtDNA control region, genotypes of APOE gene) in order to identify a possible association with the early neurocognitive decline observed in DS. Results. MtDNA point mutations do not accumulate with age in our study sample and do not correlate with early neurocognitive decline of DS subjects. It seems that D-loop heteroplasmy is largely not inherited and tends to accumulate somatically. Furthermore, in our study sample no association of cognitive impairment and ApoE genotype is found. Conclusions. Overall, our data cast some doubts on the involvement of these mutations in the decline of cognitive functions observed in DS.

Sonno e funzioni cognitive: ruolo della microstruttura del sonno NREM

STUDY OBJECTIVE: Cyclic Alternating Pattern (CAP) is a fluctuation of the arousal level during NREM sleep and consists of the alternation between two phases: phase A (divided into three subtypes A1, A2, and A3) and phase B. A1 is thought to be generated by the frontal cortex and is characterized by the presence of K complexes or delta bursts; additionally, CAP A1 seems to have a role in the involvement of sleep slow wave activity in cognitive processing. Our hypothesis was that an overall CAP rate would have a negative influence on cognitive performance due to excessive fluctuation of the arousal level during NREM sleep. However, we also predicted that CAP A1 would be positively correlated with cognitive functions, especially those related to frontal lobe functioning. For this reason, the objective of our study was to correlate objective sleep parameters with cognitive behavioral measures in normal healthy adults. METHODS: 8 subjects (4 males; 4 females; mean age 27.75 years, range 2334) were recruited for this study. Two nocturnal polysomnography (night 2 and 3 = N2 and N3) were carried out after a night of adaptation. A series of neuropsychological tests were performed by the subjects in the morning and afternoon of the second day (D2am; D2pm) and in the morning of the third day (D3am). Raw scores from the neuropsychological tests were used as dependent variables in the statistical analysis of the results. RESULTS: We computed a series of partial correlations between sleep microstructure parameters (CAP, A1, A2 and A3 rate) and a number of indices of cognitive functioning. CAP rate was positively correlated with visuospatial working memory (Corsi block test), Trial Making Test Part A (planning and motor sequencing) and the retention of words from the Hopkins Verbal Learning Test (HVLT). Conversely, CAP was negatively correlated with visuospatial fluency (Ruff Figure Fluency Test). CAP A1 were correlated with many of the tests of neuropsychological functioning, such as verbal fluency (as measured by the COWAT), working memory (as measured by the Digit Span – Backward test), and both delay recall and retention of the words from the HVLT. The same parameters were found to be negatively correlated with CAP A2 subtypes. CAP 3 were negatively correlated with the Trial Making Test Parts A and B. DISCUSSION: To our knowledge this is the first study indicating a role of CAP A1 and A2 on behavioral cognitive performance of healthy adults. The results suggest that high rate of CAP A1 might be related to an improvement whereas high rate of CAP A2 to a decline of cognitive functions. Further studies need to be done to better determine the role of the overall CAP rate and CAP A3 on cognitive behavioral performances.

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.

Visual scanning in sports actions: comparison between soccer goalkeepers and judo fighters

Visual search and oculomotor behaviour are believed to be very relevant for athlete performance, especially for sports requiring refined visuo-motor coordination skills. Modern coaches believe that a correct visuo-motor strategy may be part of advanced training programs. In this thesis two experiments are reported in which gaze behaviour of expert and novice athletes were investigated while they were doing a real sport specific task. The experiments concern two different sports: judo and soccer. In each experiment, number of fixations, fixation locations and mean fixation duration (ms) were considered. An observational analysis was done at the end of the paper to see perceptual differences between near and far space. Purpose: The aim of the judo study was to delineate differences in gaze behaviour characteristics between a population of athletes and one of non athletes. Aspects specifically investigated were: search rate, search order and viewing time across different conditions in a real-world task. The second study was aimed at identifying gaze behaviour in varsity soccer goalkeepers while facing a penalty kick executed with instep and inside foot. Then an attempt has been done to compare the gaze strategies of expert judoka and soccer goalkeepers in order to delineate possible differences related to the different conditions of reacting to events occurring in near (peripersonal) or far (extrapersonal) space. Judo Methods: A sample of 9 judoka (black belt) and 11 near judoka (white belt) were studied. Eye movements were recorded at 500Hz using a video based eye tracker (EyeLink II). Each subject participated in 40 sessions for about 40 minutes. Gaze behaviour was considered as average number of locations fixated per trial, the average number of fixations per trial, and mean fixation duration. Soccer Methods: Seven (n = 7) intermediate level male volunteered for the experiment. The kickers and goalkeepers, had at least varsity level soccer experience. The vision-in-action (VIA) system (Vickers 1996; Vickers 2007) was used to collect the coupled gaze and motor behaviours of the goalkeepers. This system integrated input from a mobile eye tracking system (Applied Sciences Laboratories) with an external video of the goalkeeper’s saving actions. The goalkeepers took 30 penalty kicks on a synthetic pitch in accordance with FIFA (2008) laws. Judo Results: Results indicate that experts group differed significantly from near expert for fixations duration, and number of fixations per trial. The expert judokas used a less exhaustive search strategy involving fewer fixations of longer duration than their novice counterparts and focused on central regions of the body. The results showed that in defence and attack situation expert group did a greater number of transitions with respect to their novice counterpart. Soccer Results: We found significant main effect for the number of locations fixated across outcome (goal/save) but not for foot contact (instep/inside). Participants spent more time fixating the areas in instep than inside kick and in goal than in save situation. Mean and standard error in search strategy as a result of foot contact and outcome indicate that the most gaze behaviour start and finish on ball interest areas. Conclusions: Expert goalkeepers tend to spend more time in inside-save than instep-save penalty, differences that was opposite in scored penalty kick. Judo results show that differences in visual behaviour related to the level of expertise appear mainly when the test presentation is continuous, last for a relatively long period of time and present a high level of uncertainty with regard to the chronology and the nature of events. Expert judoist performers “anchor” the fovea on central regions of the scene (lapel and face) while using peripheral vision to monitor opponents’ limb movements. The differences between judo and soccer gaze strategies are discussed on the light of physiological and neuropsychological differences between near and far space perception.

The spatial representation of time

Numerosi studi mostrano che gli intervalli temporali sono rappresentati attraverso un codice spaziale che si estende da sinistra verso destra, dove gli intervalli brevi sono rappresentati a sinistra rispetto a quelli lunghi. Inoltre tale disposizione spaziale del tempo può essere influenzata dalla manipolazione dell’attenzione-spaziale. La presente tesi si inserisce nel dibattito attuale sulla relazione tra rappresentazione spaziale del tempo e attenzione-spaziale attraverso l’uso di una tecnica che modula l’attenzione-spaziale, ovvero, l’Adattamento Prismatico (AP). La prima parte è dedicata ai meccanismi sottostanti tale relazione. Abbiamo mostrato che spostando l’attenzione-spaziale con AP, verso un lato dello spazio, si ottiene una distorsione della rappresentazione di intervalli temporali, in accordo con il lato dello spostamento attenzionale. Questo avviene sia con stimoli visivi, sia con stimoli uditivi, nonostante la modalità uditiva non sia direttamente coinvolta nella procedura visuo-motoria di AP. Questo risultato ci ha suggerito che il codice spaziale utilizzato per rappresentare il tempo, è un meccanismo centrale che viene influenzato ad alti livelli della cognizione spaziale. La tesi prosegue con l’indagine delle aree corticali che mediano l’interazione spazio-tempo, attraverso metodi neuropsicologici, neurofisiologici e di neuroimmagine. In particolare abbiamo evidenziato che, le aree localizzate nell’emisfero destro, sono cruciali per l’elaborazione del tempo, mentre le aree localizzate nell’emisfero sinistro sono cruciali ai fini della procedura di AP e affinché AP abbia effetto sugli intervalli temporali. Infine, la tesi, è dedicata allo studio dei disturbi della rappresentazione spaziale del tempo. I risultati ci indicano che un deficit di attenzione-spaziale, dopo danno emisferico destro, provoca un deficit di rappresentazione spaziale del tempo, che si riflette negativamente sulla vita quotidiana dei pazienti. Particolarmente interessanti sono i risultati ottenuti mediante AP. Un trattamento con AP, efficace nel ridurre il deficit di attenzione-spaziale, riduce anche il deficit di rappresentazione spaziale del tempo, migliorando la qualità di vita dei pazienti.

Longitudinal evolution of cognitive functions in patients with multiple system atrophy: a prospective study

Introduction and Background: Multiple system atrophy (MSA) is a sporadic, adult-onset, progressive neurodegenerative disease characterized clinically by parkinsonism, cerebellar ataxia, and autonomic failure. We investigated cognitive functions longitudinally in a group of probable MSA patients, matching data with sleep parameters. Patients and Methods: 10 patients (7m/3f) underwent a detailed interview, a general and neurological examination, laboratory exams, MRI scans, a cardiovascular reflexes study, a battery of neuropsychological tests, and video-polysomnographic recording (VPSG). Patients were revaluated (T1) a mean of 16±5 (range: 12-28) months after the initial evaluation (T0). At T1, the neuropsychological assessment and VPSG were repeated. Results: The mean patient age was 57.8±6.4 years (range: 47-64) with a mean age at disease onset of 53.2±7.1 years (range: 43-61) and symptoms duration at T0 of 60±48 months (range: 12-144). At T0, 7 patients showed no cognitive deficits while 3 patients showed isolated cognitive deficits. At T1, 1 patient worsened developing multiple cognitive deficits from a normal condition. At T0 and T1, sleep efficiency was reduced, REM latency increased, NREM sleep stages 1-2 slightly increased. Comparisons between T1 and T0 showed a significant worsening in two tests of attention and no significant differences of VPSG parameters. No correlation was found between neuropsychological results and VPSG findings or RBD duration. Discussion and Conclusions: The majority of our patients do not show any cognitive deficits at T0 and T1, while isolated cognitive deficits are present in the remaining patients. Attention is the cognitive function which significantly worsened. Our data confirm the previous findings concerning the prevalence, type and the evolution of cognitive deficits in MSA. Regarding the developing of a condition of dementia, our data did not show a clear-cut diagnosis of dementia. We confirm a mild alteration of sleep structure. RBD duration does not correlate with neuropsychological findings.

Development, degeneration and neural network of the bodily self

The question addressed by this dissertation is how the human brain builds a coherent representation of the body, and how this representation is used to recognize its own body. Recent approaches by neuroimaging and TMS revealed hints for a distinct brain representation of human body, as compared with other stimulus categories. Neuropsychological studies demonstrated that body-parts and self body-parts recognition are separate processes sub-served by two different, even if possibly overlapping, networks within the brain. Bodily self-recognition is one aspect of our ability to distinguish between self and others and the self/other distinction is a crucial aspect of social behaviour. This is the reason why I have conducted a series of experiment on subjects with everyday difficulties in social and emotional behaviour, such as patients with autism spectrum disorders (ASD) and patients with Parkinson’s disease (PD). More specifically, I studied the implicit self body/face recognition (Chapter 6) and the influence of emotional body postures on bodily self-processing in TD children as well as in ASD children (Chapter 7). I found that the bodily self-recognition is present in TD and in ASD children and that emotional body postures modulate self and others’ body processing. Subsequently, I compared implicit and explicit bodily self-recognition in a neuro-degenerative pathology, such as in PD patients, and I found a selective deficit in implicit but not in explicit self-recognition (Chapter 8). This finding suggests that implicit and explicit bodily self-recognition are separate processes subtended by different mechanisms that can be selectively impaired. If the bodily self is crucial for self/other distinction, the space around the body (personal space) represents the space of interaction and communication with others. When, I studied this space in autism, I found that personal space regulation is impaired in ASD children (Chapter 9).

Epileptic and developmental encephalopathies: clinical and genetic study of adult patients attending a tertiary Epilepsy Centre

Objectives: To fully re-evaluate patients with early-onset epilepsy and intellectual disability with neurological, neurophysiological and neuropsychological examination in order to contribute to expanding the phenotypic spectrum of known epileptic encephalopathy (EE)-related genes and to identify novel genetic defects underlying EEs. Methods: We recruited patients with epilepsy and intellectual disability (ID) referring to our Epilepsy Centre. Patients underwent full clinical and neurophysiologic evaluation. When possible they underwent neuroradiologic investigations. Selected cases also underwent genetic analysis. Results: We recruited 200 patients (109 M, 91 F; mean age 36 years old). Mean age at epilepsy onset was 4 years old. The degree of ID was borderline in 4.5% of patients, mild in 25%, moderate in 38% and severe in 32.5%. EEG showed epileptiform abnormalities in 79.5% of patients. One hundred and thirty-one patients out of the 200 recruited (65.5%) did not have an aetiological diagnosis. All the patients underwent full clinical reassessment and when necessary they performed neuroradiologic and genetic investigations as well. We identified 35 patients with a genetic aetiology. In 8 cases a structural brain lesion was observed. In 33 patients, a genetic aetiology was identified. In 2 patients with drug-resistant seizures video-EEG allowed the identification of non-epileptic seizures, and in one patient we discontinued anti-epileptic drugs. In these patients, the aetiological diagnosis was made after 30 years (range 9-60 years) from the disease onset. Conclusions: In a population of 200 adult patients with epilepsy and ID, an aetiological cause was identified in 45 patients after 30 years from the disease onset. Aetiological diagnosis, especially if genetic, has significant positive implications for patients, even if it has been made after years from the beginning of the disease. Benefits include better-focused antiepileptic drug (AED) choice, sparing of further unnecessary investigations and improved knowledge of comorbidities.

Myotonic syndromes: analysis of factors with pathogenetic and prognostic significance

Background: The natural history of Myotonic Dystrophy type 1 is largely unclear, longitudinal studies are lacking. Objectives: to collect clinical and laboratory data, to evaluate sleep disorders, somatic and autonomic skin fibres, neuropsychological and neuroradiological aspects in DM1 patients. Methods: 72 DM1 patients underwent a standardized clinical and neuroradiological evaluation performed by a multidisciplinary team during 3 years of follow-up. Results: longer disease duration was associated with higher incidence of conduction disorders and lower ejection fraction; higher CVF values were predictors for a reduced risk of cardiopathy. Lower functional pulmonary values were associated with class of expansion and were negatively associated with disease duration; arterial blood gas parameters were not associated with expansion size, disease duration nor with respiratory function test. Excessive daytime sleepiness was not associated with class of expansion nor with any of the clinical parameters examined. We detected apnoea in a large percentage of patients, without differences between the 3 genetic classes; higher CVF values were predictors for a reduced risk of apnoea. Skin biopsies demonstrated the presence of a subclinical small fibre neuropathy with involvement of the somatic fibres. The pupillometry study showed lower pupil size at baseline and a lower constriction response to light. The most affected neuropsychological domains were executive functions, visuoconstructional, attention and visuospatial tasks, with a worse performance of E1 patients in the visuoperceptual ability and social cognition tasks. MRI study demonstrated a decrease in the volumes of frontal, parietal, temporal, occipital cortices, accumbens, putamen nuclei and a more severe volume reduction of the isthmus cingulate, transverse temporal, superior parietal and temporal gyri in E2 patients. Discussion: only some clinical parameters could predict the risk of cardiopathy, pulmonary syndrome and sleep disorders, while other clinical aspects proved to be unpredictable, confirming the importance of periodic clinical follow-up of these patients.

Development and characterization of deep learning techniques for neuroimaging data

Deep learning methods are extremely promising machine learning tools to analyze neuroimaging data. However, their potential use in clinical settings is limited because of the existing challenges of applying these methods to neuroimaging data. In this study, first a data leakage type caused by slice-level data split that is introduced during training and validation of a 2D CNN is surveyed and a quantitative assessment of the model’s performance overestimation is presented. Second, an interpretable, leakage-fee deep learning software written in a python language with a wide range of options has been developed to conduct both classification and regression analysis. The software was applied to the study of mild cognitive impairment (MCI) in patients with small vessel disease (SVD) using multi-parametric MRI data where the cognitive performance of 58 patients measured by five neuropsychological tests is predicted using a multi-input CNN model taking brain image and demographic data. Each of the cognitive test scores was predicted using different MRI-derived features. As MCI due to SVD has been hypothesized to be the effect of white matter damage, DTI-derived features MD and FA produced the best prediction outcome of the TMT-A score which is consistent with the existing literature. In a second study, an interpretable deep learning system aimed at 1) classifying Alzheimer disease and healthy subjects 2) examining the neural correlates of the disease that causes a cognitive decline in AD patients using CNN visualization tools and 3) highlighting the potential of interpretability techniques to capture a biased deep learning model is developed. Structural magnetic resonance imaging (MRI) data of 200 subjects was used by the proposed CNN model which was trained using a transfer learning-based approach producing a balanced accuracy of 71.6%. Brain regions in the frontal and parietal lobe showing the cerebral cortex atrophy were highlighted by the visualization tools.

Hierarchical active inference for cognitive architectures

This thesis explores the methods based on the free energy principle and active inference for modelling cognition. Active inference is an emerging framework for designing intelligent agents where psychological processes are cast in terms of Bayesian inference. Here, I appeal to it to test the design of a set of cognitive architectures, via simulation. These architectures are defined in terms of generative models where an agent executes a task under the assumption that all cognitive processes aspire to the same objective: the minimization of variational free energy. Chapter 1 introduces the free energy principle and its assumptions about self-organizing systems. Chapter 2 describes how from the mechanics of self-organization can emerge a minimal form of cognition able to achieve autopoiesis. In chapter 3 I present the method of how I formalize generative models for action and perception. The architectures proposed allow providing a more biologically plausible account of more complex cognitive processing that entails deep temporal features. I then present three simulation studies that aim to show different aspects of cognition, their associated behavior and the underlying neural dynamics. In chapter 4, the first study proposes an architecture that represents the visuomotor system for the encoding of actions during action observation, understanding and imitation. In chapter 5, the generative model is extended and is lesioned to simulate brain damage and neuropsychological patterns observed in apraxic patients. In chapter 6, the third study proposes an architecture for cognitive control and the modulation of attention for action selection. At last, I argue how active inference can provide a formal account of information processing in the brain and how the adaptive capabilities of the simulated agents are a mere consequence of the architecture of the generative models. Cognitive processing, then, becomes an emergent property of the minimization of variational free energy.