Neural correlates of task switching in paternal 15q11-q13 deletion Prader-Willi syndrome

We report a first study of brain activity linked to task switching in individuals with Prader-Willi syndrome (PWS) PWS individuals show a specific cognitive deficit in task switching which may be associated with the display of temper outbursts and repetitive questioning The performance of participants with PWS and typically developing controls was matched in a cued task switching procedure and brain activity was contrasted on switching and non switching blocks using SARI Individuals with PWS did not show the typical frontal-parietal pattern of neural activity associated with switching blocks, with significantly reduced activation in regions of the posterior parietal and ventromedial prefrontal cortices We suggest that this is linked to a difficulty in PWS in setting appropriate attentional weights to enable task set reconfiguration In addition to this, PWS individuals did not show the typical pattern of deactivation, with significantly less deactivation in an anterior region of the ventromedial prefrontal cortex One plausible explanation for this is that individuals with PWS show dysfunction within the default mode network which has been linked to attentional control The data point to functional changes in the neural circuitry supporting task switching in PWS even when behavioural performance is matched to controls and thus highlight neural mechanisms that may be involved in a specific pathway between genes cognition and behaviour (C) 2010 Elsevier B V All rights reserved

Object categorisations using templates constructed from multi-scale line and edge representations

Object categorisation is linked to detection, segregation and recognition. In the visual system, these processes are achieved in the ventral \what"and dorsal \where"pathways [3], with bottom-up feature extractions in areas V1, V2, V4 and IT (what) in parallel with top-down attention from PP via MT to V2 and V1 (where). The latter is steered by object templates in memory, i.e. in prefrontal cortex with a what component in PF46v and a where component in PF46d.

Controlo cognitivo na memória episódica : dados de adolescentes e jovens adultos

Dissertação de mestrado, Ciência Cognitiva, Universidade de Lisboa, Faculdade de Psicologia, Faculdade de Medicina, Faculdade de Ciências, Faculdade de Letras, 2014

Effects of early life permethrin exposure on spatial working memory and on monoamine levels in different brain areas of pre-senescent rats

Pesticide exposure during brain development could represent an important risk factor for the onset of neurodegenerative diseases. Previous studies investigated the effect of permethrin (PERM) administered at 34 mg/kg, a dose close to the no observable adverse effect level (NOAEL) from post natal day (PND) 6 to PND 21 in rats. Despite the PERM dose did not elicited overt signs of toxicity (i.e. normal body weight gain curve), it was able to induce striatal neurodegeneration (dopamine and Nurr1 reduction, and lipid peroxidation increase). The present study was designed to characterize the cognitive deficits in the current animal model. When during late adulthood PERM treated rats were tested for spatial working memory performances in a T-maze-rewarded alternation task they took longer to choose for the correct arm in comparison to age matched controls. No differences between groups were found in anxiety-like state, locomotor activity, feeding behavior and spatial orientation task. Our findings showing a selective effect of PERM treatment on the T-maze task point to an involvement of frontal cortico-striatal circuitry rather than to a role for the hippocampus. The predominant disturbances concern the dopamine (DA) depletion in the striatum and, the serotonin (5-HT) and noradrenaline (NE) unbalance together with a hypometabolic state in the medial prefrontal cortex area. In the hippocampus, an increase of NE and a decrease of DA were observed in PERM treated rats as compared to controls. The concentration of the most representative marker for pyrethroid exposure (3-phenoxybenzoic acid) measured in the urine of rodents 12 h after the last treatment was 41.50 µ/L and it was completely eliminated after 96 h.

Potential Therapeutic Effects of Physical Exercise for Bipolar Disorder

Cognitive deficits are observed in a variety of domains in patients with bipolar disorder (BD). These deficits are attributed to neurobiological, functional and structural brain factors, particularly in prefrontal cortex. Furthermore, cortical alterations in each phase (mania/hypomania, euthymia and depression) are also present. A growing basis of evidence supports aerobic exercise as an alternative treatment method for BD symptoms. Its benefits for physical health in healthy subjects and some psychiatric disorders are fairly established; however evidence directly addressed to BD is scant. Lack of methodological consistency, mainly related to exercise, makes it difficult accuracy and extrapolation of the results. Nevertheless, mechanisms related to BD physiopathology, such as hormonal and neurotransmitters alterations and mainly related to brain-derived neurotrophic factors (BDNF) can be explored. BDNF, specially, have a large influence on brain ability and its gene expression is highly responsive to aerobic exercise. Moreover, aerobic exercise trough BDNF may induce chronic stress suppression, commonly observed in patients with BD, and reduce deleterious effects caused by allostatic loads. Therefore, it is prudent to propose that aerobic exercise plays an important role in BD physiopathological mechanisms and it is a new way for the treatment for this and others psychiatric disorders.

Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: Relevance to schizophrenia.

A series of studies in schizophrenic patients report a decrease of glutathione (GSH) in prefrontal cortex (PFC) and cerebrospinal fluid, a decrease in mRNA levels for two GSH synthesizing enzymes and a deficit in parvalbumin (PV) expression in a subclass of GABA neurons in PFC. GSH is an important redox regulator, and its deficit could be responsible for cortical anomalies, particularly in regions rich in dopamine innervation. We tested in an animal model if redox imbalance (GSH deficit and excess extracellular dopamine) during postnatal development would affect PV-expressing neurons. Three populations of interneurons immunolabeled for calcium-binding proteins were analyzed quantitatively in 16-day-old rat brain sections. Treated rats showed specific reduction in parvalbumin immunoreactivity in the anterior cingulate cortex, but not for calbindin and calretinin. These results provide experimental evidence for the critical role of redox regulation in cortical development and validate this animal model used in schizophrenia research.

Controversies about the enhanced vulnerability of the adolescent brain to develop addiction.

Adolescence, defined as a transition phase toward autonomy and independence, is a natural time of learning and adjustment, particularly in the setting of long-term goals and personal aspirations. It also is a period of heightened sensation seeking, including risk taking and reckless behaviors, which is a major cause of morbidity and mortality among teenagers. Recent observations suggest that a relative immaturity in frontal cortical neural systems may underlie the adolescent propensity for uninhibited risk taking and hazardous behaviors. However, converging preclinical and clinical studies do not support a simple model of frontal cortical immaturity, and there is substantial evidence that adolescents engage in dangerous activities, including drug abuse, despite knowing and understanding the risks involved. Therefore, a current consensus considers that much brain development during adolescence occurs in brain regions and systems that are critically involved in the perception and evaluation of risk and reward, leading to important changes in social and affective processing. Hence, rather than naive, immature and vulnerable, the adolescent brain, particularly the prefrontal cortex, should be considered as prewired for expecting novel experiences. In this perspective, thrill seeking may not represent a danger but rather a window of opportunities permitting the development of cognitive control through multiple experiences. However, if the maturation of brain systems implicated in self-regulation is contextually dependent, it is important to understand which experiences matter most. In particular, it is essential to unveil the underpinning mechanisms by which recurrent adverse episodes of stress or unrestricted access to drugs can shape the adolescent brain and potentially trigger life-long maladaptive responses.

Autonomic and electrocortical indices of performance monitoring and source memory discrimination in older and younger adults

Reduced capacity for executive cognitive function and for the autonomic control of cardiac responsivity are both concomitants of the aging process. These may be linked through their mutual dependence on medial prefrontal function, but the specifics ofthat linkage have not been well explored. Executive functions associated with medial prefrontal cortex involve various aspects ofperformance monitoring, whereas centrally mediated autonomic functions can be observed as heart rate variability (HRV), i.e., variability in the length of intervals between heart beats. The focus for this thesis was to examine the degree to which the capacity for phasic autonomic adjustments to heart rate relates to performance monitoring in younger and older adults, using measures of electrocortical and autonomic activity. Behavioural performance and attention allocation during two age-sensitive tasks could be predicted by various aspects of autonomic control. For young adults, greater influence of the parasympathetic system on HRV was beneficial for learning unfamiliar maze paths; for older adults, greater sympathetic influence was detrimental to these functions. Further, these relationships were primarily evoked when the task required the construction and use of internalized representations of mazes rather than passive responses to feedback. When memory for source was required, older adults made three times as many source errors as young adults. However, greater parasympathetic influence on HRV in the older group was conducive to avoiding source errors and to reduced electrocortical responses to irrelevant information. Higher sympathetic predominance, in contrast, was associated with higher rates of source error and greater electrocortical responses tq non-target information in both groups. These relations were not seen for 11 errors associated with a speeded perceptual task, irrespective of its difficulty level. Overall, autonomic modulation of cardiac activity was associated with higher levels of performance monitoring, but differentially across tasks and age groups. With respect to age, those older adults who had maintained higher levels of autonomic cardiac regulation appeared to have also maintained higher levels of executive control over task performance.

Individual differences in risk-taking and associated characteristics : a test of specificity in executive functions /

Multiple measures have been devised by clinicians and theorists from many different backgrounds for the purpose of assessing the influence of the frontal lobes on behaviour. Some utilize self-report measures to investigate behavioural characteristics such as risktaking, sensation seeking, impulsivity, and sensitivity to reward and punishment in an attempt to understand complex human decision making. Others rely more on neuroimaging and electrophysiological investigation involving experimental tasks thought to demonstrate executive functions in action, while other researchers prefer to study clinical populations with selective damage. Neuropsychological models of frontal lobe functioning have led to a greater appreciation of the dissociations among various aspects of prefrontal cortex function. This thesis involves (1) an examination of various psychometric and experimental indices of executive functions for coherence as one would predict on the basis of highly developed neurophysiological models of prefrontal function, particularly those aspects of executive function that involve predominantly cognitive abilities versus processes characterized by affect regulation; and (2) investigation of the relations between risk-taking, attentional abilties and their associated characteristics using a neurophysiological model of prefrontal functions addressed in (1). Late adolescence is a stage in which the prefrontal cortices undergo intensive structural and functional maturational changes; this period also involves increases in levels of risky and sensation driven behaviours, as well as a hypersensitivity to reward and a reduction in inhibition. Consequently, late adolescence spears to represent an ideal developmental period in which to examine these decision-making behaviours due to the maximum variability of behavioural characteristics of interest. Participants were 45 male undergraduate 18- to 19-year olds, who completed a battery of measures that included self-report, experimental and behavioural measures designed to assess particular aspects of prefrontal and executive functioning. As predicted, factor analysis supported the grouping of executive process by type (either primarily cognitive or affective), conforming to the orbitofrontal versus dorsolateral typology; risk-taking and associated characteristics were associated more with the orbitofrontal than the dorsolateral factor, whereas attentional and planning abilities tended to correlate more strongly with the dorsolateral factor. Results are discussed in light of future assessment, investigation and understanding of complex human decision-making and executive functions. Implications, applications and suggestions for future research are also proposed.

Investigating the effects of arousal state on cognitive performance in individuals with and without mild head injury

We examined the cognitive and emotional sequelae following mild head injury (MHI; e.g., concussion) in high-functioning individuals and whether persons with MHI pre~ent, both physiologically and via self-report, in a manner different from (i.e., underaroused) that of persons who have no history of head injury. We also investigated the effect arousal state ~as on the cognitive performance of this population. Using a quasiexperimental research design (N = 91), we examined changes in attention, working memory, and cognitive flexibility (subtests ofthe WAIS-III, 1997,WMS-III, 1997, & DKEFS, 2002) as a function of manipulated arousal (i.e., induced psychosocial stress/activation; reduced activation/relaxation). In addition to self-reported arousal and state anxiety (State-Trait Anxiety Inventory; Speilberger, 1983a) measures, physiological indices of arousal state (i.e., electrodermal responsivity, heart rate, and respiration activity) were recorded (via Polygraph Professional Suite, 2008) across a 2.5 hour interval while completing various cognitive tasks. Students also completed the Post-concussive Symptom Checklist (Gouvier et aI., 1992). The results demonstrate that university students who report a history ofMHI (i.e., "altered state of consciousness") experience significantly lower levels of anxiety, were physiologically underaroused, and were less responsive to stressors in their environment, compared to their non-~HI cohorts. As expected, cognitive flexibility (but not other neuropsychological measures of cognition) was advantaged with increased stress, and disadvantaged with reduced stress, in persons with reported MHI, but not for those without reported MHI which provided limited support for our hypothesis. Further, university students who had no complaints related to their previous MHI endorsed a greater number of traditional post-concussive symptoms in terms of intensity, duration and frequency as compared to students who did not report a MHI. The underarousal in traumatic brain injury has been associated with (ventromedial prefrontal cortex) VMPFC disruption and may be implicated in MHI generally. Students who report sustaining a previous MHI may be less able to physiologically respond and/or cognitively appraise, stressful experiences as compared to their no-MHI cohort and experience persistent, long-lasting consequences despite the subtle nature of a history of head injury.

Developmental differences in locomotor responsiveness to amphetamine in rats

The developmental remodelling of motivational systems that underlie drug dependence and addiction may account for the greater frequency and severity of drug abuse in adolescence compared to adulthood. Recent advances in animal models have begun to identify the morphological and the molecular factors that are being remodelled, but little is known about the culmination of these factors in altered sensitivity to psycho stimulant drugs, like amphetamine, in adolescence. Amphetamine induces potent locomotor activating effects in rodents through increased dopamine release in the mesocorticolimbic dopamine system, which makes locomotor activity a useful behavioural marker of age differences in amphetamine sensitivity. The aim of the thesis was to investigate the neural basis for age differences in amphetamine sensitivity with a focus on the nucleus accumbens and the medial prefrontal cortex, which initiate and regulate amphetamine-induced locomotor activity, respectively. In study 1, I found pre- and post- pubertal adolescent rats to be less active (i.e., hypoactive) than adults to a first injection of 0.5, but not of 1.5, mg/kg of intraperitonealy (i.p.) administered amphetamine. Although initially hypoactive, only adolescent rats exhibited an increase in activity to a second injection of amphetamine given 24 h later, indicating that adolescents may be more sensitive to the rapid changes in amphetamineinduced plasticity than adults. Given that the locomotor activating effects of amphetamine are initiated in the nucleus accumbens, age differences in response to direct injections of amphetamine into this brain region were investigated in study 2. In contrast to i.p. injections, adolescents were more active than adults when amphetamine was given directly into the nucleus accumbens, indicating that hypo activity may be attributed to the development of regulatory regions outside of the accumbens. The medial prefrontal cortex (mPFC) is a key regulator of the locomotor activating effects of amphetamine that undergoes extensive remodelling in adolescence. In study 3, I found that an i.p. injection of 1.5, and not of 0.5, mg/kg of amphetamine resulted in a high expression of c-fos, a marker of neural activation, in the pre limbic mPFC only in pre-pubertal adolescent rats. This finding suggests that the ability of adolescent rats to overcome hypo activity at the 1.5 mg/kg dose may involve greater activation of the prelimbic mPFC compared to adulthood. In support of this hypothesis, I found that pharmacological inhibition of prelimbic D 1 dopamine receptors disrupted the locomotor activating effects of the 1.5 mg/kg dose of amphetamine to a greater extent in adolescent than in adult rats. In addition, the stimulation of prelimbic D 1 dopamine receptors potentiated locomotor activity at the 0.5 mg/kg dose of amphetamine only in adolescent rats, indicating that the prelimbic D1 dopamine receptors are involved in overcoming locomotor hypoactivity during adolescence. Given my finding that the locomotor activating effects of amphetamine rely on slightly different mechanisms in adolescence than in adulthood, study 4 was designed to determine whether the lasting consequences of drug use would also differ with age. A short period of pre-treatment with 0.5 mg/kg of amphetamine in adolescence, but not in adulthood, resulted in heightened sensitivity to an injection of amphetamine given 30 days after the start of the procedure, when adolescent rats had reached adulthood. The finding of an age-specific increase in amphetamine sensitivity is consistent with evidence for increased risk for addiction when drug use is initiated in adolescence compared to adulthood in people (Merline et aI., 2002), and with the hypothesis that adolescence is a sensitive period of development.

Effects of social context on endocrine function and Zif268 expression in response to an acute stressor in adolescent and adult rats

There is a paucity of studies comparing social buffering in adolescents and adults, despite their marked differences in social behaviour. I investigated whether greater effects of social buffering on plasma corticosterone concentrations and expression of Zif268 in neural regions after an acute stressor would be found in adolescent compared with adult rats. Samples were obtained before and after one hour of isolation stress and after either one or three hours of recovery back in the colony with either a familiar or unfamiliar cage partner. Adolescent and adult rats did not differ in plasma concentrations of corticosterone at any time point. Corticosterone concentrations were higher after one hour isolation than at baseline (p < 0.001), and rats with a familiar partner during the recovery phase had lower corticosterone concentrations than did rats with an unfamiliar partner (p = 0.02). Zif268 immunoreactive cell counts were higher in the arcuate nucleus in both age groups after isolation (p = 0.007) and higher in the paraventricular nucleus of adolescents compared with adults during the recovery phase irrespective of partner familiarity. There was a significant decrease in immunoreactive cell counts after one hour isolation compared to baseline in the basolateral amygdala, central nucleus of the amygdala, and in the pyramidal layer of the hippocampus (all p < 0.05). An effect of partner familiarity on Zif268 immunoreactive cell counts was found in the granule layer of the dentate gyrus irrespective of age (higher in those with a familiar partner, p = 0.03) and in the medial prefrontal cortex in adolescents (higher with an unfamiliar partner, p = 0.02). Overall, the acute stress and partner familiarity produced a similar pattern of results in adolescents and adults, with both age groups sensitive to the social context.

Les effets d’un traitement au corticostérone sur la transmission dopaminergique mésocorticale du rat en période de stress

L’axe hypothalamo-hypophyso-surrénalien joue un rôle essentiel dans l’adaptation et la réponse au stress. Toutefois, l’hyperactivation de cet axe ou des niveaux chroniquement élevés de glucocorticoïdes (GC) entraînent des conséquences pathologiques. Le système dopaminergique mésocortical, qui se projette dans le cortex préfrontal médian (CPFm), joue un rôle adaptatif en protégeant contre le stress. Jusqu’à présent, les interactions fonctionnelles entre les GC (ex : corticostérone) et le système dopaminergique mésocortical ne sont pas élucidées. Dans ce mémoire, nous avons évalué les effets des GC sur les fonctions dopaminergiques préfrontales en élevant chroniquement, à l’aide de minipompes osmotiques, les niveaux de corticostérone aux concentrations physiologiques maximales (1 mg/kg/h pendant 7 jours). Ce traitement n’a pas modifié significativement, chez les rats stressés ou non, les niveaux post mortem de dopamine et de son métabolite dans le tissu du CPFm. Toutefois, l’évaluation par voltamétrie in vivo des changements de dopamine extracellulaire dans le CPFmv a permis d’observer que la corticostérone augmente significativement la libération de dopamine en réponse à l’exposition à l’odeur de renard et au pincement de la queue. Nos études nous permettent de conclure que la corticostérone potentialise la fonction dopaminergique mésocorticale qui, à son tour, facilite la régulation négative en période de stress.

Influence du vieillissement sur la réorganisation cérébrale dans la compréhension du discours : apport de l’imagerie optique

Au cours du vieillissement, des modifications dans la compréhension du discours ont été rapportées, attribuées en partie aux changements cognitifs encourus lors du vieillissement. Néanmoins, diverses études suggèrent une réorganisation cérébrale lors du vieillissement. Cette étude a pour but d'évaluer l'influence de l'âge lors d'une tâche de compréhension du discours à l'aide de l'imagerie optique. Comme première hypothèse, il est attendu que les participants jeunes auront plus de bonnes réponses au niveau des micropropositions et des macropropositions et des performances équivalentes au niveau du modèle de situation. La deuxième hypothèse est que les réseaux neuronaux utilisés lors de la compréhension du discours subiront une réorganisation cérébrale lors du vieillissement. Trente-deux participants ont pris part à cette étude : 16 jeunes adultes et 16 adultes âgés. Alors que les participants étaient sous enregistrement en imagerie optique au niveau du cortex préfrontal (CPF), ils ont lu des courtes histoires chacune suivie d’une phrase et devaient décider si elle était en accord ou non avec la précédente histoire. Les résultats ne montrent aucune différence entre les groupes au niveau de l’exactitude des réponses, contrairement à la littérature. Le CPF a été davantage activé par les adultes âgés comparativement aux jeunes adultes témoignant d’une réorganisation cérébrale.

Effets d’un entraînement neuromoteur et d’un entraînement aérobie sur les fonctions exécutives chez l’enfant

Les études des effets de l’activité physique sur la cognition humaine et animale ne permettent pas de clarifier si ces effets sont spécifiques au type d’exercice pratiqué et si les gains cognitifs pour un cerveau en développement sont globaux ou exclusifs à certaines fonctions cognitives. Considérant le circuit nerveux entre le cervelet et le cortex préfrontal dorsolatéral, nous croyons qu’un entraînement neuromoteur stimulant les fonctions motrices du cervelet améliorera les fonctions exécutives associées au cortex préfrontal. Comme l’entraînement aérobie a affecté positivement différentes fonctions cognitives dans des études précédentes, nous croyons que ce type d’exercice améliorera les fonctions exécutives et la mémoire à long-terme. Trois classes de sixième année (âge moyen = 11,4 ans) ont été aléatoirement assignées aux groupes neuromoteur (n=22), aérobie (n=19) et contrôle (n=15). Nous nous sommes assurés que l’entraînement neuromoteur ne stimulait aucunement la capacité aérobie et que l’entraînement aérobie n’améliorait aucune habileté motrice. Les entraînements pour les deux groupes expérimentaux consistaient en 30 minutes d’activités par jour d’école pendant les heures de classe, pour 10 semaines ; le groupe contrôle suivait le programme scolaire régulier. Des tests moteurs et cognitifs ont été administrés avant et après l’intervention. Une série d’ANOVAs a révélé que l’entraînement neuromoteur avait amélioré la fluence verbale avec un effet marginal sur la génération de verbe, deux fonctions exécutives associées au circuit fronto-cérébelleux, et que l’entraînement aérobie avait mené à une amélioration distincte de la fluence verbale. Ainsi, nos résultats démontrent que les améliorations des fonctions exécutives sont spécifiques à chaque entraînement pratiqué.