Intellectual, adaptive and behavioural characteristics in four patients with 18p deletion syndrome.

BACKGROUND: The association of behavioural phenotype assessment with cytogenomic characterisation may provide a better comprehension of genotype-phenotype correlations in syndromes caused by chromosomal abnormalities, such as 18p deletion syndrome. METHOD: We report on four Brazilian patients with 18p deletion syndrome characterised by cytogenomic techniques and detailed neuropsychological evaluation. Intellectual, adaptive and behavioural characteristics were assessed through the Wechsler's Scales, the Vineland-II Scale and the Child Behaviour Checklist, respectively. Socio-economic measures including main caretaker educational level and family income as defined by Brazilian criteria for social class classification were also collected to evaluate a possible contribution of environmental factors in neurocognitive variability. RESULTS: Two out of four patients showed intellectual disability (IQ < 70). Wechsler's scale results suggest that in our sample, interpretation of social situations based on observation of non-verbal behaviour constitute a cognitive strength while judgement of social rules and language skills associated with word knowledge and verbal fluency may be a cognitive weakness. Concerning adaptive behaviour, motor and socialisation domains showed to better develop than communication and daily living skills on the Vineland-II Scale. Only one patient presented internalising behavioural problems based on the Child Behaviour Checklist. Our results also suggested that socio-economic status may contribute to overall patient development. CONCLUSION: Our results suggest that some 18p deletion syndrome patients may present average intellectual performance and that the segment deletion size and some families' socio-economic conditions may influence cognitive development.

Latent class analysis of attention and white matter correlation in children with attention-deficit/hyperactivity disorder.

This study aimed to explore attentional patterns among children with inattentive attention-deficit/hyperactivity disorder (ADHD-I) and children with typical development (TD), using a latent class analysis (LCA). Patterns of brain connectivity were also explored. The sample comprised 29 ADHD-I and 29 TD matched children. An LCA was conducted to reclassify subjects according to their attentional performance, considering cognitive measures of attention and behavioral symptoms, regardless of group of origin. The new clusters were then compared in respect to brain white matter measurements (extracted from diffusion tensor imaging). Participants were rearranged in 2 new latent classes, according to their performance in an attention task and the results of behavioral scales, resulting in groups with more homogeneous attentional profiles. A comparison of the 2 new classes using the white matter measurements revealed increased fractional anisotropy in the left inferior fronto-occipital fasciculus and left inferior longitudinal fasciculus for the class composed by participants with a higher risk of attentional problems. The findings indicated that it was possible to observe variability regarding neuropsychological profile, accompanied by underpinning neurobiological differences, even among individuals with the same disorder subtype - inattentive ADHD. This specific data-driven clustering analysis may help to enhance understanding of the pathophysiology of the disorder's phenotypes.

Latent class analysis of attention and white matter correlation in children with attention-deficit/hyperactivity disorder

This study aimed to explore attentional patterns among children with inattentive attention-deficit/hyperactivity disorder (ADHD-I) and children with typical development (TD), using a latent class analysis (LCA). Patterns of brain connectivity were also explored. The sample comprised 29 ADHD-I and 29 TD matched children. An LCA was conducted to reclassify subjects according to their attentional performance, considering cognitive measures of attention and behavioral symptoms, regardless of group of origin. The new clusters were then compared in respect to brain white matter measurements (extracted from diffusion tensor imaging). Participants were rearranged in 2 new latent classes, according to their performance in an attention task and the results of behavioral scales, resulting in groups with more homogeneous attentional profiles. A comparison of the 2 new classes using the white matter measurements revealed increased fractional anisotropy in the left inferior fronto-occipital fasciculus and left inferior longitudinal fasciculus for the class composed by participants with a higher risk of attentional problems. The findings indicated that it was possible to observe variability regarding neuropsychological profile, accompanied by underpinning neurobiological differences, even among individuals with the same disorder subtype - inattentive ADHD. This specific data-driven clustering analysis may help to enhance understanding of the pathophysiology of the disorder's phenotypes.

Effects of a physical fitness program on memory and blood viscosity in sedentary elderly men.

The aim of this study was to investigate the effects of a 6-month exercise program on cognitive function and blood viscosity in sedentary elderly men. Forty-six healthy inactive men, aged 60-75 years were randomly distributed into a control group (n=23) and an experimental group (n=23). Participants underwent blood analysis and physical and memory evaluation, before and after the 6-month program of physical exercise. The control group was instructed not to alter its everyday activities; the experimental group took part in the fitness program. The program was conducted using a cycle ergometer, 3 times per week on alternate days, with intensity and volume individualized at ventilatory threshold 1. Sessions were continuous and maximum duration was 60 min each. There was significant improvement in memory (21%; P<0.05), decreased blood viscosity (-19%; P<0.05), and higher aerobic capacity (48%; P<0.05) among participants in the experimental group compared with the control group. These data suggest that taking part in an aerobic physical fitness program at an intensity corresponding to ventilatory threshold-1 may be considered a nonmedication alternative to improve physical and cognitive function.

Acute effects of donepezil in healthy young adults underline the fractionation of executive functioning.

The cholinergic system is involved in the modulation of both bottom-up and top-down attentional control. Top-down attention engages multiple executive control processes, but few studies have investigated whether all or selective elements of executive functions are modulated by the cholinergic system. To investigate the acute effects of the pro-cholinergic donepezil in young, healthy volunteers on distinct components of executive functions we conducted a double-blind, placebo-controlled, independent-groups design study including 42 young healthy male participants who were randomly assigned to one of three oral treatments: glucose (placebo), donepezil 5 mg or donepezil 7.5 mg. The test battery included measures of different executive components (shifting, updating, inhibition, dual-task performance, planning, access to long-term memory), tasks that evaluated arousal/vigilance/visuomotor performance, as well as functioning of working memory subsidiary systems. Donepezil improved sustained attention, reaction times, dual-task performance and the executive component of digit span. The positive effects in these executive tasks did not correlate with arousal/visuomotor/vigilance measures. Among the various executive domains investigated donepezil selectively increased dual-task performance in a manner that could not be ascribed to improvement in arousal/vigilance/visuomotor performance nor working memory slave systems. Other executive tasks that rely heavily on visuospatial processing may also be modulated by the cholinergic system.

The Prospective and Retrospective Memory Questionnaire: a population-based random sampling study.

The Prospective and Retrospective Memory Questionnaire (PRMQ) has been shown to have acceptable reliability and factorial, predictive, and concurrent validity. However, the PRMQ has never been administered to a probability sample survey representative of all ages in adulthood, nor have previous studies controlled for factors that are known to influence metamemory, such as affective status. Here, the PRMQ was applied in a survey adopting a probabilistic three-stage cluster sample representative of the population of Sao Paulo, Brazil, according to gender, age (20-80 years), and economic status (n=1042). After excluding participants who had conditions that impair memory (depression, anxiety, used psychotropics, and/or had neurological/psychiatric disorders), in the remaining 664 individuals we (a) used confirmatory factor analyses to test competing models of the latent structure of the PRMQ, and (b) studied effects of gender, age, schooling, and economic status on prospective and retrospective memory complaints. The model with the best fit confirmed the same tripartite structure (general memory factor and two orthogonal prospective and retrospective memory factors) previously reported. Women complained more of general memory slips, especially those in the first 5 years after menopause, and there were more complaints of prospective than retrospective memory, except in participants with lower family income.

Cognitive performance of young and elderly subjects on the free word recall memory test: effect of presentation order on recall order

The influence of aging on memory has been extensively studied, but the importance of short-term memory and recall sequence has not. The objective of the current study was to examine the recall order of words presented on lists and to determine if age affects recall sequence. Physically and psychologically healthy male subjects were divided into two groups according to age, i.e., 23 young subjects (20 to 30 years) and 50 elderly subjects (60 to 70 years) submitted to the Wechsler Adult Intelligence Scale-Revised and the free word recall test. The order of word presentation significantly affected the 3rd and 4th words recalled (P < 0.01; F = 14.6). In addition, there was interaction between the presentation order and the type of list presented (P < 0.05; F = 9.7). Also, both groups recalled the last words presented from each list (words 13-15) significantly more times 3rd and 4th than words presented in all remaining positions (P < 0.01). The order of word presentation also significantly affected the 5th and 6th words recalled (P = 0.05; F = 7.5) and there was a significant interaction between the order of presentation and the type of list presented (P < 0.01; F = 20.8). The more developed the cognitive functions, resulting mainly from formal education, the greater the cognitive reserve, helping to minimize the effects of aging on the long-term memory (episodic declarative).

Calcineurin deficiency decreases inflammatory lesions in transforming growth factor beta1-deficient mice.

Transforming growth factor (TGF) beta1) is an immunoregulatory cytokine involved in self-tolerance and lymphocyte homeostasis. Tgfb1 knock-out (KO) mice develop severe multi-focal autoimmune inflammatory lesions due to [Ca(2+)]i deregulation in T cells, and die within 3 weeks after birth. Because the calcineurin inhibitor FK506 inhibits the hyperresponsiveness of Tgfb1(-/-) thymocytes, and because calcineurin Abeta (CNAbeta)-deficient mice do not reject allogenic tumours, we have generated Tgfb1(-/-) Cnab(-/-) mice to address whether CNAbeta deficiency prevents T cell activation and inflammation in Tgfb1(-/-) mice. Here we show that in Tgfb1(-/-) Cnab(-/-) mice inflammation is reduced significantly relative to that in Tgfb1(-/-) mice. However, both CD4(+) and CD8(+) T cells in double knock-out (DKO) mice are activated, as revealed by up-regulation of CD11a lymphocyte function-associated antigen-1 (LFA-1), CD44 and CD69 and down-regulation of CD62L. These data suggest that deficiency of CNAbeta decreases inflammatory lesions but does not prevent activation of autoreactive T cells. Also Tgfb1(-/-) T cells can undergo activation in the absence of CNAbeta, probably by using the other isoform of calcineurin (CNAalpha) in a compensatory manner. CNAbeta-deficient T cells undergo spontaneous activation in vivo and are activated upon anti-T cell receptor stimulation in vitro. Understanding the role of calcineurin in T cell regulation should open up new therapeutic opportunities for inflammation and cancer.

Cognitive performance of young and elderly subjects on the free word recall memory test: effect of presentation order on recall order.

The influence of aging on memory has been extensively studied, but the importance of short-term memory and recall sequence has not. The objective of the current study was to examine the recall order of words presented on lists and to determine if age affects recall sequence. Physically and psychologically healthy male subjects were divided into two groups according to age, i.e., 23 young subjects (20 to 30 years) and 50 elderly subjects (60 to 70 years) submitted to the Wechsler Adult Intelligence Scale-Revised and the free word recall test. The order of word presentation significantly affected the 3rd and 4th words recalled (P < 0.01; F = 14.6). In addition, there was interaction between the presentation order and the type of list presented (P < 0.05; F = 9.7). Also, both groups recalled the last words presented from each list (words 13-15) significantly more times 3rd and 4th than words presented in all remaining positions (P < 0.01). The order of word presentation also significantly affected the 5th and 6th words recalled (P = 0.05; F = 7.5) and there was a significant interaction between the order of presentation and the type of list presented (P < 0.01; F = 20.8). The more developed the cognitive functions, resulting mainly from formal education, the greater the cognitive reserve, helping to minimize the effects of aging on the long-term memory (episodic declarative).

The indirect amygdala-dorsal striatum pathway mediates conditioned freezing: insights on emotional memory networks.

The dorsal striatum (DS) is involved in various forms of learning and memory such as procedural learning, habit learning, reward-association and emotional learning. We have previously reported that bilateral DS lesions disrupt tone fear conditioning (TFC), but not contextual fear conditioning (CFC) [Ferreira TL, Moreira KM, Ikeda DC, Bueno OFA, Oliveira MGM (2003) Effects of dorsal striatum lesions in tone fear conditioning and contextual fear conditioning. Brain Res 987:17-24]. To further elucidate the participation of DS in emotional learning, in the present study, we investigated the effects of bilateral pretest (postraining) electrolytic DS lesions on TFC. Given the well-acknowledged role of the amygdala in emotional learning, we also examined a possible cooperation between DS and the amygdala in TFC, by using asymmetrical electrolytic lesions, consisting of a unilateral lesion of the central amygdaloid nucleus (CeA) combined to a contralateral DS lesion. The results show that pre-test bilateral DS lesions disrupt TFC responses, suggesting that DS plays a role in the expression of TFC. More importantly, rats with asymmetrical pre-training lesions were impaired in TFC, but not in CFC tasks. This result was confirmed with muscimol asymmetrical microinjections in DS and CeA, which reversibly inactivate these structures. On the other hand, similar pretest lesions as well as unilateral electrolytic lesions of CeA and DS in the same hemisphere did not affect TFC. Possible anatomical substrates underlying the observed effects are proposed. Overall, the present results underscore that other routes, aside from the well-established CeA projections to the periaqueductal gray, may contribute to the acquisition/consolidation of the freezing response associated to a TFC task. It is suggested that CeA may presumably influence DS processing via a synaptic relay on dopaminergic neurons of the substantia nigra compacta and retrorubral nucleus. The present observations are also in line with other studies showing that TFC and CFC responses are mediated by different anatomical networks.

Effects of lorazepam on visual perceptual abilities.

OBJECTIVE: To evaluate the effects of an acute dose of the benzodiazepine (BZ) lorazepam in young healthy volunteers on five distinguishable visual perception abilities determined by previous factor-analytic studies. METHODS: This was a double-blind, cross-over design study of acute oral doses of lorazepam (2 mg) and placebo in young healthy volunteers. We focused on a set of paper-and-pencil tests of visual perceptual abilities that load on five correlated but distinguishable factors (Spatial Visualization, Spatial Relations, Perceptual Speed, Closure Speed, and Closure Flexibility). Some other tests (DSST, immediate and delayed recall of prose; measures of subjective mood alterations) were used to control for the classic BZ-induced effects. RESULTS: Lorazepam impaired performance in the DSST and delayed recall of prose, increased subjective sedation and impaired tasks of all abilities except Spatial Visualization and Closure Speed. Only impairment in Perceptual Speed (Identical Pictures task) and delayed recall of prose were not explained by sedation. CONCLUSION: Acute administration of lorazepam, in a dose that impaired episodic memory, selectively affected different visual perceptual abilities before and after controlling for sedation. Central executive demands and sedation did not account for results, so impairment in the Identical Pictures task may be attributed to lorazepam's visual processing alterations.

Effects of lorazepam on deductive reasoning.

RATIONALE: Benzodiazepines slow reasoning performance, but it is still unknown which phase of reasoning is affected and whether this effect is present for different types of relations between entities in reasoning problems. OBJECTIVES: We investigated which phases of deductive reasoning are affected by lorazepam and whether this effect varies according to the type of relations in deductive reasoning problems. METHODS: This was a double-blind, crossover design study of acute oral doses of lorazepam (2 mg) and placebo, using young healthy volunteers. We focused on response delay of three separable phases of deductive reasoning and matched working memory tasks (that involved only maintenance of information) the premise processing phase, the premise integration phase, and the validation phase, in which reasoners decide whether a conclusion logically follows from the premises (reasoning task) or is identical to one of the premises (maintenance task). Type of relations in the premises was also manipulated. We employed material that was difficult to envisage visually and visuospatially ("subiconic") and material easy to envisage visually or visuospatially. RESULTS: Lorazepam slowed response as memory load increased, irrespective of type of relations. It also specifically slowed validation in reasoning problems with visual relations, an effect that disappeared after subtraction of maintenance scores, and increased validation time in problems with subiconic relations, which remained after this subtraction. CONCLUSION: Acute lorazepam administration affected reasoning in two ways: it slowed processing nonspecifically when working memory demands increased and augmented validation time depending on the difficulty in generating and/or manipulating mental representations by the central executive.

Errors in nonword repetition: bridging short- and long-term memory

According to the working memory model, the phonological loop is the component of working memory specialized in processing and manipulating limited amounts of speech-based information. The Children's Test of Nonword Repetition (CNRep) is a suitable measure of phonological short-term memory for English-speaking children, which was validated by the Brazilian Children's Test of Pseudoword Repetition (BCPR) as a Portuguese-language version. The objectives of the present study were: i) to investigate developmental aspects of the phonological memory processing by error analysis in the nonword repetition task, and ii) to examine phoneme (substitution, omission and addition) and order (migration) errors made in the BCPR by 180 normal Brazilian children of both sexes aged 4-10, from preschool to 4th grade. The dominant error was substitution [F(3,525) = 180.47; P < 0.0001]. The performance was age-related [F(4,175) = 14.53; P < 0.0001]. The length effect, i.e., more errors in long than in short items, was observed [F(3,519) = 108.36; P < 0.0001]. In 5-syllable pseudowords, errors occurred mainly in the middle of the stimuli, before the syllabic stress [F(4,16) = 6.03; P = 0.003]; substitutions appeared more at the end of the stimuli, after the stress [F(12,48) = 2.27; P = 0.02]. In conclusion, the BCPR error analysis supports the idea that phonological loop capacity is relatively constant during development, although school learning increases the efficiency of this system. Moreover, there are indications that long-term memory contributes to holding memory trace. The findings were discussed in terms of distinctiveness, clustering and redintegration hypotheses.

Errors in nonword repetition: bridging short- and long-term memory.

According to the working memory model, the phonological loop is the component of working memory specialized in processing and manipulating limited amounts of speech-based information. The Children's Test of Nonword Repetition (CNRep) is a suitable measure of phonological short-term memory for English-speaking children, which was validated by the Brazilian Children's Test of Pseudoword Repetition (BCPR) as a Portuguese-language version. The objectives of the present study were: i) to investigate developmental aspects of the phonological memory processing by error analysis in the nonword repetition task, and ii) to examine phoneme (substitution, omission and addition) and order (migration) errors made in the BCPR by 180 normal Brazilian children of both sexes aged 4-10, from preschool to 4th grade. The dominant error was substitution [F(3,525) = 180.47; P < 0.0001]. The performance was age-related [F(4,175) = 14.53; P < 0.0001]. The length effect, i.e., more errors in long than in short items, was observed [F(3,519) = 108.36; P < 0.0001]. In 5-syllable pseudowords, errors occurred mainly in the middle of the stimuli, before the syllabic stress [F(4,16) = 6.03; P = 0.003]; substitutions appeared more at the end of the stimuli, after the stress [F(12,48) = 2.27; P = 0.02]. In conclusion, the BCPR error analysis supports the idea that phonological loop capacity is relatively constant during development, although school learning increases the efficiency of this system. Moreover, there are indications that long-term memory contributes to holding memory trace. The findings were discussed in terms of distinctiveness, clustering and redintegration hypotheses.

Cross-cultural differences for three visual memory tasks in Brazilian children.

Norms for three visual memory tasks, including Corsi's block tapping test and the BEM 144 complex figures and visual recognition, were developed for neuropsychological assessment in Brazilian children. The tasks were measured in 127 children ages 7 to 10 years from rural and urban areas of the States of São Paulo and Minas Gerais. Analysis indicated age-related but not sex-related differences. A cross-cultural effect was observed in relation to copying and recall of Complex pictures. Different performances between rural and urban children were noted.

Zolpidem and memory: a study using the process-dissociation procedure.

RATIONALE: There is a dearth of studies which have employed sophisticated paradigms to investigate the effects of zolpidem on memory. OBJECTIVES: To explore anterograde cognitive deficits induced by acute oral doses of zolpidem by means of the process-dissociation procedure (PDP). METHODS: The present study followed a placebo-controlled, double-blind, parallel-group design. Young, healthy females were randomly allocated to one of three treatments with 12 subjects each: placebo, 5 mg and 10 mg zolpidem. Two word-stem completion tasks were carried out close to theoretical peak-plasma concentration: a) direct inclusion task with cued recall, in which participants had to try to use words seen at study to complete stems; and b) direct exclusion task, in which words seen at study were to be avoided as completions. The PDP was applied to the results in these tasks to yield indices of explicit/controlled (C) and implicit/automatic (A) memory. Classical psychometric tests were also carried out. RESULTS: Zolpidem 10 mg led to cognitive effects similar to benzodiazepines (except for the atypical lorazepam), including impairment of exclusion, but not inclusion-task performance. Results of the application of the PDP were inconclusive but concurred with the pattern established in previously published work on benzodiazepine effects, i.e. that zolpidem (10 mg) impaired C. CONCLUSIONS: Zolpidem leads to cognitive effects similar to most benzodiazepines. Although the application of PDP in drug studies may be counterproductive in view of methodological difficulties that are discussed, the pattern of effects on the stem-completion tasks involved in this paradigm is potentially useful in the investigation of cognitive effects of psychoactive drugs.

Validation of the Brazilian Children's Test of Pseudoword Repetition in Portuguese speakers aged 4 to 10 years

The phonological loop is a component of the working memory system specifically involved in the processing and manipulation of limited amounts of information of a sound-based phonological nature. Phonological memory can be assessed by the Children's Test of Nonword Repetition (CNRep) in English speakers but not in Portuguese speakers due to phonotactic differences between the two languages. The objectives of the present study were: 1) to develop the Brazilian Children's Test of Pseudoword Repetition (BCPR), a Portuguese version of the CNRep, and 2) to validate the BCPR by correlation with the Auditory Digit Span Test from the Stanford-Binet Intelligence Scale. The BCPR and Digit Span were assessed in 182 children aged 4-10 years, 84 from Minas Gerais State (42 from a rural region) and 98 from the city of Säo Paulo. There are subject age and word length effects causing repetition accuracy to decline as a function of the number of syllables of the pseudowords. Correlations between BCPR and Digit Span forward (r = 0.50; P <= 0.01) and backward (r = 0.43; P <= 0.01) were found, and partial correlation indicated that higher BCPR scores were associated with higher Digit Span scores. BCPR appears to depend more on schooling, while Digit Span was more related to development. The results demonstrate that the BCPR is a reliable measure of phonological working memory, similar to the CNRep.

Stem-completion tasks (indirect, direct inclusion and exclusion) are differently affected by equipotent doses of lorazepam and flunitrazepam.

This study was designed to explore the effects on performance in stem-completion tasks of two benzodiazepines (BZ) in equipotent doses: lorazepam, a drug that atypically disrupts perceptual priming, and flunitrazepam, a compound with standard BZ effects. The study followed a placebo-controlled, double-blind, parallel-group design. Thirty-six young and healthy subjects carried out three completion tasks at theoretical peak-plasma concentrations of drugs: (a) indirect tasks, in which the subjects were instructed to complete stems with the first word that came to mind; (b) direct inclusion tasks/cued recall, in which the participants had to try to use words seen at study as completions; and (c) direct exclusion tasks, in which words seen at study were to be avoided. The PDP was applied to the results in the inclusion and exclusion tasks, to obtain indices of explicit/controlled (C) and implicit/automatic (A) memory. The C index was lowered by both BZs and A was equivalent in all treatments, confirming the general amnestic action of BZs. However, lorazepam led to decreases in completions in the indirect and inclusion tasks, while flunitrazepam impaired performance in the exclusion task. The qualitative differences between the drugs in their effects on performance suggest that these BZs may lead to differences in response bias.

Validation of the Brazilian Children's Test of Pseudoword Repetition in Portuguese speakers aged 4 to 10 years.

The phonological loop is a component of the working memory system specifically involved in the processing and manipulation of limited amounts of information of a sound-based phonological nature. Phonological memory can be assessed by the Children's Test of Nonword Repetition (CNRep) in English speakers but not in Portuguese speakers due to phonotactic differences between the two languages. The objectives of the present study were: 1). to develop the Brazilian Children's Test of Pseudoword Repetition (BCPR), a Portuguese version of the CNRep, and 2). to validate the BCPR by correlation with the Auditory Digit Span Test from the Stanford-Binet Intelligence Scale. The BCPR and Digit Span were assessed in 182 children aged 4-10 years, 84 from Minas Gerais State (42 from a rural region) and 98 from the city of S o Paulo. There are subject age and word length effects causing repetition accuracy to decline as a function of the number of syllables of the pseudowords. Correlations between BCPR and Digit Span forward (r = 0.50; P