Brain oscillatory responses, working memory and cognitive developmental stages in 11- and 14-year-old children: an ERD/ERS study

Aim: So far, most of the cognitive neuroscience studies investigating the development of brain activity in childhood have made comparisons between different age groups and ignored the individual stage of cognitive development. Given the wide variation in the rate of cognitive development, this study argues that chronological age alone cannot explain the developmental changes in brain activity. This study demonstrates how Piaget s theory and information on child s individual stage of development can complement the age-related evaluations of brain oscillatory activity. In addition, the relationship between cognitive development and working memory is investigated. Method: A total of 33 children (17 11-year-olds, 16 14-year-olds) participated in this study. The study consisted of behavioural tests and an EEG experiment. Behavioral tests included two Piagetian tasks (the Volume and Density task, the Pendulum task) and Raven s Standard Progressive Matrices task. During EEG experiment, subjects performed a modified version of the Sternberg s memory search paradigm which consisted of an auditorily presented memory set of 4 words and a probe word following these. The EEG data was analyzed using the event-related desynchronization / synchronization (ERD/ERS) method. The Pendulum task was used to assess the cognitive developmental stage of each subject and to form four groups based on age (11- or 14-year-olds) and cognitive developmental stage (concrete or formal operational stage). Group comparisons between these four groups were performed for the EEG data. Results and conclusions: Both age- and cognitive stage-related differences in brain oscillatory activity were found between the four groups. Importantly, age-related changes similar to those reported by previous studies were found also in this study, but these changes were modified by developmental stage. In addition, the results support a strong link between working memory and cognitive development by demonstrating differences in memory task related brain activity and cognitive developmental stages. Based on these findings it is suggested that in the future, comparisons of development of brain activity should not be based only on age but also on the individual cognitive developmental stage.

Language learning in infancy

Although immensely complex, speech is also a very efficient means of communication between humans. Understanding how we acquire the skills necessary for perceiving and producing speech remains an intriguing goal for research. However, while learning is likely to begin as soon as we start hearing speech, the tools for studying the language acquisition strategies in the earliest stages of development remain scarce. One prospective strategy is statistical learning. In order to investigate its role in language development, we designed a new research method. The method was tested in adults using magnetoencephalography (MEG) as a measure of cortical activity. Neonatal brain activity was measured with electroencephalography (EEG). Additionally, we developed a method for assessing the integration of seen and heard syllables in the developing brain as well as a method for assessing the role of visual speech when learning phoneme categories. The MEG study showed that adults learn statistical properties of speech during passive listening of syllables. The amplitude of the N400m component of the event-related magnetic fields (ERFs) reflected the location of syllables within pseudowords. The amplitude was also enhanced for syllables in a statistically unexpected position. The results suggest a role for the N400m component in statistical learning studies in adults. Using the same research design with sleeping newborn infants, the auditory event-related potentials (ERPs) measured with EEG reflected the location of syllables within pseudowords. The results were successfully replicated in another group of infants. The results show that even newborn infants have a powerful mechanism for automatic extraction of statistical characteristics from speech. We also found that 5-month-old infants integrate some auditory and visual syllables into a fused percept, whereas other syllable combinations are not fully integrated. Auditory syllables were paired with visual syllables possessing a different phonetic identity, and the ERPs for these artificial syllable combinations were compared with the ERPs for normal syllables. For congruent auditory-visual syllable combinations, the ERPs did not differ from those for normal syllables. However, for incongruent auditory-visual syllable combinations, we observed a mismatch response in the ERPs. The results show an early ability to perceive speech cross-modally. Finally, we exposed two groups of 6-month-old infants to artificially created auditory syllables located between two stereotypical English syllables in the formant space. The auditory syllables followed, equally for both groups, a unimodal statistical distribution, suggestive of a single phoneme category. The visual syllables combined with the auditory syllables, however, were different for the two groups, one group receiving visual stimuli suggestive of two separate phoneme categories, the other receiving visual stimuli suggestive of only one phoneme category. After a short exposure, we observed different learning outcomes for the two groups of infants. The results thus show that visual speech can influence learning of phoneme categories. Altogether, the results demonstrate that complex language learning skills exist from birth. They also suggest a role for the visual component of speech in the learning of phoneme categories.

Genetic background of bipolar disorder and related cognitive impairments

Bipolar disorder (BP) is a complex psychiatric disorder characterized by episodes of mania and depression. BP affects approximately 1% of the world’s population and shows no difference in lifetime prevalence between males and females. BP arises from complex interactions among genetic, developmental and environmental factors, and it is likely that several predisposing genes are involved in BP. The genetic background of BP is still poorly understood, although intensive and long-lasting research has identified several chromosomal regions and genes involved in susceptibility to BP. This thesis work aims to identify the genetic variants that influence bipolar disorder in the Finnish population by candidate gene and genome-wide linkage analyses in families with many BP cases. In addition to diagnosis-based phenotypes, neuropsychological traits that can be seen as potential endophenotypes or intermediate traits for BP were analyzed. In the first part of the thesis, we examined the role of the allelic variants of the TSNAX/DISC1 gene cluster to psychotic and bipolar spectrum disorders and found association of distinct allelic haplotypes with these two groups of disorders. The haplotype at the 5’ end of the Disrupted-in-Schizophrenia-1 gene (DISC1) was over-transmitted to males with psychotic disorder (p = 0.008; for an extended haplotype p = 0.0007 with both genders), whereas haplotypes at the 3’ end of DISC1 associated with bipolar spectrum disorder (p = 0.0002; for an extended haplotype p = 0.0001). The variants of these haplotypes also showed association with different cognitive traits. The haplotypes at the 5’ end associated with perseverations and auditory attention, while the variants at the 3’ end associated with several cognitive traits including verbal fluency and psychomotor processing speed. Second, in our complete set of BP families with 723 individuals we studied six functional candidate genes from three distinct signalling systems: serotonin-related genes (SLC6A4 and TPH2), BDNF -related genes (BDNF, CREB1 and NTRK2) and one gene related to the inflammation and cytokine system (P2RX7). We replicated association of the functional variant Val66Met of BDNF with BP and better performance in retention. The variants at the 5’ end of SLC6A4 also showed some evidence of association among males (p = 0.004), but the widely studied functional variants did not yield any significant results. A protective four-variant haplotype on P2RX7 showed evidence of association with BP and executive functions: semantic and phonemic fluency (p = 0.006 and p = 0.0003, respectively). Third, we analyzed 23 bipolar families originating from the North-Eastern region of Finland. A genome-wide scan was performed using the 6K single nucleotide polymorphism (SNP) array. We identified susceptibility loci at chromosomes 7q31 with a LOD score of 3.20 and at 9p13.1 with a LOD score of 4.02. We followed up both linkage findings in the complete set of 179 Finnish bipolar families. The finding on chromosome 9p13 was supported (maximum LOD score of 3.02), but the susceptibility gene itself remains unclarified. In the fourth part of the thesis, we wanted to test the role of the allelic variants that have associated with bipolar disorder in recent genome-wide association studies (GWAS). We could confirm findings for the DFNB31, SORCS2, SCL39A3, and DGKH genes. The best signal in this study comes from DFNB31, which remained significant after multiple testing corrections. Two variants of SORCS2 were allelic replications and presented the same signal as the haplotype analysis. However, no association was detected with the PALB2 gene, which was the most significantly associated region in the previous GWAS. Our results indicate that BP is heterogeneous and its genetic background may accordingly vary in different populations. In order to fully understand the allelic heterogeneity that underlies common diseases such as BP, complete genome sequencing for many individuals with and without the disease is required. Identification of the specific risk variants will help us better understand the pathophysiology underlying BP and will lead to the development of treatments with specific biochemical targets. In addition, it will further facilitate the identification of environmental factors that alter risk, which will potentially provide improved occupational, social and psychological advice for individuals with high risk of BP.

Carotid Stenosis, Endarterectomy, and the Brain : Brain microcirculation, diffusion, and cognitive function before and after carotid endarterectomy in patients with a high-grade carotid stenosis

Carotid atherosclerotic disease is a major cause of stroke, but it may remain clinically asymptomatic. The factors that turn the asymptomatic plaque into a symptomatic one are not fully understood, neither are the subtle effects that a high-grade carotid stenosis may have on the brain. The purpose of this study was to evaluate brain microcirculation, diffusion, and cognitive performance in patients with a high-grade stenosis in carotid artery, clinically either symptomatic or asymptomatic, undergoing carotid endarterectomy (CEA). We wanted to find out whether the stenoses are associated with diffusion or perfusion abnormalities of the brain or variation in the cognitive functioning of the patients, and to what extent the potential findings are affected by CEA, and compare the clinically symptomatic and asymptomatic subjects as well as strictly healthy controls. Coagulation and fibrinolytic parameters were compared with the rate microembolic signals (MES) in transcranial Doppler (TCD) and the macroscopic appearance of stenosing plaques in surgery. Patients (n=92) underwent CEA within the study. Blood samples pertaining to coagulation and fibrinolysis were collected before CEA, and the subjects underwent repeated TCD monitoring for MES. A subpopulation (n= 46) underwent MR imaging and repeated neuropsychological examination (preoperative, as well 4 and 100 days after CEA). In MRI, the average apparent diffusion coefficients were higher in the ipsilateral white matter (WM), and altough the interhemispheric difference was abolished by CEA, the levels remained higher than in controls. Symptomatic stenoses were associated with more sluggish perfusion especially in WM, and lower pulsatility of flow in TCD. All patients had poorer cognitive performance than healthy controls. Cognitive functions improved as expected by learning effect despite transient postoperative worsening in a few subjects. Improvement was greater in patients with deepest hypoperfusion, primarily in executive functions. Symptomatic stenoses were associated with higher hematocrit and tissue plasminogen activator antigen levels, as well as higher rate of MES and ulcerated plaques, and better postoperative improvement of vasoreactivity and pulsatility. In light of the findings, carotid stenosis is associated with differences in brain diffusion, perfusion, and cognition. The effect on diffusion in the ipsilateral WM, partially reversible by CEA, may be associated with WM degeneration. Asymptomatic and symptomatic subpopulations differ from each other in terms of hemodynamic adaptation and in their vascular physiological response to removal of stenosis. Although CEA may be associated with a transient cognitive decline, a true improvement of cognitive performance by CEA is possible in patients with the most pronounced perfusion deficits. Mediators of fibrinolysis and unfavourable hemorheology may contribute to the development of a symptomatic disease in patients with a high-grade stenosis.

Cognitive Functioning in Alcohol and Other Substance Use Disorders in Young Adulthood : A Genetic Epidemiological Study

Alcohol and other substance use disorders (SUDs) result in great costs and suffering for individuals and families and constitute a notable public health burden. A multitude of factors, ranging from biological to societal, are associated with elevated risk of SUDs, but at the level of individuals, one of the best predictors is a family history of SUDs. Genetically informative twin and family studies have consistently indicated this familial risk to be mainly genetic. In addition, behavioral and temperamental factors such as early initiation of substance use and aggressiveness are associated with the development of SUDs. These familial, behavioral and temperamental risk factors often co-occur, but their relative importance is not well known. People with SUDs have also been found to differ from healthy controls in various domains of cognitive functioning, with poorer verbal ability being among the most consistent findings. However, representative population-based samples have rarely been used in neuropsychological studies of SUDs. In addition, both SUDs and cognitive abilities are influenced by genetic factors, but whether the co-variation of these traits might be partly explained by overlapping genetic influences has not been studied. Problematic substance use also often co-occurs with low educational level, but it is not known whether these outcomes share part of their underlying genetic influences. In addition, educational level may moderate the genetic etiology of alcohol problems, but gene-environment interactions between these phenomena have also not been widely studied. The incidence of SUDs peaks in young adulthood rendering epidemiological studies in this age group informative. This thesis investigated cognitive functioning and other correlates of SUDs in young adulthood in two representative population-based samples of young Finnish adults, one of which consisted of monozygotic and dizygotic twin pairs enabling genetically informative analyses. Using data from the population-based Mental Health in Early Adulthood in Finland (MEAF) study (n=605), the lifetime prevalence of DSM-IV any substance dependence or abuse among persons aged 21—35 years was found to be approximately 14%, with a majority of the diagnoses being alcohol use disorders. Several correlates representing the domains of behavioral and affective factors, parental factors, early initiation of substance use, and educational factors were individually associated with SUDs. The associations between behavioral and affective factors (attention or behavior problems at school, aggression, anxiousness) and SUDs were found to be largely independent of factors from other domains, whereas daily smoking and low education were still associated with SUDs after adjustment for behavioral and affective factors. Using a wide array of neuropsychological tests in the MEAF sample and in a subsample (n=602) of the population-based FinnTwin16 (FT16) study, consistent evidence of poorer verbal cognitive ability related to SUDs was found. In addition, participants with SUDs performed worse than those without disorders in a task assessing psychomotor processing speed in the MEAF sample, whereas no evidence of more specific cognitive deficits was found in either sample. Biometrical structural equation models of the twin data suggested that both alcohol problems and verbal ability had moderate heritabilities (0.54—0.72), and that their covariation could be explained by correlated genetic influences (genetic correlations -0.20 to -0.31). The relationship between educational level and alcohol problems, studied in the full epidemiological FT16 sample (n=4,858), was found to reflect both genetic correlation and gene-environment interaction. The co-occurrence of low education and alcohol problems was influenced by overlapping genetic factors. In addition, higher educational level was associated with increased relative importance of genetic influences on alcohol problems, whereas environmental influences played a more important role in young adults with lower education. In conclusion, SUDs, especially alcohol abuse and dependence, are common among young Finnish adults. Behavioral and affective factors are robustly related to SUDs independently of many other factors, and compared to healthy peers, young adults who have had SUDs during their life exhibit significantly poorer verbal cognitive ability, and possibly less efficient psychomotor processing. Genetic differences between individuals explain a notable proportion of individual differences in risk of alcohol dependence, verbal ability, and educational level, and the co-occurrence of alcohol problems with poorer verbal cognition and low education is influenced by shared genetic backgrounds. Finally, various environmental factors related to educational level in young adulthood moderate the relative importance of genetic factors influencing the risk of alcohol problems, possibly reflecting differences in social control mechanisms related to educational level.

Dietary habits and obesity: the role of emotional and cognitive factors

In post-industrialised societies, food is more plentiful, accessible and palatable than ever before and technological development has reduced the need for physical activity. Consequently, the prevalence of obesity is increasing, which is problematic as obesity is related to a number of diseases. Various psychological and social factors have an important influence on dietary habits and the development of obesity in the current food-rich and sedentary environments. The present study concentrates on the associations of emotional and cognitive factors with dietary intake and obesity as well as on the role these factors play in socioeconomic disparities in diet. Many people cognitively restrict their food intake to prevent weight gain or to lose weight, but research on whether restrained eating is a useful weight control strategy has produced conflicting findings. With respect to emotional factors, the evidence is accumulating that depressive symptoms are related to less healthy dietary intake and obesity, but the mechanisms explaining these associations remain unclear. Furthermore, it is not fully understood why socioeconomically disadvantaged individuals tend to have unhealthier dietary habits and the motives underlying food choices (e.g., price and health) could be relevant in this respect. The specific aims of the study were to examine 1) whether obesity status and dieting history moderate the associations of restrained eating with overeating tendencies, self-control and obesity indicators; 2) whether the associations of depressive symptoms with unhealthier dietary intake and obesity are attributable to a tendency for emotional eating and a low level of physical activity self-efficacy; and 3) whether the absolute or relative importance of food choice motives (health, pleasure, convenience, price, familiarity and ethicality) contribute to the socioeconomic disparities in dietary habits. The study was based on a large population-based sample of Finnish adults: the participants were men (N=2325) and women (N=2699) aged 25-74 who took part in the DILGOM (Dietary, Lifestyle and Genetic Determinants of Obesity and Metabolic Syndrome) sub-study of the National FINRISK Study 2007. The participants weight, height, waist circumference and body fat percentage were measured in a health examination. Psychological eating styles (the Three-Factor Eating Questionnaire-R18), food choice motives (a shortened version of the Food Choice Questionnaire), depressive symptoms (the Center for Epidemiological Studies Depression Scale) and self-control (the Brief Self-Control Scale) were measured with pre-existing questionnaires. A validated food frequency questionnaire was used to assess the average consumption of sweet and non-sweet energy-dense foods and vegetables/fruit. Self-reported total years of education and gross household income were used as indicators of socioeconomic position. The results indicated that 1) restrained eating was related to a lower body mass index, waist circumference, emotional eating and uncontrolled eating, and to a higher self-control in obese participants and current/past dieters. In contrast, the associations were the opposite in normal weight individuals and those who had never dieted. Thus, restrained eating may be related to better weight control among obese individuals and those with dieting experiences, while among others it may function as an indicator of problems with eating and an attempt to solve them. 2) Emotional eating and depressive symptoms were both related to less healthy dietary intake, and the greater consumption of energy-dense sweet foods among participants with elevated depressive symptoms was attributable to the susceptibility for emotional eating. In addition, emotional eating and physical activity self-efficacy were both important in explaining the positive association between depressive symptoms and obesity. 3) The lower vegetable/fruit intake and higher energy-dense food intake among individuals with a low socioeconomic position were partly explained by the higher priority they placed on price and familiarity and the lower priority they gave to health motives in their daily food choices. In conclusion, although policy interventions to change the obesogenic nature of the current environment are definitely needed, knowledge of the factors that hinder or facilitate people s ability to cope with the food-rich environment is also necessary. This study implies that more emphasis should be placed on various psychological and social factors in weight control programmes and interventions.