Cognitive deficits and the Paced Auditory Serial Addition Test performance among patients with multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system, characterized especially by myelin and axon damage. Cognitive impairment in MS is common but difficult to detect without a neuropsychological examination. Valid and reliable methods are needed in clinical practice and research to detect deficits, follow their natural evolution, and verify treatment effects. The Paced Auditory Serial Addition Test (PASAT) is a measure of sustained and divided attention, working memory, and information processing speed, and it is widely used in MS patients neuropsychological evaluation. Additionally, the PASAT is the sole cognitive measure in an assessment tool primarly designed for MS clinical trials, the Multiple Sclerosis Functional Composite (MSFC). The aims of the present study were to determine a) the frequency, characteristics, and evolution of cognitive impairment among relapsing-remitting MS patients, and b) the validity and reliability of the PASAT in measuring cognitive performance in MS patients. The subjects were 45 relapsing-remitting MS patients from Seinäjoki Central Hospital, Department of Neurology and 48 healthy controls. Both groups underwent comprehensive neuropsychological assessments, including the PASAT, twice in a one-year follow-up, and additionally a sample of 10 patients and controls were evaluated with the PASAT in serial assessments five times in one month. The frequency of cognitive dysfunction among relapsing-remitting MS patients in the present study was 42%. Impairments were characterized especially by slowed information processing speed and memory deficits. During the one-year follow-up, the cognitive performance was relatively stable among MS patients on a group level. However, the practice effects in cognitive tests were less pronounced among MS patients than healthy controls. At an individual level the spectrum of MS patients cognitive deficits was wide in regards to their characteristics, severity, and evolution. The PASAT was moderately accurate in detecting MS-associated cognitive impairment, and 69% of patients were correctly classified as cognitively impaired or unimpaired when comprehensive neuropsychological assessment was used as a "gold standard". Self-reported nervousness and poor arithmetical skills seemed to explain misclassifications. MS-related fatigue was objectively demonstrated as fading performance towards the end of the test. Despite the observed practice effect, the reliability of the PASAT was excellent, and it was sensitive to the cognitive decline taking place during the follow-up in a subgroup of patients. The PASAT can be recommended for use in the neuropsychological assessment of MS patients. The test is fairly sensitive, but less specific; consequently, the reasons for low scores have to be carefully identified before interpreting them as clinically significant.

Temporal acuity in developmental dyslexia across the life span : Tactile, auditory, visual, and crossmodal estimations

Taustaa Kehityksellinen dysleksia (lukivaikeus) on erityinen lukemaan oppimisen vaikeus, johon liittyy usein myös vaikeuksia kirjoittamaan oppimisessa. Lukivaikeuden oletetaan useissa tapauksissa johtuvan vaikeudesta käsitellä kielen äännerakenteita (fonologinen prosessointi). Tämä poikkeavuus voi olla joko lukivaikeuden perimmäinen syy tai vaihtoehtoisesti ongelmat äänteiden käsittelyssä voivat heijastaa jotain vielä perustavamman tason vaikeutta. Eräs tällainen ehdotettu perustavan tasoin syy on poikkeavuus aistien toiminnoissa, erityisesti aistien aikatarkkuudessa. Aikatarkkuudella tarkoitetaan kykyä ja rajoja siinä, kuinka nopeasti esitettyä aistitiedon virtaa henkilö kykenee vastaanottamaan ja käsittelemään. Monet arjen toiminnot lukemisen rinnalla edellyttävät aistien erittäin tarkkaa ajallista erottelukykyä (esimerkiksi kuulo puheen ymmärtämisessä, tunto pintamateriaalin tunnistamisessa). Aikatarkkuusvaikeuksien esiintyvyyttä lukivaikeudessa on tutkittu aiemminkin, mutta yksimielisyyteen ei ole päästy siitä, onko kaikilla lukivaikeuksisilla näitä ongelmia tai mihin aisteihin vaikeudet mahdollisesti rajoittuvat. Myöskään ei tiedetä, havaitaanko aikatarkkuuden ongelmia kaiken ikäisillä lukivaikeuksisilla vai vaihteleeko mahdollinen ongelmien kuva iän mukana. Lisäksi on epäselvää, kuinka aikatarkkuuden ongelmat itseasiassa ovat yhteydessä kielen käsittelyn ja varsinaisen lukemisen vaikeuksiin. Tutkimussarjan aihe Tässä tutkimussarjassa aikatarkkuutta tutkittiin kolmessa yksittäisessä aistissa, joita olivat tunto, näkö ja kuulo, sekä kolmessa aistien välisessä yhdistelmässä, joita olivat audiotaktiilinen (kuulo-tunto), visuotaktiilinen (näkö-tunto) ja audiovisuaalinen (näkö-kuulo). Aikatarkkuutta arvioitiin kahdella eri menetelmällä, jotta saataisiin lisää tietoa siitä, missä tietyssä aikatarkkuuden osa-alueessa lukivaikeuksisilla mahdollisesti on vaikeuksia. Ensimmäisessä tehtävässä tutkittavan tuli arvioida, ovatko esitetyt ei-kielelliset ärsykkeet samanaikaisia vai eriaikaisia. Toisessa tehtävässä koehenkilön tuli arvioida esitettyjen ei-kielellisten ärsykkeiden esitysjärjestys. Molemmissa tehtävissä määriteltiin millisekuntitasolla (sekunnin tuhannesosa) se esitysnopeus, jolla koehenkilö kykeni arvioimaan ärsykkeiden ajalliset suhteet oikein. Englanninkielinen demonstraatio aikatarkkuustehtävistä löytyy internetistä (http://www.helsinki.fi/hum/ylpsy/neuropsy). Itse aikatarkkuustehtävien lisäksi tutkimussarjassa arvioitiin tutkimushenkilöiden päättelykykyä, kielellisiä toimintoja ja lukemista. Tutkimushenkilöt Tutkimuksiin osallistui 53 lukivaikeuksista ja 66 sujuvaa lukijaa, jotka oli jaettu kolmeen pääikäryhmään: lapset (8-12 vuotta), nuoret aikuiset (20-36 vuotta) ja ikääntyneemmät aikuiset (20-59 vuotta). Ikääntyneempien aikuisten ryhmä oli edelleen jaettu ikävuosikymmenluokkiin, mikä mahdollisti sen tutkimisen, vaikuttaako lisääntyvä aikuisikä lukivaikeuksisten aikatarkkuuteen (20-29, 30-39, 40-49 ja 50-59 -vuotiaat). Tutkimussarjan tulokset Aikatarkkuuden ongelmat lukivaikeuksisilla olivat yleistyneitä yli iän, aistien ja tehtävien Lukivaikeuksiset kaikissa pääikäryhmissä (lapset, nuoret aikuiset, ikääntyneemmän aikuiset) tarvitsivat samanikäisiä sujuvia lukijoita hitaamman esitystahdin, jotta he kykenivät arvioimaan ei-kielellisten ärsykkeiden ajallisen esitystavan oikein. Tämä aikatarkkuuden ongelma havaittiin lukivaikeuksisilla kaikissa aisteissa (tunto, kuulo, näkö) ja niiden yhdistelmissä (audiotaktiilinen, visuotaktiilinen, audiovisuaalinen). Lukivaikeuksisten aikatarkkuusongelmat ilmenivät edelleen molemmissa tehtävätyypeissä (samanaikaisuuden ja järjestyksen arvioinnissa). Aikatarkkuus ja sen ongelmat olivat yhteydessä äänteiden käsittelyyn Aikatarkkuus oli yhteydessä äänteiden käsittelykykyyn (fonologiseen prosessointiin), niin lapsilla kuin aikuisillakin, kaikissa aisteissa, niiden yhdistelmissä ja tehtävätyypeissä. Yhteys ei-kielellisen aikatarkkuuden ja kielellisten toimintojen välillä oli kuitenkin selkeämpi lukivaikeuksisilla kuin sujuvilla lukijoilla. Tämä tarkoittaa, että etenkin lukivaikeuksisilla ryhmätason huono aikatarkkuus oli yhteydessä huonoon äänteiden käsittelyyn (fonologiseen prosessointiin) ja päinvastoin. Suoraa yhteyttä lukemisen ja aikatarkkuuden välillä ei kuitenkaan havaittu. Lisääntyvä aikuisikä heikensi lukivaikeuksisten aikatarkkuutta suhteettoman paljon Tiedonkäsittelyn nopeuden on toistuvasti osoitettu hidastuvan normaalissa ikääntymisessä. Lisääntyvä aikuisikä (20-59 -vuotiailla) heikensikin sekä sujuvien että lukivaikeuksisten aikatarkkuutta. Toisin sanoen, mitä iäkkäämmästä aikuisesta oli kysymys, sitä hitaammin hänelle tuli esittää ärsykkeet, jotta hän kykeni arvioimaan niiden ajalliset suhteet oikein. Tämä ikään liittyvä tavanomainen hidastuminen oli kuitenkin yllättäen suhteettoman nopeaa lukivaikeuksisilla. Toisin sanoen, jo nuorilla lukivaikeuksisilla havaittu aikatarkkuuden vaikeus (ryhmäero verrattuna sujuviin lukijoihin) ei pysynyt saman suuruisena, vaan ryhmien ero kasvoi aikuisiän lisääntyessä. Tulosten merkitys Lukivaikeuden osoitettiin tässä tutkimussarjassa olevan yhteydessä yleistyneeseen vaikeuteen käsitellä ajassa nopeasti muuttuvaa ei-kielellistä aistitietoa (yli aistien ja niiden yhdistelmien, tehtävätyyppien, tutkittavien iän). Tämä osoittaa, että lukivaikeus ei ole ongelma, joka rajoittuu vain kielellisen materiaalin käsittelyn vaikeuksiin (äänteiden käsittely, lukeminen, kirjoittaminen). Nyt havaitut vaikeudet eivät myöskään rajoittuneet vain niihin aisteihin, jotka selkeimmin liittyvät lukemiseen (näkö) ja puhuttuun kieleen (kuulo); Ongelmia esiintyi myös muissa aisteissa (tunto). Lukivaikeuksisten lukijoiden ryhmätasolla havaittu aikatarkkuuden ongelma ei kuitenkaan heijastunut yksilötasolle; Jokainen lukivaikeuksinen ei ollut huono aikatarkkuustehtävissä. Näin ollen ei siis voida väittää, että kaikkien lukivaikeuksisten äänteiden käsittelyn tai lukemaan oppimisen vaikeudet voisivat selittyä aistien toimintojen poikkeavuudella. Aikatarkkuuden ongelmat eivät olleet yhteydessä varsinaiseen lukemiseen. Sekä lukivaikeuksisilla lapsilla että aikuisilla todettiin kuitenkin selkeä yhteys aikatarkkuuden ongelmien ja lukemaan oppimisen keskeisen ennakkoehdon, fonologisen prosessoinnin, välillä. Saattaa siis olla, että synnynnäinen aistien toimintojen poikkeavuus vaikuttaa yksilön suoriutumiseen jo ennen varsinaista lukemaan oppimista, kun ne taidot kehittyvät (fonologinen prosessointi), joille myöhempi lukemaan oppiminen perustuu. Ikäännyttäessä havaittu lukivaikeuksisten suhteettoman nopea aikatarkkuuden heikkeneminen osoittaa, että lukivaikeus ei voi olla ongelma, joka koskee vain lapsuusikää, tai vaikeus, joka johtuu vain kehityksen viivästymästä joka kurottaisiin iän myötä umpeen. Tulosten ymmärtämiseksi onkin muistettava kaksi seikkaa. Lukivaikeus on ensinnäkin yhdistetty synnynnäisiin, pieniin, poikkeavuuksiin aivojen rakenteissa ja toiminnoissa. Toisaalta tavanomaiseen ikääntymiseen liittyy se, että aivot kykenevät yhä huonommin korjaamaan ja kiertämään (kompensoimaan) pieniä vaurioita. Tämän perusteella tutkimussarjan tuloksista voidaan päätellä, että lukivaikeuksisten jo synnynnäisesti heikentyneet aivojen kompensointimahdollisuudet eivät ole yhtä tehokkaita puskuroimaan ikääntymisen tavanomaisia vaikutuksia kuin sujuvilla lukijoilla. Yllättävää kuitenkin on, että tämä korostunut heikkeneminen havaittiin jo suhteellisen nuorilla, työikäisillä, lukivaikeuksisilla, ennen 60 ikävuotta. Samanlaista ikäännyttäessä korostuvaa vaikeutta ei lukivaikeuksilla kuitenkaan havaittu päättelyssä, kielellisissä toiminnoissa tai itse lukemisessa. Vaikuttaakin siis siltä, että ne toiminnot, joita on harjaannutettu aktiivisesti, eivät heikkene kasvavan aikuisiän myötä yhtä suhteettomasti. Alkuperäiset artikkelit Laasonen M, Tomma-Halme J, Lahti-Nuuttila P, Service E, and Virsu V (2000) Rate of information segregation in developmentally dyslexic children, Brain and Language, 75(1), 66-81. Laasonen M, Service E, and Virsu V (2001) Temporal order and processing acuity of visual, auditory, and tactile perception in developmentally dyslexic young adults, Cognitive, Affective, and Behavioral Neuroscience, 1(4), 394-410. Laasonen M, Service E, and Virsu V (2002) Crossmodal temporal order and processing acuity in developmentally dyslexic young adults, Brain and Language, 80(3), 340-354. Laasonen M, Lahti-Nuuttila P, and Virsu V (2002) Developmentally impaired processing speed decreases more than normally with age, NeuroReport, 13(9), 1111-1113.

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.

Very Low Birth Weight Infants as Young Adults : Focus on aspects of cognition, behavior and sleep

Major advances in the treatment of preterm infants have occurred during the last three decades. Survival rates have increased, and the first generations of preterm infants born at very low birth weight (VLBW; less than 1500 g) who profited from modern neonatal intensive care are now in young adulthood. The literature shows that VLBW children achieve on average lower scores on cognitive tests, even after exclusion of individuals with obvious neurosensory deficits. Evidence also exists for an increased risk in VLBW children for various neuropsychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and related behavioral symptoms. Up till now, studies extending into adulthood are sparse, and it remains to be seen whether these problems persist into adulthood. The aim of this thesis was to study ADHD-related symptoms and cognitive and executive functioning in young adults born at VLBW. In addition, we aimed to study sleep disturbances, known to adversely affect both cognition and attention. We hypothesized that preterm birth at VLBW interferes with early brain development in a way that alters the neuropsychological phenotype; this may manifest itself as ADHD symptoms and impaired cognitive abilities in young adulthood. In this cohort study from a geographically defined region, we studied 166 VLBW adults and 172 term-born controls born from 1978 through 1985. At ages 18 to 27 years, the study participants took part in a clinic study during which their physical and psychological health was assessed in detail. Three years later, 213 of these individuals participated in a follow-up. The current study is part of a larger research project (The Helsinki Study of Very Low Birth Weight Adults), and the measurements of interest for this particular study include the following: 1) The Adult Problem Questionnaire (APQ), a self-rating scale of ADHD-related symptoms in adults; 2) A computerized cognitive test battery designed for population studies (CogState®) which measures core cognitive abilities such as reaction time, working memory, and visual learning; 3) Sleep assessment by actigraphy, the Basic Nordic Sleep Questionnaire, and the Morningness-Eveningness Questionnaire. Actigraphs are wrist-worn accelerometers that separate sleep from wakefulness by registering body movements. Contrary to expectations, VLBW adults as a group reported no more ADHD-related behavioral symptoms than did controls. Further subdivision of the VLBW group into SGA (small for gestational age) and AGA (appropriate for gestational age) subgroups, however, revealed more symptoms on ADHD subscales pertaining to executive dysfunction and emotional instability among those born SGA. Thus, it seems that intrauterine growth retardation (for which SGA served as a proxy) is a more essential predictor for self-perceived ADHD symptoms in adulthood than is VLBW birth as such. In line with observations from other cohorts, the VLBW adults reported less risk-taking behavior in terms of substance use (alcohol, smoking, and recreational drugs), a finding reassuring for the VLBW individuals and their families. On the cognitive test, VLBW adults free from neurosensory deficits had longer reaction times than did term-born peers on all tasks included in the test battery, and lower accuracy on the learning task, with no discernible effect of SGA status over and above the effect of VLBW. Altogether, on a group level, even high-functioning VLBW adults show subtle deficits in psychomotor processing speed, visual working memory, and learning abilities. The sleep studies provided no evidence for differences in sleep quality or duration between the two groups. The VLBW adults were, however, at more than two-fold higher risk for sleep-disordered breathing (in terms of chronic snoring). Given the link between sleep-disordered breathing and health sequelae, these results suggest that VLBW individuals may benefit from an increased awareness among clinicians of this potential problem area. An unexpected finding from the sleep studies was the suggestion of an advanced sleep phase: The VLBW adults went to bed earlier according to the actigraphy registrations and also reported earlier wake-up times on the questionnaire. In further study of this issue in conjunction with the follow-up three years later, the VLBW group reported higher levels of morningness propensity, further corroborating the preliminary findings of an advanced sleep phase. Although the clinical implications are not entirely clear, the issue may be worth further study, since circadian rhythms are closely related to health and well-being. In sum, we believe that increased understanding of long-term outcomes after VLBW, and identification of areas and subgroups that are particularly vulnerable, will allow earlier recognition of potential problems and ultimately lead to improved prevention strategies.

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.

Cognitive functioning and its heritability in bipolar I disorder

Bipolar I disorder is a severe psychiatric disorder characterized by episodic mood alterations that can be manic, depressive or mixed. Bipolar disorder seems to be highly genetic, but the etiology of this complex disorder has remained elusive. In recent years, studies have found that euthymic patients with bipolar disorder may have impairments particularly in executive functioning, verbal learning and memory. These impairments may be present also among some of the relatives of these patients, who may be vulnerable to the disorder. Using neuropsychological variables as endophenotypes, i.e. intermediate phenotypes between genes and the phenotypes, has been suggested to aid search for the etiological background of the disorder, but evidence is sparse on whether these variables fulfill the criteria for endophenotypes. The present thesis is part of the Genetic Epidemiology and Molecular Genetics of Severe Mental Disorders in Finland project. The specific aim was to investigate whether neuropsychological test variables would indicate genetic liability to the disorder and could therefore be regarded as endophenotypes. Thus, cognitive functions and their heritability were studied in bipolar I disorder patients and in their unaffected first-degree relatives from a population-based sample of families, comparing them to a population-based control group. In order to add homogeneity to the subgroups of bipolar disorder patients and their relatives, cognitive functions and their heritability were further studied in a group of families affected by bipolar I disorder only (bipolar families) and another group of families affected by both bipolar I disorder and schizophrenia or schizoaffective disorders (mixed families). Finally, the effect of processing speed on other cognitive functions was investigated. The study showed that especially executive functioning and processing speed fulfilled the endophenotype criteria. Impairments in these functions were found in bipolar patients and in their relatives irrespective of other severe psychopathology in the family. These functions were highly heritable in these families. Study also showed that generalized impairment in verbal memory may associate more with bipolar disorder than to vulnerability to other psychotic disorders, and be more related to fully developed disease; impairments in verbal learning and memory were found only in patients, and they were not found to be highly heritable. Finally, the most potential endophenotype, i.e. processing speed, seemed to contribute to a range of other cognitive dysfunctions seen in bipolar disorder patients. Processing speed, in particular, has also been shown to be a valid endophenotype in subsequent association analyses in psychiatric genetics in Finland and internationally. Information concerning cognitive impairments and their association with the psychosocial consequences of bipolar disorder is important in planning treatment. It is also important to understand and acknowledge that patients may have cognitive impairments that affect their everyday life. Psychosocial interventions and neuropsychological rehabilitation may supplement other conventional treatments for bipolar patients.

Plasma brain-derived neurotrophic factor levels, learning capacity and cognition in patients with first episode psychosis

Background: Cognitive impairments are seen in first psychotic episode (FEP) patients. The neurobiological underpinnings that might underlie these changes remain unknown. The aim of this study is to investigate whether Brain Derived Neurotrophic Factor (BDNF) levels are associated with cognitive impairment in FEP patients compared with healthy controls. Methods: 45 FEP patients and 45 healthy controls matched by age, gender and educational level were selected from the Basque Country area of Spain. Plasma BDNF levels were assessed in healthy controls and in patients. A battery of cognitive tests was applied to both groups, with the patients being assessed at 6 months after the acute episode and only in those with a clinical response to treatment. Results: Plasma BDNF levels were altered in patients compared with the control group. In FEP patients, we observed a positive association between BDNF levels at six months and five cognitive domains (learning ability,immediate and delayed memory, abstract thinking and processing speed) which persisted after controlling for medications prescribed, drug use, intelligence quotient (IQ) and negative symptoms. In the healthy control group, BDNF levels were not associated with cognitive test scores. Conclusion: Our results suggest that BDNF is associated with the cognitive impairment seen after a FEP. Further investigations of the role of this neurotrophin in the symptoms associated with psychosis onset are warranted.

Paralelização do algoritmo FDK para reconstrução 3D de imagens tomográficas usando unidades gráficas de processamento e CUDA-C

A obtenção de imagens usando tomografia computadorizada revolucionou o diagnóstico de doenças na medicina e é usada amplamente em diferentes áreas da pesquisa científica. Como parte do processo de obtenção das imagens tomográficas tridimensionais um conjunto de radiografias são processadas por um algoritmo computacional, o mais usado atualmente é o algoritmo de Feldkamp, David e Kress (FDK). Os usos do processamento paralelo para acelerar os cálculos em algoritmos computacionais usando as diferentes tecnologias disponíveis no mercado têm mostrado sua utilidade para diminuir os tempos de processamento. No presente trabalho é apresentada a paralelização do algoritmo de reconstrução de imagens tridimensionais FDK usando unidades gráficas de processamento (GPU) e a linguagem CUDA-C. São apresentadas as GPUs como uma opção viável para executar computação paralela e abordados os conceitos introdutórios associados à tomografia computadorizada, GPUs, CUDA-C e processamento paralelo. A versão paralela do algoritmo FDK executada na GPU é comparada com uma versão serial do mesmo, mostrando maior velocidade de processamento. Os testes de desempenho foram feitos em duas GPUs de diferentes capacidades: a placa NVIDIA GeForce 9400GT (16 núcleos) e a placa NVIDIA Quadro 2000 (192 núcleos).

Utilização de marcadores salivares para avaliação e controle do desempenho físico e cognitivo em atletas de futebol

A elaboração de um programa de treinamento físico depende do controle de diferentes parâmetros bioquímicos, que se relacionam com fatores como a intensidade do exercício, imunidade e com o estado redox. Além disso, estudos recentes também começaram a apontar a relevância da função executiva como componente determinante para o alcance de um alto nível de desempenho esportivo. Por outro lado, poucos estudos foram realizados em atletas até o momento utilizando estes marcadores na saliva juntamente com os testes de função cognitiva. O objetivo desse trabalho foi estudar a capacidade discriminatória das análises bioquímicas realizadas em saliva para avaliação do desempenho físico e sua relação com a função cognitiva em atletas de futebol. Trinta e dois atletas foram submetidos ao Bangsbo Sprint Test (BST) para avaliação da capacidade física e 48 horas depois ao Teste de Stroop (TSt) e Torre de Hanoi (ToH) para avaliação da função executiva. Os níveis de lactato na saliva aumentaram quando comparados aos valores Pré-BST (6,9 vezes; p<0,05). A proteína total salivar seguiu o mesmo padrão com aumento observado após o BST (+34%; p<0,05). As concentrações de imunoglobulina-A salivar (IgA-s) não mostraram diferença significativa após o BST. Os níveis de GSH e TBARs na saliva não mostraram diferença significativa, enquanto que a concentração de ácido úrico diminuiu após o BST (-26%; p<0,05). Interessantemente, a superóxido dismutase (SOD) salivar aumentou (3,6 vezes; p<0,05), enquanto que os níveis de catalase (CAT) na saliva não alteraram significativamente. Não houve correlação de nenhum dos parâmetros analisados com o desempenho no TSt, entretanto atletas localizados no percentil superior (P90) de cortisol na saliva (11,2 ng/ mL à 32,7 ng/ mL) apresentaram tempos mais longos para a resolução do ToH. A eletroforese 2D mostrou que 215 spots só apareceram no momento Pré-BST, 63 spots aumentaram e 108 diminuíram a sua expressão após o BST. Concluindo, a saliva é sensível às modificações induzidas pelo BST. A manutenção dos níveis salivares de TBARs após o BST parece ocorrer em função da diminuição dos níveis de ácido úrico, componente este que possui uma expressiva ação antioxidante. Neste sentido, o aumento de SOD pós-exercício parece agir como uma segunda linha de defesa antioxidante contra a produção de ROS induzidas pelo BST. Além disso, os resultados dos testes de função executiva indicam que níveis elevados de cortisol salivar possuem um efeito deletério no tempo de resolução da ToH, que se refere à memória de trabalho, o planejamento e solução de problemas. No entanto o TSt, que envolve a atenção seletiva e a velocidade de processamento de informações parecem não ser afetados pelos níveis de cortisol em repouso. E finalmente, a eletroforese 2D mostrou que o BST induziu a expressão diferencial de proteínas, visto que não surgiram proteínas novas após o teste, e dezenas de proteínas foram up-reguladas e down-reguladas após o BST. Estes dados sugerem que após uma análise proteômica, estas proteínas possam ser candidatas a marcadores de desempenho físico e/ou cognitivo em futuros estudos.

基于SIM1-2的现场总线仪表电路设计

媒体结合单元(MAU)是现场总线仪表中的重要部件。介绍一种新型的媒体结合单元电路器件SIM1-2,该器件符合IEC61158-2数据链路层协议规范。在详细分析该器件的系统结构和主要功能的基础上,介绍其在总线仪表系统中的应用。并从资源需要,处理速度和功耗等方面分析单片机、通讯控制器、MAU电路的选择等关键问题。

Understanding GPU programming for statistical computation: Studies in massively parallel massive mixtures

This article describes advances in statistical computation for large-scale data analysis in structured Bayesian mixture models via graphics processing unit (GPU) programming. The developments are partly motivated by computational challenges arising in fitting models of increasing heterogeneity to increasingly large datasets. An example context concerns common biological studies using high-throughput technologies generating many, very large datasets and requiring increasingly high-dimensional mixture models with large numbers of mixture components.We outline important strategies and processes for GPU computation in Bayesian simulation and optimization approaches, give examples of the benefits of GPU implementations in terms of processing speed and scale-up in ability to analyze large datasets, and provide a detailed, tutorial-style exposition that will benefit readers interested in developing GPU-based approaches in other statistical models. Novel, GPU-oriented approaches to modifying existing algorithms software design can lead to vast speed-up and, critically, enable statistical analyses that presently will not be performed due to compute time limitations in traditional computational environments. Supplementalmaterials are provided with all source code, example data, and details that will enable readers to implement and explore the GPU approach in this mixture modeling context. © 2010 American Statistical Association, Institute of Mathematical Statistics, and Interface Foundation of North America.

Apolipoprotein epsilon4 and neuropsychological performance in Alzheimer's disease and vascular dementia

The apolipoprotein (APOE) epsilon4 allele is a genetic risk factor for the development of Alzheimer's disease (AD). It has also been associated with vascular dementia (VaD) in some but not all studies. Previous studies have examined the role of APOE in predicting performance on cognitive tests in both demented and non-demented populations. In cognitively intact individuals, statistically significant group differences between APOE epsilon4 carriers and non-carriers have been demonstrated for several cognitive domains. In AD studies of the impact of APOE epsilon4 on cognition have been conflicting while no previous study has assessed cognition and impact of APOE epsilon4 in VaD. In this study we investigated the impact of APOE epsilon4 on performance in neuropsychological tests including information processing speed in patients with mild-moderate AD and VaD. We incorporated both computerized and pen and paper tests to ensure a sensitive method of assessing cognition. 109 patients participated in the study (VaD=41, AD=68). Neurocognitive performance of 44 epsilon4 present AD patients was compared to 24 epsilon4absent patients and performance of 23 epsilon4 present VaD patients was compared to 18 epsilon4 absent patients. There was evidence that APOE epsilon4 conferred a risk of poorer cognitive functioning in both patient groups. In the AD group presence of epsilon4 conferred a negative impact on some measures of speed of information processing and immediate recall while in the VaD group epsilon4 present patients had evidence of poorer accuracy on tasks such as choice reaction time and spatial working memory. In AD and VaD groups epsilon4 present patients showed impairment in selective attention. These findings provide further support of the negative impact of the epsilon4 allele in cognition.

The Analogical Peacock Hypothesis: The Sexual Selection of Mind-Reading and Relational Cognition in Human Communication

This integrative review presents a novel hypothesis as a basis for integrating two evolutionary viewpoints on the origins of human cognition and communication, the sexual selection of human mental capacities, and the social brain hypothesis. This new account suggests that mind-reading social skills increased reproductive success and consequently became targets for sexual selection. The hypothesis proposes that human communication has three purposes: displaying mind-reading abilities, aligning and maintaining representational parity between individuals to enable displays, and the exchange of propositional information. Intelligence, creativity, language, and humor are mental fitness indicators that signal an individual’s quality to potential mates, rivals, and allies. Five features central to the proposed display mechanism unify these indicators, the relational combination of concepts, large conceptual knowledge networks, processing speed, contextualization, and receiver knowledge. Sufficient between-mind alignment of conceptual networks allows displays based upon within-mind conceptual mappings. Creative displays communicate previously unnoticed relational connections and novel conceptual combinations demonstrating an ability to read a receiver’s mind. Displays are costly signals of mate quality with costs incurred in the developmental production of the neural apparatus required to engage in complex displays and opportunity costs incurred through time spent acquiring cultural knowledge. Displays that are fast, novel, spontaneous, contextual, topical, and relevant are hard-to-fake for lower quality individuals. Successful displays result in elevated social status and increased mating options. The review addresses literatures on costly signaling, sexual selection, mental fitness indicators, and the social brain hypothesis; drawing implications for nonverbal and verbal communication.

Cascaded multimodal biometric recognition framework

A practically viable multi-biometric recognition system should not only be stable, robust and accurate but should also adhere to real-time processing speed and memory constraints. This study proposes a cascaded classifier-based framework for use in biometric recognition systems. The proposed framework utilises a set of weak classifiers to reduce the enrolled users' dataset to a small list of candidate users. This list is then used by a strong classifier set as the final stage of the cascade to formulate the decision. At each stage, the candidate list is generated by a Mahalanobis distance-based match score quality measure. One of the key features of the authors framework is that each classifier in the ensemble can be designed to use a different modality thus providing the advantages of a truly multimodal biometric recognition system. In addition, it is one of the first truly multimodal cascaded classifier-based approaches for biometric recognition. The performance of the proposed system is evaluated both for single and multimodalities to demonstrate the effectiveness of the approach.

Atividade física e aptidão física funcional em pessoas idosas com défice cognitivo

Objetivo: Estudar os níveis de atividade física e a aptidão física funcional de pessoas idosas com défice cognitivo. Pretendemos também estudar a velocidade de processamento da informação deste grupo de pessoas. Método: Participaram no estudo 81 pessoas idosas (82.9  7.8 anos ) institucionalizadas, de ambos os sexos, sendo que 53 pessoas tinham défice cognitivo. Os dados da atividade física foram recolhidos através da acelerometria onde foi pedido a cada participante que usasse o aparelho durante 500 minutos diários, no mínimo 3 dias. Para avaliação da atividade física funcional foi utilizado a Berg Balance Scale, o Functional Reach Test e alguns testes do Senior Fitness Test. Foi ainda avaliado o tempo de reação simples. Resultados: Os participantes não cumprem com as recomendações diárias de atividade física e apresentam um comportamento sedentário muito elevado. As pessoas idosas sem défice cognitivo apresentam melhor velocidade de processamento da informação e melhores níveis de aptidão física funcional. A maioria das variáveis da aptidão física funcional correlaciona-se positivamente com a quantidade de atividade física realizada. Conclusões: Os níveis de atividade física e de aptidão física funcional, bem como a velocidade de processamento da informação são bastante baixos nas pessoas institucionalizadas com défice cognitivo; Physical activity and functional fitness in older adults with mild cognitive impairment Abstract: Objective: Study the physical activities levels and functional fitness in older adults with mild cognitive impairment. We also intend to study the processing speed from this group. Method: Eighty two nursing home residents (82.9  7.8 years), both genders, have participated in this study. Fifty three older adults had mild cognitive impairment. The data about physical activity were collected through accelerometer where it was established that each participant would have to use at least 500 minutes a day the unit for at least 3 days. Functional fitness was evaluated by Berg Balance Scale, Functional Reach Test and some test of Senior Fitness Test. It was further evaluated simple reaction time Results: The sample of this study doesn’t accomplish the recommended standars for physical activity and they have a very high sedentary behavior. Older adults without mild cognitve impariment showed to have better results ininformation processing speed and functional fitness. Most variables of functional fitness is related positively with the amount of physical activity performed. Conclusions: The functional fitness, physical activity levels and information processing speed are too low in all nursing home residente with mild cognitive impairment.