Impulsivity, health-related behaviour and disease : A prospective study

In clinical settings impulsivity refers to a symptom of psychiatric disorder, but nonclinically oriented research treats impulsivity as a personality and temperament dimension. This prospective study examined whether impulsivity predicts adverse health-related behaviour and increased risk of health problems in a large, nonclinical sample of 5433 subjects working in 12 Finnish hospitals. The data were collected using two questionnaire surveys at a 2-year interval. After controlling for alcohol use at baseline, higher impulsivity predicted increased alcohol consumption at follow-up in both genders (p < .01) and was associated with increased likelihood of becoming a heavy drinker or taking up smoking (p < .05). Impulsivity also predicted an increased number of cigarettes smoked per day in the follow-up among women (p < .001), but not among men, although adjustment for the number of cigarettes smoked at baseline attenuated these associations (p = .08 for women). In men, higher impulsivity was associated with shorter sleep duration and waking up several times per night independent of baseline characteristics (p < .01), whereas in women, higher impulsivity predicted difficulty in falling asleep and waking up feeling tired after the usual amount of sleep (p < .05). In women, these associations became nonsignificant after adjustment for pre-existing somatic and psychiatric diseases. Finally, higher impulsivity was associated with an increased 2-year incidence of physician-diagnosed peptic ulcer disease (adjusted odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.21 - 4.82) and onset of depression (OR = 1.95, 95% CI = 1.28 - 2.97) after adjustment for a variety of baseline covariates. In conclusion, this study shows that in a nonclinical population, impulsivity appears to be a risk factor for various unhealthy behaviour and health problems.

Molecular Pathways of Disturbed Sleep and Depression: Studies on Adenosine and Gene Expression Patterns

Background: Adenosine is a potent sleep-promoting substance, and one of its targets is the basal forebrain. Fairly little is known about its mechanism of action in the basal forebrain and about the receptor subtype mediating its regulating effects on sleep homeostasis. Homeostatic deficiency might be one of the causes of the profoundly disturbed sleep pattern in major depressive disorder, which could explain the reduced amounts of delta-activity-rich stages 3 and 4. Since major depression has a relatively high heritability, and on the other hand adenosine regulates sleep homeostasis and might also be involved in mood modulation, adenosine-related genes should be considered for their possible contribution to a predisposition for depression and disturbed sleep in humans. Depression is a complex disorder likely involving the abnormal functioning of several genes. Novel target genes which could serve as the possible common substrates for depression and comorbid disturbed sleep should be identified. In this way specific brain areas related to sleep regulation should be studied by using animal model of depression which represents more homogenous phenotype as compared to humans. It is also important to study these brain areas during the development of depressive-like features to understand how early changes could facilitate pathophysiological changes in depression. Aims and methods: We aimed to find out whether, in the basal forebrain, adenosine induces recovery non-rapid eye movement (NREM) sleep after prolonged waking through the A1 or/and A2A receptor subtype. A1 and A2A receptor antagonists were perfused into the rat basal forebrain during 3 h of sleep deprivation, and the amount of NREM sleep and delta power during recovery NREM sleep were analyzed. We then explored whether polymorphisms in genes related to the metabolism, transport and signaling of adenosine could predispose to depression accompanied by signs of disturbed sleep. DNA from 1423 individuals representative of the Finnish population and including controls and cases with depression, depression accompanied by early morning awakenings and depression accompanied by fatigue, was used in the study to investigate the possible association between polymorphisms from adenosine-related genes and cases. Finally to find common molecular substrates of depression and disturbed sleep, gene expression changes were investigated in specific brain areas in the rat clomipramine model of depression. We focused on the basal forebrain of 3-week old clomipramine-treated rats which develop depressive-like symptoms later in adulthood and on the hypothalamus of adult female clomipramine-treated rats. Results: Blocking of the A1 receptor during sleep deprivation resulted in a reduction of the recovery NREM sleep amount and delta power, whereas A2A receptor antagonism had no effect. Polymorphisms in adenosine-related genes SLC29A3 (equilibrative nucleoside transporter type 3) in women and SLC28A1 (concentrative nucleoside transporter type 1) in men associated with depression alone as well as when accompanied by early morning awakenings and fatigue. In Study III the basal forebrain of postnatal rats treated with clomipramine displayed disturbances in gamma-aminobutyric acid (GABA) receptor type A signaling, in synaptic transmission and possible epigenetic changes. CREB1 was identified as a common transcription denominator which also mediates epigenetic regulation. In the hypothalamus the major changes included the expression of genes in GABA-A receptor pathway, K+ channel-related, glutamatergic and mitochondrial genes, as well as an overexpression of genes related to RNA and mRNA processing. Conclusions: Adenosine plays an important role in sleep homeostasis by promoting recovery NREM sleep via the A1 receptor subtype in the basal forebrain. Also adenosine levels might contribute to the risk of depression with disturbed sleep, since the genes encoding nucleoside transporters showed the strongest associations with depression alone and when accompanied by signs of disturbed sleep in both women and men. Sleep and mood abnormalities in major depressive disorder could be a consequence of multiple changes at the transcriptional level, GABA-A receptor signaling and synaptic transmission in sleep-related basal forebrain and the hypothalamus.

Circadian Rhythm Disruptions and Health

The doctoral thesis defined connections between circadian rhythm disruptions and health problems. Sleep debt, jet-lag, shift work, as well as transitions into and out of the daylight saving time may lead to circadian rhythm disruptions. Disturbed circadian rhythm causes sleep deprivation and decrease of mood and these effects may lead to higher accident rates and trigger mental illnesses. Circadian clock genes are involved in the regulation of the cell cycle and metabolism and thus unstable circadian rhythmicity may also lead to cancer development. In publications I-III it was explored how transitions into and out of the daylight saving time impact the sleep efficiency and the rest-activity cycles of healthy individuals. Also it was explored whether the effect of transition is different in fall as compared to spring, and whether there are subgroup specific differences in the adjustment to transitions into and out of daylight saving time. The healthy participants of studies I-III used actigraphs before and after the transitions and filled in the morningness-eveningness and seasonal pattern assessment questionnaires. In publication IV the incidence of hospital-treated accidents and manic episodes was explored two weeks before and two weeks after the transitions into and out of the daylight saving time in years 1987-2003. In publication V the relationship between circadian rhythm disruption and the prevalence of Non-Hodgkin lymphoma was studied. The study V consisted of all working aged Finns who participated in the national population census in 1970. For our study, all the cancers diagnosed during the years 1971-1995 were extracted from the Finnish Cancer Register and linked with the 1970 census files. In studies I-III it was noticed that transitions into and out of the daylight saving time disturbs the sleep-wake cycle and the sleep efficiency of the healthy participants. We also noticed that short sleepers were more sensitive than long sleepers for sudden changes in the circadian rhythm. Our results also indicated that adaptation to changes in the circadian rhythm is potentially sex, age and chronotype-specific. In study IV no significant increase in the occurrence of hospital treated accidents or manic episodes was noticed. However, interesting observations about the seasonal fluctuation of the occurrence rates of accidents and manic episodes were made. Study V revealed that there might be close relationship between circadian rhythm disruption and cancer. The prevalence of Non-Hodgkin lymphoma was the highest among night workers. The five publications included in this thesis together point out that disturbed circadian rhythms may have adverse effect on health. Disturbed circadian rhythms decrease the quality of sleep and weaken the sleep-wake cycle. A continuous circadian rhythm disruption may also predispose individuals to cancer development. Since circadian rhythm disruptions are common in modern society they might have a remarkable impact on the public health. Thus it is important to continue circadian rhythm research so that better prevention and treatment methods can be developed. Keywords: Circadian rhythm, daylight saving time, manic episodes, accidents, Non-Hodgkin lymphoma 11

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.

Social factors at work and the health of employees

Masennus, ahdistuneisuus, alkoholiriippuvuus ja alkoholin väärinkäyttö sekä unihäiriöt ovat yleisiä ongelmia työssä käyvän väestön keskuudessa. Nämä sairaudet ja oireet aiheuttavat huomattavia kuluja myös yhteiskunnalle. Sosiaalisen tuen ja työilmapiirin yhteyttä työssä käyvien (n = 3 347–3 430) terveyteen tutkittiin Terveyden ja hyvinvoinnin laitoksen Terveys 2000 -aineistossa. Sosiaalista tukea työssä mitattiin JCQ-kyselyllä (Job Content Questionnaire) ja yksityiselämän sosiaalista tukea SSQ-kyselyllä (Social Support Questionnaire). Työilmapiiriä mitattiin kyselyllä, joka on osa Terve työyhteisö -kyselyä. Mielenterveyshäiriöiden diagnoosit perustuivat CIDI-haastatteluun (Composite International Diagnostic Interview). Tiedot lääkärin määräämistä masennus- ja unilääkkeistä poimittiin Kelan lääkerekisteristä ja tiedot työkyvyttömyyseläkkeistä Eläketurvakeskuksen ja Kelan rekistereistä. Ilmapiirin kokemisessa ei ollut merkitsevää eroa sukupuolten välillä. Sen sijaan naiset kokivat saavansa sosiaalista tukea enemmän sekä työssä että yksityiselämässä. Vähäinen sosiaalinen tuki sekä työssä että yksityiselämässä oli yhteydessä masennukseen, ahdistuneisuushäiriöihin ja moniin uniongelmiin. Huono työilmapiiri oli yhteydessä sekä masennukseen että ahdistuneisuushäiriöihin. Vähäinen tuki sekä esimiehiltä että työtovereilta oli yhteydessä myöhempään masennuslääkkeiden käyttöön. Huono työilmapiiri ennusti myös masennuslääkkeiden käyttöä. Vähäinen sosiaalinen tuki esimieheltä näytti lisäävän työkyvyttömyyseläkkeen todennäköisyyttä. Työhyvinvointiin täytyy kiinnittää huomiota, koska vähäinen sosiaalinen tuki ja huono työilmapiiri ovat yhteydessä mielenterveysongelmiin ja lisäävät työkyvyn menettämisen riskiä. – Englanninkielinen julkaisu. Suomenkielinen yhteenveto s. 89–90.