Sleep in brain health

Early Sleep as a Foundation for Brain Development

The brain is at its most malleable during early childhood, when the basic neurophysiological systems develop. Experiences during this period have long-term effects on mental health, and consequently, major stress or trauma during early life has been linked to an increased risk of mental health problems later in life. Neurodevelopmental disorders, such as ADHD and autism spectrum disorders, originate in early infancy, and for many psychiatric disorders diagnosed later in life, including psychotic disorders, disease liability accumulates gradually throughout development. 

Both the structure and function of sleep undergo substantial changes during early development. Given the integral role of sleep in maintaining neural plasticity, the quality and quantity of sleep in early childhood are likely to have a profound impact on future health and wellbeing. Early signs of disturbed sleep may also serve as biomarkers of vulnerability to impaired functioning under stressful conditions. 

Study of sleep and development using population-based birth cohorts

We have explored the development of sleep and emotion regulation, as well as their underlying genetic mechanisms, in two parallel population-based birth cohorts from Finland: () and  (). Through these cohorts, we have examined multiple aspects of early sleep development, neurocognitive functioning, and emotional regulation from infancy onward (e.g. ,  ,  , , , , , , , ). 

Development of sleep and sleep–wake rhythms in infancy

Our findings from these cohorts indicate that variability in sleep decreases toward the second year of life (). Infants with slower sleep-wake rhythm development experienced greater difficulties settling to sleep, later bedtimes, and longer periods of wakefulness during the night (). Maternal, but not paternal, diurnal preference for eveningness (evening chronotype) associated with infant sleep difficulties (), as were maternal depressiveness, ADHD symptomatology, and irregular sleep routines (). A genetic predisposition toward eveningness was associated with longer sleep onset latency, later bedtimes, and reduced objectively measured sleep efficiency in infancy (). Furthermore, infants with genetically predicted weaker melatonin signaling exhibited slower neurocognitive development and an absence of seasonal variation in sleep duration (). 

Sleep and the emergence of self-regulation

We demonstrated robust associations between short sleep duration and sleep problems in infancy and subsequent self-regulation difficulties at ages 2 and 5 years () (). The development of self-regulation was influenced by parental and family characteristics as well as genetic factors (). Notably, genetic liability to ADHD interacted significantly with short sleep duration, so that the combination of parent-reported short sleep and elevated genetic risk for ADHD was associated with a substantially increased of inattention and hyperactivity symptoms at 5 years of age (). Taken together, these findings support the view that short sleep in infancy should be identified and addressed early to ensure that children obtain adequate sleep according to their physiological needs.

Identifying early biomarkers of neuropsychiatric vulnerability

Currently, we are identifying EEG-based biomarkers of early-life brain development that may serve as indicators of vulnerability to later psychiatric diseases (collaboration: the and study groups and Prof. Sampsa Vanhatalo, UH). We are also investigating the genetic determinants of gross motor development during the first two years of life. In addition, we participate in the international MIND consortium aimed at identifying epigenetic correlates of brain development (), as well as genetic influences on development of emotions and parental emotion processing. 

Longitudinal studies on sleep and mental health

Both birth cohorts are being followed longitudinally, and our ongoing research seeks to clarify the role of sleep-related traits as potential endophenotypes of neuropsychiatric diseases.  

Our studies on sleep and sleep-wake rhythms in psychiatric disorders are based on the hypothesis that sleep and circadian traits contribute to disease pathogenesis, can be used to stratify patients into more etiologically homogeneous subgroups, and that these subgroups differ in prognosis and treatment response.

Sleep as a predictive indicator of brain health

These studies build on our earlier and more recent findings regarding the role of sleep in brain health. In a nationwide twin cohort using genetic modeling, we demonstrated a longitudinal and potentially causal association between poor sleep and the development of depressive symptoms at follow-up (P). Subsequent analyses of the cohort showed that poor sleep was associated with a two- to threefold increased risk of work disability due to depression (), highlighting the clinical relevance of subjectively perceived poor sleep quality. Later, we identified distinct DNA methylation patterns among adolescents with depression and comorbid insomnia ().

Using data from the National FINRISK Surveys, we showed that both self-reported insomnia and genetic liability to insomnia were associated with an increased risk of incident Parkinson’s disease, suggesting insomnia may act as a risk factor rather than merely a prodromal symptom (). In a series of population-based studies, we also characterized the prevalence, determinants, and mental-health correlates of nightmares. These studied provided strong evidence that nightmares index emotional burden and warrant systematic clinical attention (Sandman , , , ).

Sleep phenotypes in psychotic disorders

More recently, as a part of the international Stanley Global Neuropsychiatric Genomic Initiative, we identified robust sleep-based clusters among patients with psychotic disorders in the large Finnish . Three distinct subgroups emerged : 1) a relatively symptom-free group, 2) a group characterized by insomnia (difficulties initiating sleep) and 3) a group characterized by hypersomnia (long sleep duration and fatigue)(Cederlöf, Schizophrenia Bulletin Open, ). Sleep problems were strongly associated with antipsychotic medication profiles, emphasizing the clinical relevance of systematic sleep assessment in treatment planning. Importantly, sleep problems were more common also among non-medicated patients than in the general population, raising the possibility that sleep traits may represent endophenotypes for psychotic disorders ().

Genetic mechanisms linking sleep and psychosis

Our search for the genetic basis of cognitive endophenotypes and insomnia in schizophrenia revealed partially distinct associations. While the polygenic risk score (PRS) for schizophrenia was associated with poorer cognitive performance  and greater disease severity, reflected by involuntary hospitalizations and clozapine use, PRS for insomnia was associated with symptoms of disturbed sleep, lower quality of life, and poorer subjective cognitive functioning (). Notably, the PRS for eveningness was higher among individuals with schizophrenia than among those with other psychotic disorders or the general population. Because a slower build-up and dissipation of sleep pressure is one of the mechanisms underlying evening chronotype, these findings suggest deviating homeostatic sleep regulation in schizophrenia. This interpretation is consistent with previous studies indicating deficits in slow-wave sleep among individuals with schizophrenia.

Treating sleep problems in patients with chronic psychosis

Taken together, our findings demonstrate that sleep problems are frequent in schizophrenia and other psychotic disorders and constitute a distinct symptom domain with partly independent etiological mechanisms. These observations led us to initiate a registered randomized controlled trial () evaluating the treatment of insomnia symptoms in chronic schizophrenia () using a CBT-I protocol we developed for HUCH Mental.hub.

The UNIT Study: a multimodal assessment of sleep and mental health

Our ongoing multicenter UNIT study () examines the role of sleep and circadian rhythms in the course of first-episode psychosis, mood and anxiety disorders as well as ADHD using digital surveys and mobile monitoring methods. A subsample of participants undergoes comprehensive multimodal assessment, including home monitoring of sleep, sleep-wake behavior, and circadian rhythms; sleep laboratory studies with high-density wake and sleep EEG; assessment of vigilance and verbal memory, and measurements of emotional responses to video stimuli, completed by functional MRI at Aalto University (collaboration: Profs Iiro Jääskeläinen and Hanna Renvall). In addition, blood samples (plasma and blood cells) are being collected through the Helsinki Biobank to investigate genetic influences on disease trajectories and sleep-related traits.

Building infrastructure for clinical sleep research

Complementing the UNIT, we have established a PSG data bank for clinical sleep research at HUS Acamedic, where we have developed a comprehensive pipeline for biosignal analysis (EEG, EOG, EMG, ECG, airflow, and PPG) using automatic scoring and machine learning methods (collaboration: Prof. Timo Leppänen, UEF).

Previous studies have demonstrated how acute sleep deprivation leads to impaired physiological and psychological functioning. Subjective sleepiness, lowered mood, and increased anxiety typically emerge early and precede impairments in vigilance and cognitive performance, whereas prolonged sleep deprivation results in more extensive disturbances of mental functioning, in some cases resembling the clinical picture of acute psychosis. However, responses to sleep deprivation vary considerably between individuals, suggesting an important role for genetic susceptibility factors. At the population level, chronic sleep insufficiency and unstable sleep–wake rhythms are associated with adverse health outcomes, including increased risks of cardiometabolic disorders such as type 2 diabetes and cardiovascular disease, as well as a range of mental disorders.

To better understand the role of disturbed sleep and sleep–wake rhythms in mental disorders, we have sought to characterize epigenetic modifications induced by sleep loss and to identify genetic factors that contribute to individual vulnerability to the adverse effects of sleep deprivation. 

Epigenetic biomarkers of sleep insufficiency

In our search for biomarkers of sleep insufficiency, we first identified a distinctive DNA methylation pattern characterized by widespread hypomethylation in peripheral blood cells among men from a population-based cohort and among shift workers in two occupational cohorts () (L). Using sleep laboratory data from the University of Surrey to examine the accumulation of epigenetic changes during extended wakefulness, we observed a similar pattern of global DNA hypomethylation accompanied by enrichment of immune-related pathways, towards the end of acute sleep deprivation ().

The dynamic nature of DNA methylation 

Using paired epigenome-wide analysis, we subsequently demonstrated the dynamic nature of DNA methylation changes and identified the CREB phosphorylation pathway as a potential mediator of recovery from circadian shift work disorder (L). Furthermore, using the data from the University of Surrey, we demonstrated for the first time that DNA methylation profiles in peripheral blood leukocytes exhibit diurnal rhythms (). This time-of-day variation needs to be considered when studying DNA methylation as a biomarker in biomedical studies (collaboration: Prof. Debra Skene, University of Surrey).

Genetic determinants of sleep and circadian vulnerability

In our efforts to identify genetic vulnerability factors for disturbed sleep and sleep-wake rhythms, and the adverse effects of sleep loss, we identified through a genome-wide association study (GWAS) a genetic variant in the vicinity of the MNTR1A gene encoding for melatonin receptor 1A that associated with vulnerability to exhaustion in shift work (). We subsequently demonstrated that the same variant was associated with susceptibility to late-onset Alzheimer’s disease and its neuropathology in two independent cohorts (). Functional analyses suggested that this risk variant influences disease susceptibility through reduced MTNR1A expression mediated by epigenetic mechanisms, implicating impaired melatonin signaling in the pathogenesis of both circadian shift work disorder and very late-onset Alzheimer’s disease.

A GWAS for nightmares did not identify individual risk factors in a sample over 45 thousand individuals, but revealed robust genetic correlations between nightmares and anxiety, depression, PTSD, and neuroticism (). In a multidisciplinary study integrating genetic epidemiology, sleep science, and economics, we demonstrated that genetic predispositions to insomnia, short sleep, and long sleep were consistently associated with poorer  human capital development in Finnish population-based cohorts ().

Genetic susceptibility to the effects of sleep deprivation

We further examined whether high polygenic risk for schizophrenia increases vulnerability to sleep deprivation-induced impairment in psychomotor vigilance in healthy adults using sleep laboratory data from Washington State University. We found that in women, higher genetic risk amplified vulnerability to psychomotor vigilance impairment during the early morning hours – the period known to be most challenging for maintaining alertness during acute sleep deprivation particularly in women ().

Current and future studies on sleep resilience

We are currently extending the sleep laboratory studies to analysis of additional genetic factors of interest (collaboration: Prof. Hans van Dongen, Washington State University),and expanding our international collaborations to University of Pennsylvania (Prof. Mathias Basner) and Stockholm University (Prof. John Axelsson).  Our hypothesis on the importance of sleep for mental health is tested by an on-going study on the general population (N > 12,000), in which we are investigating interactions between insufficient sleep and genetic risk for schizophrenia in work ability and cognitive performance (Collaboration: Prof. Markus Perola, THL). 

Unraveling the genetic architecture of psychiatric disorders 

We have investigated the genetic basis of schizophrenia and bipolar disorder in national and international collaborations for more than two decades. Our work began with linkage studies in Finnish families (see eg ,  , , ) and has subsequently expanded to large-scale consortium studies coordinated by the international Psychiatric Genomics Consortium (see eg, , ,  , , , , , , , ), as well as studies on antisocial personality and extreme violent behavior (see eg T, , ).  Collectively, the studies on schizophrenia have demonstrated that increasingly larger sample size continues to reveal robust associations implicating genes involved in neuronal and synaptic function, thereby deepening our understanding of the complex genetic architecture of the disorder.

The SUPER study: a platform for precision psychiatry in psychotic disorders

Using data from approximately 10 000 individuals with major psychiatric disorders participating in the Finnish , conducted as part of the international Stanley Global Neuropsychiatric Genomic Initiative, we showed that a high polygenic risk score for schizophrenia and low for educational attainment were both associated with a less favorable course of psychotic disease, although through partly distinct disease trajectories () (PI: Prof. Aarno Palotie, UH). These findings demonstrate how different genetic risk profiles contribute to heterogeneity in disease progression and outcomes among individuals with psychotic disorders.

From genetic discovery to personalized medicine

A follow-up study of the SUPER cohort, the  (PI Ass. Prof. Olli Pietiläinen, UH), aims to deepen the understanding of the neurophysiological consequences of the high-impact genetic variants identified in psychosis studies in Finland. The SUPER cohort has further served as a major resource for our studies on sleep and circadian disturbances in psychiatric disorders, providing a unique platform for integrating genomic, clinical, and sleep-related phenotypes. 

Psychological stress is a multifaceted concept that encompasses several stages of the stress process, including environmental challenges, the appraisal of stressors, physiological stress responses, and the associated psychological states such as fear, anxiety, and distress, together with their bodily manifestations. 

Current theories propose that psychological and physiological stress responses arise when individuals perceive that environmental demands exceed their available resources or adaptive capacity. While moderate and short-term stress may be adaptive and not necessarily detrimental to health, chronic or severe psychological stress can have adverse effects on both performance and health.  

From identifying stress-related symptoms to developing treatments 

In our efforts to understand the links between psychological distress and brain and somatic health, we identified psychological factors contributing to persistent nonspecific physical symptoms ( and ) and subsequently conducted randomized controlled trials targeting these stress-related symptoms (,  and ), as well as for psychological distress among university students (). 

Biological correlations of stress across the lifespan

In our studies on biological correlates of stress across the lifespan, shorter telomere length in adulthood was associated with adverse childhood experiences (), whereas maternal stress and self-reported insufficient sleep during pregnancy were not associated with shorter telomere length in newborns (). In a study using an occupational cohort of nurses, we found that individuals in a high-stress environment had lower promoter methylation levels of the serotonin transporter gene compared to those in a low-stress environment, which could lead to increased transcriptional activity and enhanced  serotonin reuptake, a possible coping mechanism for environmental stress in humans (

Psychological distress and risk of cognitive decline

Using a longitudinal population-based cohort and rigorous statistical modeling, we demonstrated a significant association between psychological distress and the subsequent development of dementia. Consequently, stress-related mechanisms may represent early risk indicators or pathways contributing to neurodegenerative processes ().

Web-based rehabilitation for patients with stress-related symptoms

Currently, we are evaluating the effectiveness of a web-based rehabilitation program for patients with persistent stress-related physical symptoms in a registered randomized controlled trial () (collaboration: Ass. Profs. Sanna Selinheimo and Aki Vuokko, TTL, and prof. Raimo Lappalainen, University of Jyväskylä). 

Sleep, stress, and emotional memory

We are also investigating the interplay between sleep, stress, emotion regulation, and memory consolidation in an integrated PSG and fMRI study. In this study, emotionally salient memories are induced using video stimuli, and the effects of sleep on their consolidation and longer-term consequences are examined through repeated fMRI measurements and behavioral assessments (collaboration: Aalto University, Prof. Iiro Jääskeläinen and Prof. Kimmo Kaski).  

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Building scientific infrastructure for sleep research

To facilitate clinical sleep research in Finland, we have initiated several collaborative projects involving the University of Helsinki, HUS, Aalto University, and University of Eastern Finland. One of these is the HUS SleepDataBank, which integrates polysomnography and other sleep-related data collected within HUS over the past decade. The long-term goal is to connect this resource with international sleep databases and research infrastructures, although achieving this will require coordinated efforts across multiple stakeholder groups.

Digital innovations facilitating health research

We have also developed a quality-controlled mobile application AidoQ for momentary assessment of emotions and mobility, with controlled data security at HUS, UH and Aalto University.

Advancing sleep medicine through international collaboration

In recent years, we have actively contributed to international collaboration and educational activities in sleep medicine. These efforts include chairing the European Examination in Somnology ( ; ; ), editorial activities for the Journal of Sleep Research; as well as editing and contributing to the , edition 2, Wiley 2021. 

The first Finnish textbook on sleep medicine

Recently, we contributed to Sleep Medicine (Finnish: Unilääketiede, ), the first Finnish textbook dedicated to sleep medicine as a distinct medical domain, serving both as initiators of the project and as chief editors. 

Shaping clinical practice through evidence-based guidelines

In addition, we have contributed to national and international clinical practice guidelines, including the Finnish Current Care Guideline for Insomnia (), the European Guidelines for Diagnosis and Treatment of Insomnia (, ) and the Global Council Brain Health’s recommendations on sleep and brain health ().