Estonian National Mental Health Study: Design and methods for a registry-linked longitudinal survey.

OBJECTIVES: The Estonian National Mental Health Study (EMHS) was conducted in 2021-2022 to provide population-wide data on mental health in the context of COVID-19 pandemic. The main objective of this paper is to describe the rationale, design, and methods of the EMHS and to evaluate the survey response. METHODS: Regionally representative stratified random sample of 20,000 persons aged 15 years and older was drawn from the Estonian Population Register for the study. Persons aged 18 years and older at the time of the sampling were enrolled into three survey waves where they were invited to complete an online or postal questionnaire about mental well-being and disorders, and behavioral, cognitive, and other risk factors. Persons younger than 18 years of age were invited to fill an anonymous online questionnaire starting from wave 2. To complement and validate survey data, data on socio-demographic, health-related, and environmental variables were collected from six national administrative databases and registries. Additionally, a subsample was enrolled into a validation study using ecological momentary assessment. RESULTS: In total, 5636 adults participated in the survey wave 1, 3751 in wave 2, and 4744 in wave 3. Adjusted response rates were 30.6%, 21.1%, and 27.6%, respectively. Women and older age groups were more likely to respond. Throughout the three survey waves, a considerable share of adult respondents screened positive for depression (27.6%, 25.1%, and 25.6% in waves 1, 2, and 3, respectively). Women and young adults aged 18 to 29 years had the highest prevalence of depression symptoms. CONCLUSIONS: The registry-linked longitudinal EMHS dataset comprises a rich and trustworthy data source to allow in-depth analysis of mental health outcomes and their correlates among the Estonian population. The study serves as an evidence base for planning mental health policies and prevention measures for possible future crises.

Large-scale distributed networks and cerebral hemispheres.

The two main large-scale distributed networks, Central Executive (CEN) and Default Mode (DMN) have been extensively studied, but their relationship to hemispheric specialization has not been comprehensively addressed. We present evidence that they are neuroanatomically asymmetric: the CEN components are volumetrically larger in the right hemisphere, and DMN components are volumetrically larger in the left hemisphere. Based on this, the possibility that CEN and DMN are also functionally asymmetric is introduced and implications of the putative functional asymmetry of large-scale distributed networks for refining our understanding of hemispheric specialization are examined.

E.L., a modern-day Phineas Gage: Revisiting frontal lobe injury.

Background: How the prefrontal cortex (PFC) recovers its functionality following lesions remains a conundrum. Recent work has uncovered the importance of transient low-frequency oscillatory activity (LFO; < 4 Hz) for the recovery of an injured brain. We aimed to determine whether persistent cortical oscillatory dynamics contribute to brain capability to support 'normal life' following injury. Methods: In this 9-year prospective longitudinal study (08/2012-2021), we collected data from the patient E.L., a modern-day Phineas Gage, who suffered from lesions, impacting 11% of his total brain mass, to his right PFC and supplementary motor area after his skull was transfixed by an iron rod. A systematic evaluation of clinical, electrophysiologic, brain imaging, neuropsychological and behavioural testing were used to clarify the clinical significance of relationship between LFO discharge and executive dysfunctions and compare E.L.´s disorders to that attributed to Gage (1848), a landmark in the history of neurology and neuroscience. Findings: Selective recruitment of the non-injured left hemisphere during execution of unimanual right-hand movements resulted in the emergence of robust LFO, an EEG-detected marker for disconnection of brain areas, in the damaged right hemisphere. In contrast, recruitment of the damaged right hemisphere during contralateral hand movement, resulted in the co-activation of the left hemisphere and decreased right hemisphere LFO to levels of controls enabling performance, suggesting a target for neuromodulation. Similarly, transcranial magnetic stimulation (TMS), used to create a temporary virtual-lesion over E.L.'s healthy hemisphere, disrupted the modulation of contralateral LFO, disturbing behaviour and impairing executive function tasks. In contrast to Gage, reasoning, planning, working memory, social, sexual and family behaviours eluded clinical inspection by decreasing LFO in the delta frequency range during motor and executive functioning. Interpretation: Our study suggests that modulation of LFO dynamics is an important mechanism by which PFC accommodates neurological injuries, supporting the reports of Gage´s recovery, and represents an attractive target for therapeutic interventions. Funding: Fundação de Amparo Pesquisa Rio de Janeiro (FAPERJ), Universidade Federal do Rio de Janeiro (intramural), and Fiocruz/Ministery of Health (INOVA Fiocruz).

BDNF polymorphism in non-veridical decision making and differential effects of rTMS.

Making decisions when an objectively correct option is not obvious, involves different neurobiological mechanisms than "veridical" decision making. The dorsolateral prefrontal cortex (DLPFC) exhibits a distinct pattern of prefrontal activation in non-veridical cognition, but little is known about the role of underlying neurobiological endophenotypes. A functional polymorphism in the brain-derived neurotrophic factor (BDNF) gene, causing a valine (Val) to methionine (Met) amino acid substitution at codon 66, has been shown to be associated with structural and functional changes in DLPFC and affect veridical decision making. We hypothesized that the BDNF genotype may be related to non-veridical cognition. We explored whether the BDNF Val66Met polymorphism affected preferences in a cognitive task devoid of intrinsically correct or false choice, using the Cognitive Bias Task (CBT). We also studied if manipulating the right DLPFC with rTMS stimulation changes non-veridical preferences. Sixteen healthy adults, including 9 Val/Val and 7 Val/Met subjects, participated in the study. Participants with Val/Met genotype expressed a more context-independent, internally driven choice selection preference. Val/Val subjects' selection was more dependent on the context, driven by the properties of external stimuli. rTMS stimulation enhanced a preexisting bias in choice preferences. In Val/Val subjects, TMS stimulation shifted the non-veridical preference bias towards greater dependence on external context, while in Val/Met subjects the CBT score became more context-independent. Our study showed that BDNF genotype is associated with a bias in non-veridical preferences and that Val/Val and Val/Met subjects respond differently to right DLPFC rTMS stimulation, further enhancing their preexisting selection biases.

Diminished Risk-Aversion After Right DLPFC Stimulation: Effects of rTMS on a Risky Ball Throwing Task.

OBJECTIVES: Several studies on human risk taking and risk aversion have reported the involvement of the dorsolateral prefrontal cortex (DLPFC). Yet, current knowledge of the neural mechanisms of risk-related decision making is not conclusive, mainly relying on studies using non-motor tasks. Here we examine how modulation of DLPFC activity by repetitive transcranial magnetic stimulation (rTMS) affects risk-taking behavior during a motor response task. METHODS: One-Hertz rTMS to the right DLPFC was applied to monitor risk-taking and risk-aversion performance during a goal-directed risky task with motor response. Healthy participants were instructed to aim for a high score by throwing a ball as close to the ceiling as possible, while avoiding touching the ceiling with the ball. RESULTS: One-Hertz rTMS stimulation to the right DLPFC significantly increased the frequency of ceiling hits, compared to Sham-stimulation. CONCLUSIONS: Our results suggest that the right DLPFC is a valid target for manipulating risky behavior in tasks with a motor-response. Following rTMS stimulation participants' preference shifts toward immediate awards, while becoming significantly less sensitive to potential negative consequences. The results confirm that the right DLPFC is involved in impulse control in goal-directed executive tasks. (JINS, 2019, 25, 72-78).

Effects of repetitive transcranial magnetic stimulation on non-veridical decision making.

We test the emerging hypothesis that prefrontal cortical mechanisms involved in non-veridical decision making do not overlap with those of veridical decision making. Healthy female subjects performed an experimental task assessing free choice, agent-centered decision making (The Cognitive Bias Task) and a veridical control task related to visuospatial working memory (the Moving Spot Task). Transcranial magnetic stimulation (TMS) was applied to the left and right dorsolateral prefrontal cortex (DLPFC) using 1 Hz and 10 Hz (intermittent) rTMS and sham protocols. Both 1 Hz and 10 Hz stimulation of the DLPFC triggered a shift towards a more context-independent, internal representations driven non-veridical selection bias. A significantly reduced preference for choosing objects based on similarity was detected, following both 1 Hz and 10 Hz treatment of the right as well as 1 Hz rTMS of the left DLPFC. 1 Hz rTMS treatment of the right DLPFC also triggered a significant improvement in visuospatial working memory performance on the veridical task. The effects induced by prefrontal TMS mimicked those of posterior lesions, suggesting that prefrontal stimulation influenced neuronal activity in remote cortical regions interconnected with the stimulation site via longitudinal fasciculi.

Differences between humor comprehension and appreciation in healthy children and children with epilepsy.

This study explored verbal, visual, motor, and tactile humor appreciation and comprehension among preschool children with epilepsy as compared with healthy children. Participants included 32 children with focal epilepsy, as well as 70 healthy controls. The results suggest that children with epilepsy assess humor dichotomously (as either not funny at all or as extremely funny) and generally as less amusing when compared with ratings given by controls (M = 6.08, and M = 7.44, P = .01, respectively). They also gave significantly lower ratings to verbal jokes than to visual jokes. Furthermore, children with epilepsy assessed the jokes they understood (ie, gave expected explanations to the content of jokes) as less funny. An important finding from our study was that children with epilepsy assess aggressive humor as not funny. The most frequent emotional reaction in both groups to jokes from all subtests was a smile, followed by a half-smile.