The genetic architecture of the human hypothalamus and its involvement in neuropsychiatric behaviours and disorders.

Despite its crucial role in the regulation of vital metabolic and neurological functions, the genetic architecture of the hypothalamus remains unknown. Here we conducted multivariate genome-wide association studies (GWAS) using hypothalamic imaging data from 32,956 individuals to uncover the genetic underpinnings of the hypothalamus and its involvement in neuropsychiatric traits. There were 23 significant loci associated with the whole hypothalamus and its subunits, with functional enrichment for genes involved in intracellular trafficking systems and metabolic processes of steroid-related compounds. The hypothalamus exhibited substantial genetic associations with limbic system structures and neuropsychiatric traits including chronotype, risky behaviour, cognition, satiety and sympathetic-parasympathetic activity. The strongest signal in the primary GWAS, the ADAMTS8 locus, was replicated in three independent datasets (N = 1,685-4,321) and was strengthened after meta-analysis. Exome-wide association analyses added evidence to the association for ADAMTS8, and Mendelian randomization showed lower ADAMTS8 expression with larger hypothalamic volumes. The current study advances our understanding of complex structure-function relationships of the hypothalamus and provides insights into the molecular mechanisms that underlie hypothalamic formation.

Towards a youth mental health paradigm: a perspective and roadmap.

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

Neighborhood greenspace and health in a large urban center.

Studies have shown that natural environments can enhance health and here we build upon that work by examining the associations between comprehensive greenspace metrics and health. We focused on a large urban population center (Toronto, Canada) and related the two domains by combining high-resolution satellite imagery and individual tree data from Toronto with questionnaire-based self-reports of general health perception, cardio-metabolic conditions and mental illnesses from the Ontario Health Study. Results from multiple regressions and multivariate canonical correlation analyses suggest that people who live in neighborhoods with a higher density of trees on their streets report significantly higher health perception and significantly less cardio-metabolic conditions (controlling for socio-economic and demographic factors). We find that having 10 more trees in a city block, on average, improves health perception in ways comparable to an increase in annual personal income of $10,000 and moving to a neighborhood with $10,000 higher median income or being 7 years younger. We also find that having 11 more trees in a city block, on average, decreases cardio-metabolic conditions in ways comparable to an increase in annual personal income of $20,000 and moving to a neighborhood with $20,000 higher median income or being 1.4 years younger.

Nutrition and neurodevelopment in children: focus on NUTRIMENTHE project.

There is growing evidence that early nutrition affects later cognitive performance. The idea that the diet of mothers, infants, and children could affect later mental performance has major implications for public health practice and policy development and for our understanding of human biology as well as for food product development, economic progress, and future wealth creation. To date, however, much of the evidence is from animal, retrospective studies and short-term nutritional intervention studies in humans. The positive effect of micronutrients on health, especially of pregnant women eating well to maximise their child's cognitive and behavioural outcomes, is commonly acknowledged. The current evidence of an association between gestational nutrition and brain development in healthy children is more credible for folate, n-3 fatty acids, and iron. Recent findings highlight the fact that single-nutrient supplementation is less adequate than supplementation with more complex formulae. However, the optimal content of micronutrient supplementation and whether there is a long-term impact on child's neurodevelopment needs to be investigated further. Moreover, it is also evident that future studies should take into account genetic heterogeneity when evaluating nutritional effects and also nutritional recommendations. The objective of the present review is to provide a background and update on the current knowledge linking nutrition to cognition and behaviour in children, and to show how the large collaborative European Project NUTRIMENTHE is working towards this aim.

A target sample of adolescents and reward processing: same neural and behavioral correlates engaged in common paradigms?

Adolescence is a transition period that is assumed to be characterized by increased sensitivity to reward. While there is growing research on reward processing in adolescents, investigations into the engagement of brain regions under different reward-related conditions in one sample of healthy adolescents, especially in a target age group, are missing. We aimed to identify brain regions preferentially activated in a reaction time task (monetary incentive delay (MID) task) and a simple guessing task (SGT) in a sample of 14-year-old adolescents (N = 54) using two commonly used reward paradigms. Functional magnetic resonance imaging was employed during the MID with big versus small versus no win conditions and the SGT with big versus small win and big versus small loss conditions. Analyses focused on changes in blood oxygen level-dependent contrasts during reward and punishment processing in anticipation and feedback phases. We found clear magnitude-sensitive response in reward-related brain regions such as the ventral striatum during anticipation in the MID task, but not in the SGT. This was also true for reaction times. The feedback phase showed clear reward-related, but magnitude-independent, response patterns, for example in the anterior cingulate cortex, in both tasks. Our findings highlight neural and behavioral response patterns engaged in two different reward paradigms in one sample of 14-year-old healthy adolescents and might be important for reference in future studies investigating reward and punishment processing in a target age group.

Combining functional neuroimaging with off-line brain stimulation: modulation of task-related activity in language areas.

Repetitive TMS (rTMS) provides a noninvasive tool for modulating neural activity in the human brain. In healthy participants, rTMS applied over the language-related areas in the left hemisphere, including the left posterior temporal area of Wernicke (LTMP) and inferior frontal area of Broca, have been shown to affect performance on word recognition tasks. To investigate the neural substrate of these behavioral effects, off-line rTMS was combined with fMRI acquired during the performance of a word recognition task. Twenty right-handed healthy men underwent fMRI scans before and after a session of 10-Hz rTMS applied outside the magnetic resonance scanner. Functional magnetic resonance images were acquired during the performance of a word recognition task that used English or foreign-language words. rTMS was applied over the LTMP in one group of 10 participants (LTMP group), whereas the homologue region in the right hemisphere was stimulated in another group of 10 participants (RTMP group). Changes in task-related fMRI response (English minus foreign languages) and task performances (response time and accuracy) were measured in both groups and compared between pre-rTMS and post-rTMS. Our results showed that rTMS increased task-related fMRI response in the homologue areas contralateral to the stimulated sites. We also found an effect of rTMS on response time for the LTMP group only. These findings provide insights into changes in neural activity in cortical regions connected to the stimulated site and are consistent with a hypothesis raised in a previous review about the role of the homologue areas in the contralateral hemisphere for preserving behavior after neural interference.

Functional abnormalities in the primary orofacial sensorimotor cortex during speech in Parkinson's disease.

Parkinson's disease (PD) affects speech, including respiration, phonation, and articulation. We measured the blood oxygen level-dependent (BOLD) response to overt sentence reading in: (1) 9 treated female patients with mild to moderate PD (age; mean 66.0 +/- 11.6 years, mean levodopa equivalent 583.3 +/- 397.9 mg) and (2) 8 age-matched healthy female controls (age; mean 62.2 years +/- 12.3). Speech was recorded in the scanner to assess which brain regions underlie variations in the initiation and paralinguistic aspects (e.g., pitch, loudness, and rate) of speech production in the two groups. There were no differences in paralinguistic aspects of speech except for speech loudness; it was lower in PD patients compared with that in controls, when age was used as a covariate. In both groups, we observed increases in the BOLD response (reading-baseline) in brain regions involved in speech production and perception. In PD patients, as compared with controls, we found significantly higher BOLD signal in the right primary orofacial sensorimotor cortex and more robust correlations between the measured speech parameters and the BOLD response to reading, particularly, in the left primary orofacial sensorimotor cortex. These results might reflect compensatory mechanisms and/or treatment effects that take place in mild to moderately ill PD patients with quality of speech yet comparable with that of age-matched controls.

The neural response to transcranial magnetic stimulation of the human motor cortex. II. Thalamocortical contributions.

Beta oscillations (15-30 Hz) constitute an important electrophysiological signal recorded in the resting state over the human precentral gyrus. The brain circuitry involved in generating the beta oscillations is not well understood but appears to involve both cortical and subcortical structures. We have shown that single pulses of transcranial magnetic stimulation (TMS) applied over the primary motor cortex consistently elicit a brief beta oscillation. Reducing the local cortical excitability using low-frequency repetitive TMS does not change the amplitude of the induced beta oscillation (Van Der Werf and Paus in Exp Brain Res DOI 10.1007/s00221-006-0551-2). Here, we investigated the possible involvement of the thalamus in the cortically expressed beta response to single-pulse TMS. We included eight patients with Parkinson's disease who had undergone unilateral surgical lesioning of the ventrolateral nucleus of the thalamus. We administered 50 single pulses of TMS, at an intensity of 120% of resting motor threshold, over the left and right primary motor cortex and, at the same time, recorded the electroencephalogram (EEG) using a 60-electrode cap. We were able to perform analyses on seven EEG data sets and found that stimulation of the unoperated hemisphere (with thalamus) resulted in higher amplitudes of the single-trial induced beta oscillations than in the operated hemisphere (with thalamotomy). The beta oscillation obtained in response to pulses applied over the unoperated hemisphere was also higher than that obtained in healthy controls. We suggest that (1) the beta oscillatory response to pulses of TMS applied over the primary motor cortex is higher in Parkinson's disease patients, (2) thalamotomy serves to reduce the abnormally high TMS-induced beta oscillations, and (3) the motor thalamus facilitates the cortically generated oscillation, through cortico-subcortico-cortical feedback loops.

Mechanisms of action underlying the effect of repetitive transcranial magnetic stimulation on mood: behavioral and brain imaging studies.

In a set of experiments, we applied 10-Hz repetitive transcranial magnetic stimulation (rTMS) over the left mid-dorsolateral frontal cortex (MDLFC) to investigate rTMS-induced changes in affective state and neural activity in healthy volunteers. In Experiment 1, we combined 10-Hz rTMS with a speech task to examine rTMS-induced changes in paralinguistic aspects of speech production, an affect-relevant behavior strongly linked to the ACC. In Experiment 2, we combined 10-Hz rTMS with positron emission tomography (PET) and used partial least squares (PLS) to identify a pattern of brain regions whose connectivity with the site of stimulation varied as a function of rTMS. The results of Experiment 1 revealed that following stimulation of the left MDLFC, subjects reported having less positive affect and vitality and displayed more monotonous speech. In Experiment 2, results revealed that 10-Hz rTMS influenced the covariation between blood flow at the site of stimulation (ie the left MDLFC) and blood flow in a number of affect-relevant brain regions including the perigenual anterior cingulate gyrus, insula, thalamus, parahippocampal gyrus, and caudate nucleus. Taken together, our results suggest that changes in affect and affect-relevant behaviour following 10-Hz rTMS applied over the left MDLFC may be related to changes in neural activity in brain regions widely implicated in affective states, including a frontocingulate circuit.