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.

Imager-A mobile health mental imagery-based ecological momentary intervention targeting reward sensitivity: A randomized controlled trial.

Robust reward sensitivity may help preserve mental well-being in the face of adversity and has been proposed as a key stress resilience factor. Here, we present a mobile health application, "Imager," which targets reward sensitivity by training individuals to create mental images of future rewarding experiences. We conducted a two-arm randomized controlled trial with 95 participants screened for reward sensitivity. Participants in the intervention group received an ecological momentary intervention-Imager, which encouraged participants to create mental images of rewarding events for 1 week. The control group participants received only ecological momentary assessment, without the instruction to generate mental images. Adherence to Imager was high; participants in the intervention group engaged in 88% of the planned activities. In the follow-up assessment, the intervention group reported less mental health symptoms, mainly in depression (ß = -0.34, df = 93, p = .004) and less perceived stress (ß = -0.18, df = 93, p = .035), than control group participants and compared with the baseline assessment. Our results show the positive effects of Imager on mental health symptoms. The encouraging effects of the app on mental health outcomes may lead to greater use of ecological momentary interventions in the clinical preventive practice of affective disorders.

Hypothalamic volume in pedophilia with or without child sexual offense.

The hypothalamus regulates sexual behavior and is simultaneously associated with aggression and violence. Consequently, this brain region is relevant in research of pedophilia and child sexual offenses (CSO). The distinction between these two phenomena is of great importance and was the object of consideration of this study. We analyzed exclusively men, including 73 pedophilic offenders who committed CSO, an equal number of people with pedophilia but without such offenses, and 133 non-pedophilic, non-offending subjects who formed the control group. All data were collected in a multicenter in vivo study and analyzed using a semi-automated segmentation algorithm for 3-Tesla magnetic resonance images. Men with pedophilia who committed CSO on average had a 47 mm3 smaller hypothalamus per side than people without committed CSO. This effect was driven by both the group of non-offending people with pedophilia and the control group. By contrast, the exploratory comparison of pedophilic persons without CSO with the control group showed no significant difference. The present study demonstrates a deviant hypothalamic structure as a neurobiological correlate of CSO in pedophiles, but not in people with pedophilia who have not committed CSO. Thus, it strengthens the argument to distinguish between sexual offending and paraphilic sexual preferences.

Subcortical shape alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group.

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = -0.164 to -0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = -0.173 to -0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.

The Frequent Stressor and Mental Health Monitoring-Paradigm: A Proposal for the Operationalization and Measurement of Resilience and the Identification of Resilience Processes in Longitudinal Observational Studies.

Resilience has been defined as the maintenance or quick recovery of mental health during and after times of adversity. How to operationalize resilience and to determine the factors and processes that lead to good long-term mental health outcomes in stressor-exposed individuals is a matter of ongoing debate and of critical importance for the advancement of the field. One of the biggest challenges for implementing an outcome-based definition of resilience in longitudinal observational study designs lies in the fact that real-life adversity is usually unpredictable and that its substantial qualitative as well as temporal variability between subjects often precludes defining circumscribed time windows of inter-individually comparable stressor exposure relative to which the maintenance or recovery of mental health can be determined. To address this pertinent issue, we propose to frequently and regularly monitor stressor exposure (E) and mental health problems (P) throughout a study's observation period [Frequent Stressor and Mental Health Monitoring (FRESHMO)-paradigm]. On this basis, a subject's deviation at any single monitoring time point from the study sample's normative E-P relationship (the regression residual) can be used to calculate that subject's current mental health reactivity to stressor exposure ("stressor reactivity," SR). The SR score takes into account the individual extent of experienced adversity and is comparable between and within subjects. Individual SR time courses across monitoring time points reflect intra-individual temporal variability in SR, where periods of under-reactivity (negative SR score) are associated with accumulation of fewer mental health problems than is normal for the sample. If FRESHMO is accompanied by regular measurement of potential resilience factors, temporal changes in resilience factors can be used to predict SR time courses. An increase in a resilience factor measurement explaining a lagged decrease in SR can then be considered to index a process of adaptation to stressor exposure that promotes a resilient outcome (an allostatic resilience process). This design principle allows resilience research to move beyond merely determining baseline predictors of resilience outcomes, which cannot inform about how individuals successfully adjust and adapt when confronted with adversity. Hence, FRESHMO plus regular resilience factor monitoring incorporates a dynamic-systems perspective into resilience research.

Allocentric spatial memory performance predicts intrusive memory severity in posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is characterized by distressing trauma-related memories. According to the dual representation theory, intrusive memories arise from strengthened egocentric encoding and a poor contextual encoding, with spatial context requiring allocentric processing. Contextualization of mental imagery is proposed to be formed hierarchically through the ventral visual stream (VVS) to the hippocampal formation. Here, we tested this notion by investigating whether neuronal aberrations in structures of the VVS or in the hippocampus, as well as allocentric memory performance are associated with intrusive memory severity. METHODS: The sample comprised 33 women with PTSD due to childhood trauma. Allocentric memory performance was measured with the virtual Town Square Task and T1-weighted images acquired on a 3T Siemens Scanner. Intrusive memories were evoked by presenting an audio script describing parts of their trauma (script-driven imagery). RESULTS: Using hierarchical linear regression analysis, we found a significant association between lower intrusive memory severity and higher allocentric spatial memory, controlling for age, working memory, and general visuospatial ability. No significant association was found between cortical thickness of VVS structures, hippocampal volume and intrusive memory severity. Post hoc exploratory analyses revealed a negative correlation between years since index trauma and left hippocampal volume. LIMITATIONS: Our results are based on correlational analyses, causality cannot be inferred. CONCLUSION: This study supports the dual representation theory, which emphasizes the role of allocentric spatial memory for the contextualization of mental imagery in PTSD. Clinical implications are discussed.

Risk profiles for heavy drinking in adolescence: differential effects of gender.

Abnormalities across different domains of neuropsychological functioning may constitute a risk factor for heavy drinking during adolescence and for developing alcohol use disorders later in life. However, the exact nature of such multi-domain risk profiles is unclear, and it is further unclear whether these risk profiles differ between genders. We combined longitudinal and cross-sectional analyses on the large IMAGEN sample (N ≈ 1000) to predict heavy drinking at age 19 from gray matter volume as well as from psychosocial data at age 14 and 19-for males and females separately. Heavy drinking was associated with reduced gray matter volume in 19-year-olds' bilateral ACC, MPFC, thalamus, middle, medial and superior OFC as well as left amygdala and anterior insula and right inferior OFC. Notably, this lower gray matter volume associated with heavy drinking was stronger in females than in males. In both genders, we observed that impulsivity and facets of novelty seeking at the age of 14 and 19, as well as hopelessness at the age of 14, are risk factors for heavy drinking at the age of 19. Stressful life events with internal (but not external) locus of control were associated with heavy drinking only at age 19. Personality and stress assessment in adolescents may help to better target counseling and prevention programs. This might reduce heavy drinking in adolescents and hence reduce the risk of early brain atrophy, especially in females. In turn, this could additionally reduce the risk of developing alcohol use disorders later in adulthood.

The neural correlates of movement intentions: A pilot study comparing hypnotic and simulated paralysis.

The distinct feeling of wanting to act and thereby causing our own actions is crucial to our self-perception as free human agents. Disturbances of the link between intention and action occur in several disorders. Little is known, however, about the neural correlates of wanting or intending to act. To investigate these for simple voluntary movements, we used a paradigm involving hypnotic paralysis and functional magnetic resonance imaging. Eight healthy women were instructed to sequentially perform left and right hand movements during a normal condition, as well as during simulated weakness, simulated paralysis and hypnotic paralysis of the right hand. Right frontopolar cortex was selectively hypoactivated for attempted right hand movement during simulated paralysis while it was active in all other conditions. Since simulated paralysis was the only condition lacking an intention to move, the activation in frontopolar cortex might be related to the intention or volition to move.

The suggestible brain: posthypnotic effects on value-based decision-making.

Hypnosis can affect perception, motor function and memory. However, so far no study using neuroimaging has investigated whether hypnosis can influence reward processing and decision-making. Here, we assessed whether posthypnotic suggestions can diminish the attractiveness of unhealthy food and whether this is more effective than diminishing attractiveness by one's own effort via autosuggestion. In total, 16 participants were hypnotized and 16 others were instructed to associate a color cue (blue or green) with disgust regarding specific snacks (sweet or salty). Afterwards, participants bid for snack items shown on an either blue or green background during functional magnetic resonance imaging measurement. Both hypnosis and autosuggestion successfully devalued snacks. This was indicated by participants' decision-making, their self-report and by decreased blood oxygen level-dependent signal in the ventromedial prefrontal cortex (vmPFC), a region known to represent value. Different vmPFC subregions coded for cue and snack type. The cue had significantly stronger effects on vmPFC after hypnosis than after autosuggestion, indicating that hypnosis was more effective in genuinely reducing value. Supporting previous findings, the precuneus was involved in the hypnotic effects by encoding whether a snack was sweet or salty during hypnotic cue presentation. Our results demonstrate that posthypnotic suggestions can influence valuation and decision-making.

Neural correlates of alcohol-approach bias in alcohol addiction: the spirit is willing but the flesh is weak for spirits.

Behavioral studies have shown an alcohol-approach bias in alcohol-dependent patients: the automatic tendency to faster approach than avoid alcohol compared with neutral cues, which has been associated with craving and relapse. Although this is a well-studied psychological phenomenon, little is known about the brain processes underlying automatic action tendencies in addiction. We examined 20 alcohol-dependent patients and 17 healthy controls with functional magnetic resonance imaging (fMRI), while performing an implicit approach-avoidance task. Participants pushed and pulled pictorial cues of alcohol and soft-drink beverages, according to a content-irrelevant feature of the cue (landscape/portrait). The critical fMRI contrast regarding the alcohol-approach bias was defined as (approach alcohol>avoid alcohol)>(approach soft drink>avoid soft drink). This was reversed for the avoid-alcohol contrast: (avoid alcohol>approach alcohol)>(avoid soft drink>approach soft drink). In comparison with healthy controls, alcohol-dependent patients had stronger behavioral approach tendencies for alcohol cues than for soft-drink cues. In the approach, alcohol fMRI contrast patients showed larger blood-oxygen-level-dependent responses in the nucleus accumbens and medial prefrontal cortex, regions involved in reward and motivational processing. In alcohol-dependent patients, alcohol-craving scores were positively correlated with activity in the amygdala for the approach-alcohol contrast. The dorsolateral prefrontal cortex was not activated in the avoid-alcohol contrast in patients vs controls. Our data suggest that brain regions that have a key role in reward and motivation are associated with the automatic alcohol-approach bias in alcohol-dependent patients.

Expecting unpleasant stimuli--an fMRI study.

Expecting forthcoming events and preparing adequate responses are important cognitive functions that help the individual to deal with the environment. The emotional valence of an event is decisive for the resulting action. Revealing the underlying mechanisms may help to understand the dysfunctional information processing in depression and anxiety that are associated with negative expectation of the future. We were interested in selective brain activity during the expectation of unpleasant visual stimuli. Twelve healthy female subjects were biased to expect and then perceive emotionally unpleasant, pleasant or neutral stimuli during functional magnetic resonance imaging. Expecting unpleasant stimuli relative to expecting pleasant and neutral stimuli resulted in activation of mainly cingulate cortex, insula, prefrontal areas, thalamus, hypothalamus and striatum. While certain areas were also active during subsequent presentation of the emotional stimuli, distinct regions of the anterior cingulate gyrus and the thalamus were solely active during expectation of the unpleasant stimuli. The identified areas may reflect a network for internal adaptation and preparation processes in order to react adequately to expected unpleasant events. They are known as well to be altered in depression. Disorders of this network may be relevant for psychiatric disorders such as depression.

Evaluation of a novel event-related parametric fMRI paradigm investigating prefrontal function.

While prefrontal pathology is considered to be a core feature in schizophrenia, evidence from functional magnetic resonance imaging (fMRI) studies using cognitive activation tasks is less reliable in terms of demonstrating 'functional hypofrontality'. Here we present a new event-related fMRI paradigm specifically developed to assess the gradual recruitment of brain areas during verbal working memory (WM) by taking into account theoretical and pragmatic limitations of activation tools used in clinical cognitive neuroscience. We studied 15 healthy subjects during the performance of a WM task that required the manipulation of verbal information. We observed a robust recruitment of frontoparietal areas with increasing load. Comparing the two highest loads, we found further bilateral striatal activation. A median split into good and poor performers revealed significant positive correlations of prefrontal activation in the group of good performers and correlations with striato-thalamic activation in the poor-performance group, thus emphasizing a crucial role of subcortical structures for performance in highly demanding WM tasks. Because it induces a robust bilateral frontoparietal activation pattern along with performance-related effects of cerebral activation, we consider this paradigm to be suitable to test prefrontal function in schizophrenic patients during the manipulation of items held in WM.