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.

Psyllium reduces inulin-induced colonic gas production in IBS: MRI and in vitro fermentation studies.

OBJECTIVE: Health-promoting dietary fibre including inulin often triggers gastrointestinal symptoms in patients with IBS, limiting their intake. Our aim was to test if coadministering psyllium with inulin would reduce gas production. DESIGN: A randomised, four-period, four-treatment, placebo-controlled, crossover trial in 19 patients with IBS. Subjects ingested a 500 mL test drink containing either inulin 20 g, psyllium 20 g, inulin 20 g+ psyllium 20 g or dextrose 20 g (placebo). Breath hydrogen was measured every 30 min with MRI scans hourly for 6 hours. Faecal samples from a subset of the patients with IBS were tested using an in vitro fermentation model. Primary endpoint was colonic gas assessed by MRI. RESULTS: Colonic gas rose steadily from 0 to 6 hours, with inulin causing the greatest rise, median (IQR) AUC(0-360 min) 3145 (848-6502) mL·min. This was significantly reduced with inulin and psyllium coadministration to 618 (62-2345) mL·min (p=0.02), not significantly different from placebo. Colonic volumes AUC(0-360 min) were significantly larger than placebo for both inulin (p=0.002) and inulin and psyllium coadministration (p=0.005). Breath hydrogen rose significantly from 120 min after inulin but not psyllium; coadministration of psyllium with inulin delayed and reduced the maximum increase, AUC(0-360 min) from 7230 (3255-17910) ppm·hour to 1035 (360-4320) ppm·hour, p=0.007.Fermentation in vitro produced more gas with inulin than psyllium. Combining psyllium with inulin did not reduce gas production. CONCLUSIONS: Psyllium reduced inulin-related gas production in patients with IBS but does not directly inhibit fermentation. Whether coadministration with psyllium increases the tolerability of prebiotics in IBS warrants further study. TRIAL REGISTRATION NUMBER: NCT03265002.

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.

Is Human Auditory Cortex Organization Compatible With the Monkey Model? Contrary Evidence From Ultra-High-Field Functional and Structural MRI.

It is commonly assumed that the human auditory cortex is organized similarly to that of macaque monkeys, where the primary region, or "core," is elongated parallel to the tonotopic axis (main direction of tonotopic gradients), and subdivided across this axis into up to 3 distinct areas (A1, R, and RT), with separate, mirror-symmetric tonotopic gradients. This assumption, however, has not been tested until now. Here, we used high-resolution ultra-high-field (7 T) magnetic resonance imaging (MRI) to delineate the human core and map tonotopy in 24 individual hemispheres. In each hemisphere, we assessed tonotopic gradients using principled, quantitative analysis methods, and delineated the core using 2 independent (functional and structural) MRI criteria. Our results indicate that, contrary to macaques, the human core is elongated perpendicular rather than parallel to the main tonotopic axis, and that this axis contains no more than 2 mirror-reversed gradients within the core region. Previously suggested homologies between these gradients and areas A1 and R in macaques were not supported. Our findings suggest fundamental differences in auditory cortex organization between humans and macaques.

Insights Into the Different Effects of Food on Intestinal Secretion Using Magnetic Resonance Imaging.

BACKGROUND: Plant foods may stimulate intestinal secretion through chemicals designed to deter herbivores, including lactucins in lettuce and rhein in rhubarb. This may increase ileostomy output and induce diarrhoea in people with intact bowels. OBJECTIVE: We aimed to determine the effect of food on intestinal water content using Magnetic Resonance Imaging (MRI). DESIGN: A three period crossover trial of isocaloric meals in adults without bowel disorders. Meals: 2 slices white bread with 10 g butter; 300 g rhubarb with 60 mL lactose free cream; 300 g lettuce with 30 mL mayonnaise. PRIMARY OUTCOME: Area under curve (AUC) small bowel water content (SBWC) using MRI. SECONDARY OUTCOMES: ascending colon water content; T1 relaxation time of ascending colon (T1AC); gastric volume; visual analogue scales of bloating and satiety (0-100). MRI analysts were blinded. Scanned fasting and hourly to 180 min postprandial. Symptoms scored half-hourly. RESULTS: 9 female and 6 male subjects completed the study. AUC SBWC fell after bread but rose after lettuce and even more after rhubarb, difference from baseline being (Bread AUC -5662 (1209) ml.min vs Lettuce 3194 (1574) ml.min and Rhubarb 10586 (1629) ml.min (P < 0.01). Rhubarb induced a rise in T1AC but differences at 3 hours were not significant (P = 0.06). Gastric volume at T = 0 significantly was higher for both lettuce and rhubarb (571 ± 92 and 558 ± 89 mls) respectively compared to bread (314 ± 108 mls) (p < 0.0001). Symptom scores were higher for lettuce > rhubarb > bread. CONCLUSION: Lettuce and rhubarb meals increased intestinal water content, demonstrating how different foods can alter ileal flow and stool consistency.

The effects of fasting and refeeding with a 'metabolic preconditioning' drink on substrate reserves and mononuclear cell mitochondrial function.

BACKGROUND AND AIMS: Preoperative fasting induces metabolic stress and leads to reduced postoperative insulin sensitivity, changes attenuated by preoperative carbohydrate loading. However, the mechanisms underlying these effects remain unknown. We investigated the dynamic changes in substrate metabolism and mononuclear cell mitochondrial function after fasting followed by refeeding with a drink [ONS (Fresenius Kabi, Germany)] designed to improve metabolic function preoperatively. METHODS: Twelve healthy volunteers took part in this study. They were fed a standardized meal and studied 4h later (baseline 'fed' state), after 12 and 24h of fasting, and 2, 4 and 6h after ingestion of ONS (contained 100g carbohydrate, 30g glutamine, and antioxidants). Changes in liver and muscle glycogen and lipids were studied using (13)C and (1)H magnetic resonance spectroscopy. The activities of mitochondrial electron transport chain complexes I, II and IV in blood mononuclear cells were measured spectrophotometrically. RESULTS: Compared to the baseline fed state, 12 and 24h fasts led to 29% and 57% decreases (P<0.001) in liver glycogen content, respectively. Fasting for 24h decreased mitochondrial membrane complexes I (-72%, P<0.05), II (-49%, P<0.01) and IV (-41%, P<0.05) activities compared to those following a 12h fast. A 23% increase (P<0.05) in calf intramyocellular lipid (IMCL) content occurred after a 24h fast. Liver glycogen reserves increased by 47% (P<0.05) by 2h following ingestion of ONS. CONCLUSIONS: Short-term fasting (up to 24h) affected mononuclear cell mitochondrial function adversely and increased IMCL content. Refeeding with ONS partially reversed the changes in liver glycogen.

Gastric emptying of three liquid oral preoperative metabolic preconditioning regimens measured by magnetic resonance imaging in healthy adult volunteers: a randomised double-blind, crossover study.

BACKGROUND & AIMS: Preoperative starvation has many undesirable effects but the minimum length of fasting is limited by gastric emptying, which may be dependent on nutrient content, viscosity and osmolarity of the feed. We compared the gastric emptying of two types of preoperative metabolic preconditioning drinks [Oral Nutritional Supplement (ONS) (Fresenius Kabi, Germany) and preOp (Nutricia Clinical Care, UK)] in healthy volunteers. METHODS: Twenty (10 male, 10 female) healthy adult volunteers were studied on 3 separate occasions in a randomised crossover manner. Volunteers ingested 400 ml preOp, which is a clear carbohydrate drink (CCD) (50 g carbohydrate, 0 g protein), 70 g ONS (50 g carbohydrate and 15 g glutamine) dissolved in water to a total volume of 400 ml (ONS400) and 300 ml (ONS300). Gastric emptying time was measured using magnetic resonance imaging. RESULTS: Mean (95% CI) T(50) and T(100) gastric emptying times for CCD were significantly lower (p<0.001) compared with ONS400 and ONS300. T(50) was 47 (39-55), 78 (69-87) and 81 (70-92)min for CCD, ONS400 and ONS300 respectively. Correspondingly T(100) was 94 (79-110), 156 (138-173) and 162 (140-184)min. Residual gastric volumes returned to baseline 120 min after CCD and 180 min after ONS400 and ONS300. CONCLUSIONS: The faster gastric emptying for CCD compared to ONS400 and ONS300 signifies that gastric emptying may be more dependent on nutrient load than volume or viscosity in healthy volunteers. While it is safe to give CCD 2h preoperatively, ONS400 and ONS300 should be given at least 3h preoperatively.

Enhancement of intragastric acid stability of a fat emulsion meal delays gastric emptying and increases cholecystokinin release and gallbladder contraction.

Preprocessed fatty foods often contain calories added as a fat emulsion stabilized by emulsifiers. Emulsion stability in the acidic gastric environment can readily be manipulated by altering emulsifier chemistry. We tested the hypothesis that it would be possible to control gastric emptying, CCK release, and satiety by varying intragastric fat emulsion stability. Nine healthy volunteers received a test meal on two occasions, comprising a 500-ml 15% oil emulsion with 2.5% of one of two emulsifiers that produced emulsions that were either stable (meal A) or unstable (meal B) in the acid gastric environment. Gastric emptying and gallbladder volume changes were assessed by MRI. CCK plasma levels were measured and satiety scores were recorded. Meal B layered rapidly owing to fat emulsion breakdown. The gastric half-emptying time of the aqueous phase was faster for meal B (72 +/- 13 min) than for meal A (171 +/- 35 min, P < 0.008). Meal A released more CCK than meal B (integrated areas, respectively 1,095 +/- 244 and 531 +/- 111 pmol.min.l(-1), P < 0.02), induced a greater gallbladder contraction (P < 0.02), and decreased postprandial appetite (P < 0.05), although no significant differences were observed in fullness and hunger. We conclude that acid-stable emulsions delayed gastric emptying and increased postprandial CCK levels and gallbladder contraction, whereas acid-instability led to rapid layering of fat in the gastric lumen with accelerated gastric emptying, lower CCK levels, and reduced gallbladder contraction. Manipulation of the acid stability of fat emulsion added to preprocessed foods could maximize satiety signaling and, in turn, help to reduce overconsumption of calories.

Magnetic resonance imaging of the behaviour of oil-in-water emulsions in the gastric lumen of man.

Pre-processed foods often contain a high percentage of lipid, present as emulsions stabilised with various surface-active agents. The acidic gastric environment can affect the behaviour of such emulsions, modifying the lipid spatial distribution and, in turn, the rate of gastric emptying and nutrient delivery to the gut. The aim of the present study was to use echo-planar magnetic resonance imaging (EPI) to determine the behaviour of model olive oil emulsions during gastric processing. Six healthy male volunteers were intubated nasogastrically on two separate occasions and fed 500 ml 15 % (w/w) olive oil-in-water, surfactant-stabilised emulsions designed to have identical droplet size distribution and which were either stable or unstable under gastric acid conditions. EPI was used to assess the oil fraction of the intragastric emulsions, gastric emptying and to visualise the spatial distribution of the oil at 10, 30 and 50 min postprandially. The in vivo imaging measurements of the oil volume fraction of the emulsions correlated well (r 0.66, acid-stable; r 0.52, acid-unstable) with that assayed in the gastric aspirates. Compared with the acid-stable emulsion, the acid-unstable emulsion in the gastric lumen rapidly separated into lipid-depleted 'aqueous' and lipid layers. Phase separation in the acid-unstable meal allowed the oil-depleted component to empty first and more rapidly than the stable emulsion as determined by the gastric emptying curves. These pilot data suggest that gastric processing and emptying of high-fat foods could be manipulated by careful choice of emulsifier.

Fetal brain activity and hemodynamic response to a vibroacoustic stimulus.

Previous studies have demonstrated the practicality of using functional magnetic resonance imaging (fMRI) techniques to assess fetal brain activity. The purpose of this study was to compare the fetal hemodynamic response to that of the adult. Seventeen pregnant subjects, all of whom were at more than 36 weeks gestation were scanned while the fetus was exposed to a vibroacoustic stimulus. Thirteen adult subjects were scanned with an equivalent acoustic stimulus. Of the fetal subjects, two could not be analyzed due to technical problems, eight did not show significant activation, and seven showed significant activation. In all cases, activation was localized within the temporal region. Measures of fetal hemodynamic responses revealed an average time to peak (ttp) of 7.36 +/- 0.94 sec and an average percentage change of 2.67 +/- 0.93%. In contrast, activation was detected in 5 of 13 adults with an average ttp of 6.54 +/- 0.54 sec and an average percentage change of 1.02 +/- 0.40%. The measurement of changes in the fetal hemodynamic response may be important in assessing compromised pregnancies.