M.O. Nielsen

Alterations of the Brain Reward System in Antipsychotic Naïve Schizophrenia Patients

BACKGROUND Various schizophrenic symptoms are suggested to be linked to a dysfunction of the brain reward system. Several studies have found alterations in the reward processing in patients with schizophrenia; however, most previous findings might be confounded by medication effects. METHODS Thirty-one antipsychotic-naïve schizophrenia patients and 31 age- and gender-matched healthy control subjects were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task. The task variant made it possible to separate overall salience (defined as arousing events) into behavioral salience (events where a predicted reward requires performance) and valence anticipation (the anticipation of a monetarily significant outcome). Furthermore, the evaluation of monetary gain and loss was assessed. RESULTS During reward anticipation, patients had a significant attenuation of the activation in ventral tegmentum, ventral striatum, and anterior cingulate cortex during presentation of salient cues. This signal attenuation in ventral striatum was correlated with the degree of positive symptoms. Signal attenuation was most pronounced for behavioral salience and nonsignificant for value anticipation. Furthermore, patients showed a changed activation pattern during outcome evaluation in right prefrontal cortex. CONCLUSION Our results suggest that changes during reward anticipation in schizophrenia are present from the beginning of the disease. This supports a possible involvement of reward disturbances in the pathophysiology of schizophrenia. The most pronounced changes were seen in relation to overall salience. In ventral striatum these changes were associated with the degree of positive symptoms.

Improvement of Brain Reward Abnormalities by Antipsychotic Monotherapy in Schizophrenia

CONTEXT Schizophrenic symptoms are linked to a dysfunction of dopamine neurotransmission and the brain reward system. However, it remains unclear whether antipsychotic treatment, which blocks dopamine transmission, improves, alters, or even worsens the reward-related abnormalities. OBJECTIVE To investigate changes in reward-related brain activations in schizophrenia before and after antipsychotic monotherapy with a dopamine D2/D3 antagonist. DESIGN Longitudinal cohort study. SETTING Psychiatric inpatients and outpatients in the Capital Region of Denmark. PARTICIPANTS Twenty-three antipsychotic-naive patients with first-episode schizophrenia and 24 healthy controls initially matched on age, sex, and parental socioeconomic status were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task. INTERVENTIONS Patients were treated for 6 weeks with the antipsychotic compound amisulpride. Controls were followed up without treatment. MAIN OUTCOME MEASURES Task-related blood oxygen level-dependent activations as measured by functional magnetic resonance imaging before and after antipsychotic treatment. RESULTS At baseline, patients, as compared with controls, demonstrated an attenuation of brain activation during reward anticipation in the ventral striatum, bilaterally. After 6 weeks of treatment, patients showed an increase in the anticipation-related functional magnetic resonance imaging signal and were no longer statistically distinguishable from healthy controls. Among the patients, there was a correlation between the improvement of positive symptoms and normalization of reward-related activation. Those who showed the greatest clinical improvement in positive symptoms also showed the greatest increase in reward-related activation after treatment. CONCLUSIONS To our knowledge, this is the first controlled, longitudinal study of reward disturbances in schizophrenic patients before and after their first antipsychotic treatment. Our results demonstrate that alterations in reward processing are fundamental to the illness and are seen prior to any treatment. Antipsychotic treatment tends to normalize the response of the reward system; this was especially seen in the patients with the most pronounced treatment effect on the positive symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01154829.

Regulation of mammary glucose uptake in goats: role of mammary gland supply, insulin, IGF-1 and synthetic capacity.

Variations in mammary glucose uptake were measured during the normal pregnancy-lactation cycle in dairy goats. In addition mammary glucose uptake was studied in response to somatotropin (ST) treatment in mid-lactation and acute increases in glucose concentration induced by sodium-propionate challenge in early lactation. Mammary glucose uptake was independent of arterial glucose, insulin and Insulin-like Growth Factor-1 (IGF-1) concentrations during lactation and during acute increases in arterial glucose concentration. Glucose uptake in the lactating mammary gland of the goat must therefore be carried out by an insulin-independent carrier, possible GLUT1, and glucose supply is not a limiting factor for uptake under in vivo conditions. Extraction of glucose uptake changed markedly during the normal course of lactation, following the overall changes in milk yield. Concentrations of glucose in skimmed milk, believed to reflect intracellular glucose concentration, changed in opposite directions, resulting in decreasing ratios of arterial: skimmed milk glucose concentration with progressing lactation. Thus, mammary synthetic capacity also involves a capacity for glucose uptake, which may be influenced by variations in glucose carrier numbers, as well as mammary metabolic activity (intracellular glucose concentration). In contrast to the situation during the normal course of lactation, ST stimulated milk yield, despite less efficient glucose extraction.

Continuous Lactation in Dairy Cows: Effect on Milk Production and Mammary Nutrient Supply and Extraction

Reports over the past decade have indicated that normal lactational performance can be achieved in genetically superior and high-producing dairy cows, even when the dry period between 2 lactations is omitted. The hypothesis tested in this experiment was that normal lactogenesis I and metabolic function may be achievable in continuously milked high-yielding dairy cows as a result of the genetic selection for lactation performance and hence longevity of mammary epithelial cells. The milk production and mammary nutrient uptake in response to omission of the dry period for cows with an expected peak milk yield higher than 45 kg/d were studied in 28 Holstein dairy cows managed without bovine somatotropin. Performance and metabolic parameters were followed in late gestation and in the following early lactation. Fourteen cows were milked continuously throughout late gestation, and another 14 dairy cows experienced a 7-wk prepartum dry period. Continuous milking during the prepartum period reduced milk production in the following early lactation period by >20%. The reduced milk production could not be readily ascribed to inefficiency of the mechanisms responsible for nutrient uptake by the lactating mammary epithelial cells, nor to systemic endocrine changes. This suggests that lowered mammary nutrient uptake must have been associated with reduced mammary blood flow, metabolic activity, or both, most likely as a result of disturbed lactogenesis I prepartum or lactogenesis II postpartum triggered by as yet unknown local mechanisms. Milk protein content was elevated by 0.4 percentage units in the continuously milked cows. The underlying reason is unknown, but given the current pricing system for milk, it deserves to be further investigated.

Glucose homeostasis and metabolic adaptation in the pregnant and lactating sheep are affected by the level of nutrition previously provided during her late fetal life

This study investigated whether undernutrition (UN) during late fetal life can programme the subsequent adult life adaptation of glucose homeostasis and metabolism during pregnancy and lactation. Twenty-four primiparous experimental ewes were used. Twelve had been exposed to a prenatal NORM level of nutrition (maternal diet approximately 15 MJME/d) and 12 to a LOW level of nutrition (maternal diet approximately 7 MJME/d) during the last 6 weeks pre-partum. The experimental ewes were subjected to two intravenous glucose tolerance tests (IGTT) in late gestation (one prior to (G-IGTT) and one by the end of a feed restriction period (RG-IGTT)), and a third around peak lactation (L-IGTT). LOW had lower basal insulin concentrations during lactation, and significantly decreased absolute insulin secretion during the L-IGTT in spite of similar glucose tolerance, indicating increased insulin sensitivity in LOW during lactation. There was no effect of prenatal UN on glucose tolerance during G-IGTT, however, during RG-IGTT LOW was more glucose intolerant and apparently more insulin resistant compared to NORM. In conclusion, UN during late fetal life in sheep impairs subsequent pancreatic insulin secretory capacity during adult life, and reduces plasticity of down-regulation of insulin secretion in response to a metabolic challenge. Furthermore, prenatal UN appears to programme mechanisms, which in young adult females can shift the insulin hypersensitivity observed during early lactation into an insulin resistance observed during late gestation and feed restriction. Early postnatal UN caused by lowered milk intake in early postnatal life may have contributed to these phenomena.

Late gestation undernutrition can predispose for visceral adiposity by altering fat distribution patterns and increasing the preference for a high-fat diet in early postnatal life.

We have developed a sheep model to facilitate studies of the fetal programming effects of mismatched perinatal and postnatal nutrition. During the last trimester of gestation, twenty-one twin-bearing ewes were fed a normal diet fulfilling norms for energy and protein (NORM) or 50% of a normal diet (LOW). From day 3 postpartum to 6 months (around puberty) of age, one twin lamb was fed a conventional (CONV) diet and the other a high-carbohydrate-high-fat (HCHF) diet, resulting in four groups of offspring: NORM-CONV; NORMHCHF; LOW-CONV; LOW-HCHF. At 6 months of age, half of the lambs (all males and three females) were slaughtered for further examination and the other half (females only) were transferred to a moderate sheep diet until slaughtered at 24 months of age (adulthood). Maternal undernutrition during late gestation reduced the birth weight of LOW offspring (P<0·05), and its long-term effects were increased adrenal size in male lambs and adult females (P<0·05), increased neonatal appetite for fat-(P=0·004) rather than carbohydrate-rich feeds (P<0·001) and reduced deposition of subcutaneous fat in both sexes (P<0·05). Furthermore, LOW-HCHF female lambs had markedly higher visceral:subcutaneous fat ratios compared with the other groups (P<0·001). Postnatal overfeeding (HCHF) resulted in obesity (.30% fat in soft tissue) and widespread ectopic lipid deposition. In conclusion, our sheep model revealed strong pre- and postnatal impacts on growth, food preferences and fat deposition patterns. The present findings support a role for subcutaneous adipose tissue in the development of visceral adiposity, which in humans is known to precede the development of the metabolic syndrome in human adults.

Eukaryotic elongation factor-2 (eEF-2) activity in bovine mammary tissue in relation to milk protein synthesis

The amount of protein synthesis translational elongation factor 2 (eEF-2) was estimated employing diphtheria toxin-dependent ADP-ribosylation in samples prepared from small amounts of tissue from mammary gland, skeletal muscle and liver from lactating dairy cows. A very high level of ADP-ribosylatable eEF-2 was found in mammary gland, amounting to 20-times the level found in liver and 50-times the level found in skeletal muscle. This obviously reflects the high protein synthesis activity in mammary tissue. To our knowledge, similar high activities have previously been reported only for cancer cells. A close linear relationship was found between the amount of diphtheria-toxin catalysted ADP-ribosylated eEF-2 and protein and casein output in milk from cows in late lactation. This strongly suggests that eEF-2 may be a limiting factor in milk protein synthesis.

Striatal Reward Activity and Antipsychotic-Associated Weight Change in Patients With Schizophrenia Undergoing Initial Treatment

IMPORTANCE Weight gain is a common and serious adverse effect of antipsychotic treatment. A variable individual predisposition to development of metabolic disturbances calls for predictive biological markers. OBJECTIVES To investigate whether attenuated striatal activity during reward anticipation is associated with amisulpride-induced weight change in antipsychotic-naive patients with schizophrenia undergoing initial treatment and to examine the association between weight change and changes in reward anticipation activity after treatment. DESIGN, SETTING, AND PARTICIPANTS Sixty-nine antipsychotic-naive inpatients and outpatients with schizophrenia were included in a multimodal longitudinal cohort study from December 16, 2008, to December 11, 2013. Fifty-eight patients underwent functional magnetic resonance imaging (fMRI) while performing a monetary reward task. After 6 weeks of treatment with amisulpride, a relatively selective dopamine D2 antagonist, 39 patients underwent a second fMRI scan and measurement of change in body weight. Final follow-up was completed on January 14, 2014, and data were analyzed from October 25, 2014, to June 15, 2015 and August 31 to September 19, 2015. EXPOSURES Six weeks of individually dosed amisulpride treatment. MAIN OUTCOMES AND MEASURES Reward-anticipation activity in the striatum before and after treatment and weight change. RESULTS Of the 69 patients who consented to the study, 39 underwent the follow-up fMRI and weight measurement (age range, 18-45 years; 17 women and 22 men). The mean (SD) daily dose of amisulpride was 272 (168; range, 50-800) mg, and patients gained a mean (SD) of 2.3 (2.8; range, -4 to 8) kg in body weight. Improvement from baseline to follow-up was found on the mean (SD) positive (19.9 [4.1] to 14.3 [3.8]), general (39.7 [7.7] to 30.5 [7.7]), and total (78.5 [15.3] to 63.2 [13.9]) scores on the Positive and Negative Syndrome Scale (P < .001). Weight gain was predicted by low mean (SD) baseline reward-related activity in the right-sided putamen (0.20 [0.93]; F35,3 = 5.64; P = .003). After 6 weeks, weight gain was associated with an increase in mean (SD) reward activity in the same region during treatment (0.28 [0.74]; F37,1 = 4.48; P = .04). CONCLUSIONS AND RELEVANCE Activity in striatal regions of the reward system appears to be associated with the individual variability in the predisposition for antipsychotic-associated weight gain. Moreover, pharmacologic modulation of the reward system may play a role in antipsychotic-associated weight gain.

Effect of changes in diet energy density on feed intake, milk yield and metabolic parameters in dairy cows in early lactation.

The purpose of this experiment was to investigate how early lactating cows adjust their metabolism and production to acute, but moderate changes in the energy density of the diet. Sixty dairy cows were randomly assigned to one of four treatments: two change-over groups (HNH and NHN) and two control groups (HHH and NNN), where H and N refer to a high and normal energy density in the total mixed ration (TMR), respectively. The experimental period covered the first 9 weeks post calving, which was split up in three 3-week periods. Thus, cows assigned to HNH or NHN shifted TMR in weeks 4 and 7 after calving while cows assigned to HHH or NNN were fed the same TMR for all 9 weeks. Results from cows on treatment HNH were compared with group HHH while cows on treatment NHN were compared with group NNN. When the diet changed from N to H and H to N, cows increased and decreased their dry-matter intake (DMI), respectively compared with control groups. Cows adjusted milk yield accordingly to changes in DMI, although not always significantly. Energy-corrected milk yield was not significantly affected by any of the changes in the energy density of the diet but generally showed same tendencies as milk yield. Non-esterified fatty acids (NEFA), beta-hydroxybutyrate in blood and milk and triacylglycerol and glycogen content in the liver were not significantly affected by changes in the energy density of the diet, except from NEFA at one change. Glucose increased more when the diet changed from N to H and increased less when the diet changed from H to N, compared with control groups, although not always significantly. Collectively, these results suggest that cows adjust their DMI and partly milk yield according to the energy density of the diet and therefore only limited effects were observed in physiological parameters.

Continuous lactation effects on mammary remodeling during late gestation and lactation in dairy goats.

The present study aimed to 1) elucidate whether continuous milking during late gestation in dairy goats negatively affects mammary remodeling and hence milk production in the subsequent lactation, and 2) identify the regulatory factors responsible for changes in cell turnover and angiogenesis in the continuously lactating mammary gland. Nine multiparous dairy goats were used. One udder half was dried off approximately 9 wk prepartum (normal lactation; NL), and the other udder half of the same goat was milked continuously (continuous lactation; CL) until parturition or until the half-udder milk yields had dropped to below 50 g/d. Mammary biopsies were obtained from each udder half just before the NL gland was dried off (before dry period), within the first 2 wk after drying-off (early dry period, samples available only for NL glands), in the mid dry period, within the last 2 wk before parturition (late dry period), and at d 1 (the day of parturition), 3, 10, 60, and 180 of lactation. Mammary morphology was characterized in biopsies by quantitative histology, and cell turnover was determined by immunohistochemistry (terminal deoxynucleotidyl transferase dUTP nick end labeling and Ki-67). Transcription of genes encoding factors involved in mammary epithelial cell (MEC) turnover and vascular function was quantified by quantitative reverse transcription PCR. Results demonstrated that omitting the dry period was possible in goats but was not as easy as claimed before. Renewal of MEC was suppressed in CL glands, which resulted in a smaller MEC population in the subsequent lactation. At the time of parturition (and throughout lactation), the mammary glands subjected to CL had smaller alveoli, more fully differentiated MEC, and a substantially larger capillary fraction compared with NL glands. The continuously lactating gland thus resembled a normally lactating gland in an advanced stage of lactation. None of the studied genomic factors could account for these treatment differences. The described characteristics in CL glands compared with NL glands indicated a gland maintained in lactation for a longer period.