Christian Vollmert

Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits

Structural remodeling has been observed in the human brain over periods of weeks to months, but the molecular mechanisms governing this process remain incompletely characterized. Using multimodal pharmaco-neuroimaging, we found that acute D2 receptor blockade induced reversible striatal volume changes and structural-functional decoupling in motor circuits within hours; these alterations predicted acute extrapyramidal motor symptoms with high precision. Our findings suggest a role for D2 receptors in short-term neural plasticity and identify a potential biomarker for neuroleptic side effects in humans.

Impairment of inhibitory control in response to food-associated cues and attentional bias of obese participants and normal-weight controls

Objective:Starting from a model of impaired response inhibition and salience attribution for addictive behaviour we investigated whether obese participants show a greater impairment of inhibitory control in response to food-associated cues compared with neutral stimuli and whether this is seen in normal-weight control subjects. In addition, we questioned whether an attentional bias towards food-associated cues can be observed in an early stage of information processing.Design:Control-group study including the administration of behavioural tasks (that is, go/no-go task with food-associated and neutral words, visual dot probe task with food-associated and neutral pictures) and self-reported measures of eating behaviour and impulsivity.Results:Although self-reported measures indicated disinhibition of eating behaviour of obese patients, we found that food-associated stimuli induced an impairment of inhibitory control in both obese participants as well as normal-weight controls. Results from the visual dot-probe task indicated that food-associated cues did not modulate attention allocation in a very early stage of information processing, which suggests that the incentive salience of food-associated stimuli might be lower than that of drug-associated cues.Conclusion:These findings are not in line with hypotheses derived from models of addictive behaviour and call into question that an impairment of inhibitory control in response to food-associated cues and salience attribution might be at the core of obesity. Future studies using larger sample sizes and refined experimental procedures are warranted to further investigate mechanisms controlling food intake in obesity.

Association of Leptin With Food Cue–Induced Activation in Human Reward Pathways

CONTEXT Overlapping neurobiological pathways between obesity and addiction disorders are currently in discussion. Whereas the hypothalamic regulation of energy homeostasis by endocrine feedback signals has been widely investigated, its interplay with mesolimbic reward-associated pathways represents a rich field of future research. OBJECTIVE To assess changes in regional brain activation in response to food-related cues in association with body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and the plasma concentration of the appetite-regulating peptide leptin. DESIGN Case-control study. SETTING Academic addiction and brain imaging center, Central Institute of Mental Health, Mannheim, Germany. PARTICIPANTS Twenty-one obese subjects (BMI >30) and 23 age- and sex-matched nonobese control subjects (BMI 18.5-24.0) recruited by advertisements. MAIN OUTCOME MEASURES Regional brain activation (blood oxygen level-dependent response) in response to visual cue presentation and association of the brain activation with BMI and plasma leptin concentration. RESULTS Significant positive relationships were observed for food cue-induced brain activations in the ventral striatum in association with the plasma concentration of leptin (r = 0.27; P = .04) and with BMI (r = 0.47; P = .001). CONCLUSIONS Data suggest a physiological role of satiety factors in modulating the responsivity of mesolimbic circuits to food cues. Moreover, an altered homeostatic feedback regulation of reward pathways might explain addictionlike behavior and the inability of obese patients to adapt food intake to physiological needs.

Prefrontal-temporal gray matter deficits in bipolar disorder patients with persecutory delusions

OBJECTIVES Although brain structural deficits have been repeatedly associated with bipolar disorder (BD), inconsistency in morphometric results has been a feature of neuroimaging studies. We hypothesize that this discrepancy is related to the heterogeneity of BD, and examine the question of whether or not more homogeneous clinical subgroups display a more coherent pattern of morphometric abnormalities. METHODS In a case-control design, we examined differences in gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) concentration in 42 BD patients and 42 healthy matched controls using optimized voxel-based morphometry (VBM). Subgroup analyses of patients with a lifetime history of psychotic symptoms (BDP, n=30) and patients with mood-incongruent psychotic symptoms in the form of persecutory delusions (BDPD, n=15) were performed to accord with previous genetic findings. RESULTS Analysis of the total BD sample was largely inconclusive, but the BDPD patient subgroup displayed a widespread pattern of significant decreases in GM concentration in the dorsolateral prefrontal (DLPFC), temporal and cingulate cortices, and a significant CSF increase in the adjacent outer ventricular sulci. Comparison of BDPD patients versus BD and BDP patients without persecutory delusions revealed a significant GM decrease in the left DLPFC for the former group. CONCLUSIONS BDPD show pronounced structural abnormalities of the prefrontal and temporal lobes which are similar to the deficits previously reported for schizophrenia (SCZ). Our findings suggest that stratification based solely on psychotic symptoms is insufficient for the differentiation of BD into biologically meaningful subgroups, but also question the pathophysiological validity of the dichotomy in classification between schizophrenia and BD.

MR spectroscopy in opiate maintenance therapy: association of glutamate with the number of previous withdrawals in the anterior cingulate cortex

Pre‐clinical research indicates that opioids reduce extracellular glutamate in acute opioid treatment, whereas during withdrawal, glutamatergic neurotransmission is increased and withdrawal symptoms can be blocked by glutamate receptor antagonists. The glutamate hypothesis of addiction suggests that withdrawal‐associated hyperglutamatergic states destabilize the glutamatergic system chronically and contribute to relapse. magnetic resonance spectroscopy at three tesla optimized for glutamate assessment (TE 80 ms) was performed in the anterior cingulate gyrus (ACC) and frontal white matter (fWM) of 17 opiate‐dependent patients during opiate maintenance therapy and 20 healthy controls. Controlling for age and gray matter content, glutamate in the ACC was positively associated with the number of previous withdrawals. For glutamate + glutamine (Glx), a significant group–age interaction was found. Whereas Glx declines with age in healthy controls, Glx increases with age in opiate‐dependent patients. The number of previous withdrawals did not correlate with age. In fWM spectra, increased Cho concentrations were observed in opiate‐dependent patients. Both new findings, the positive correlation of glutamate and previous withdrawals and increasing Glx with age in contrast to an age‐dependent Glx decrease in controls indicate a destabilization of the glutamate system in opiate‐dependent patients and support the glutamate hypothesis of addiction. Increased Cho concentrations in fWM corroborate findings of WM abnormalities in opioid‐dependent subjects.

Acute and chronic nicotine effects on behaviour and brain activation during intertemporal decision making

Previous studies demonstrated higher discount rates for delayed rewards in smokers than non‐smokers. We performed this study to determine whether those differences in intertemporal choice are due to pharmacological effects of nicotine and to track related brain regions. Thirty‐three non‐smokers and 27 nicotine‐dependent smokers underwent functional magnetic resonance imaging while performing an intertemporal choice task consisting of 40 sets of monetary reward options that varied by delay to delivery. Smokers were investigated in a state of nicotine satiation. Non‐smokers were investigated twice, receiving nicotine (2 mg) and placebo gums in a double‐blinded, randomized cross‐over design. Smokers displayed steeper temporal discounting than non‐smokers. Those behavioural differences were reflected in the brain response during the decision between two alternative money/time pairs: smokers showed less activation in parietal and occipital areas (e.g. precuneus) than non‐smokers under placebo. A single dose of nicotine in non‐smokers led to a similar effect on brain activation but did not impact behaviour. Processing of the reward magnitude of money/time pairs differed between smokers and non‐smokers: smokers showed decreased reactivity of the ventral striatum. Moreover, there was an acute nicotine effect in non‐smokers on processing of the reward magnitude: nicotine increased the correlation of blood oxygen level‐dependent response and mean amount in the left hippocampus, amygdala and anterior insula. We conclude that cross‐sectional differences between smokers and non‐smokers are only, in part, due to the acute pharmacological effects of nicotine. Longitudinal studies are needed to investigate pre‐drug group characteristics as well as consequences of smoking on discounting behaviour and its neural correlates.

Nicotine increases neural response to unpleasant stimuli and anxiety in non-smokers.

Studies in smokers suggest that nicotine might exert anxiolytic, stress‐dampening and mood‐enhancing effects and beneficially influences neural processing of affective information. Regarding non‐smokers, results are inconsistent, and no data exist on the effect of nicotine on neural emotion processing. We applied functional magnetic resonance imaging (fMRI) to assess the influence of nicotine on brain activation during processing of emotional stimuli in 31 non‐smokers with a maximum lifetime cigarette consumption of 20 cigarettes. Participants were subjected to two fMRI scans with event‐related presentations of images taken from the International Affective Picture System, receiving nicotine (2 mg) and placebo gums in a double‐blinded, randomized cross‐over design. Furthermore, subjective affect was assessed. Nicotine increased brain activity in response to unpleasant stimuli in the amygdala, anterior cingulate cortex (ACC) and basal ganglia, whereas processing of pleasant stimuli was not altered. Psychophysiological interaction (PPI) analyses revealed that nicotine increased connectivity between the amygdala and the perigenual ACC (pACC) during processing of unpleasant stimuli and decreased connectivity between those structures during processing of pleasant stimuli. Participants reported higher state anxiety under nicotine than placebo. A single dose of nicotine acted as a stressor in non‐smokers, leading to increased anxiety and neural activation elicited by unpleasant stimuli as well as altered connectivity within the amygdala–pACC circuit. Besides the possibility that reactions to nicotine may differ between non‐smokers and smokers due to tolerance and neuroadaptive processes that occur during prolonged nicotine use, a priori differences in smokers and non‐smokers might potentially explain diverse effects of nicotine on affect and emotional reactivity.

Oleoylethanolamide and Human Neural Responses to Food Stimuli in Obesity

IMPORTANCE Obesity has emerged as a leading health threat but its biological basis remains insufficiently known, hampering the search for novel treatments. Here, we study oleoylethanolamide, a naturally occurring lipid that has been clearly implicated in weight regulation in animals. However, its role for weight regulation and obesity in humans is still unclear. OBJECTIVE To investigate associations between plasma oleoylethanolamide levels and body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) and functional magnetic resonance imaging response to food stimuli in obese patients and matched control participants. DESIGN, SETTING, AND PARTICIPANTS Case-control study of 21 obese patients and 24 matched control participants. Obesity was defined as having a BMI of at least 30. The mean age of participants was 40.8 years and BMIs ranged from 18.2 to 47.5. MAIN OUTCOMES AND MEASURES Interactions between plasma oleoylethanolamide levels and obesity on BMI and functional magnetic resonance imaging response to food stimuli. RESULTS Associations between oleoylethanolamide and BMI differed significantly depending on whether individuals were obese or not (P = .02). In obese individuals, oleoylethanolamide showed a trend toward a positive correlation with BMI (P = .06, ρ = 0.42), while this relationship was inverse for nonobese control participants (P = .07, ρ = -0.34). Similarly, we found significant interactions between oleoylethanolamide levels and obesity on food-related brain activation in cortical areas associated with reward processing and interoceptive signaling (P = .009). Specifically, nonobese individuals with higher oleoylethanolamide levels had higher insular brain activity (P < .001, ρ = 0.70); again, the relationship trended to be inverse for obese patients (P = .11, ρ = -0.36). These effects were not associated with plasma levels of leptin and anandamide, suggesting an independent role of oleoylethanolamide in hunger-associated interoceptive signaling. Analysis of food craving during the functional magnetic resonance imaging task suggested that the identified brain areas may be involved in suppressing food-liking reactions in nonobese individuals. CONCLUSIONS AND RELEVANCE This study suggests that oleoylethanolamide-mediated signaling plays an important role for hedonic regulation of food craving and obesity in humans and thus may be a valuable target for developing novel antiobesity drugs.

A model comparison of COMT effects on central processing of affective stimuli.

The number of studies on imaging genetics has risen considerably over the last few years, and haplotypes are being increasingly applied as a model to increase the explained variance in functional brain activation. Haplotypes, however, are not always the preferable approach. While such highly complex models have a greater capacity for fitting data, they might also lead to over-fitting. This study compares individual single nucleotide polymorphisms (SNPs) with haplotypes by applying both models to effects of catechol-O-methyltransferase (COMT), one of the most extensively studied genes in psychiatric research and imaging genetics, on the central processing of affective cues. To our knowledge, this is the first study to compare haplotypes and SNPs of the COMT gene in an imaging genetics study. The model comparison in this study is based on the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC), introducing the novel concepts of posterior evidence ratio maps and best model maps. Findings reveal the simplest model, comprising only the well studied COMT Val(158)Met polymorphism, to be the most informative one. These results do not necessarily mean that haplotype models are in general inferior to individual SNP analysis. They do underline, however, that techniques for model comparison such as the ones used in this study need to be employed to establish whether the increase in likelihood provided by a more complex haplotype-based model is large enough to warrant the increase in model complexity.

PT600. Oylethanolamide Modulates Human Neural Responses to Food Stimuli in Obesity

Objective: MSCs that have been isolated from different sources are expected to possess different secretion patterns which might influence the therapeutic mechanism in the disease environment. Introduction: Through their paracrine effects such as immunomodulation and trophic functions, mesenchymal stem cells (MSCs) have been reported to possess the therapeutic potential to be used as a viable treatment for various diseases. MSCs can be isolated from different sources including adipose tissue, bone marrow, placenta and Wharton’s Jelly(WJ), and be expanded in vitro. Although they possess similar characteristics, the source of origin of the MSCs is thought to affect the overall secretion patterns and thus their applications in the disease environment. Methods: MSCs from different sources (adipose, bone marrow, placenta, WJ) were cultured in serum free MEM-α medium for 24 hours at 37°C 5% CO2. The collected media were mixed with protease inhibitors and were then concentrated up to 250-fold. The concentrated media was then mixed with lysis buffer consisting of 8M urea, 75mM NaCl, and 50mM Tris (pH 8.2). The protein mixtures were digested into peptide samples and were then scanned under LC-MS/MS. Secreted proteins that were identified were functionally analyzed by DAVID. Results: The features and patterns of secreted proteins were highly dependent on the source of the MSC. While a majority of the secreted proteins of MSCs from neonatal sources (placenta, WJ) was highly involved in the developmental process, secreted proteins of MSCs from adult sources (adipose, bone marrow) were related to biological regulation and metabolic process. Conclusion: This study shows that source difference is an aspect that needs to be considered for disease-specific mesenchymal stem cell therapeutics and personalized therapy of neurodegenerative diseases. PT599 Effect of single ketogenic diet containing medium chain triglycerides on cognitive functions in elderly adults Junko Matsuo, Kinya Ashida, Kotaro Hattori, Hiroshi Kunugi, Miho Ota, Takeshi Takahashi, Toyisha Teraishi, Hidekazu Tonouchi, Fuyuko Yoshida National Center of Neurology and Psychiatry, Japan Abstract Introduction: Glucose is the principal energy substrate for the brain, although ketone bodies are an effective alternative. Evidence suggests that elevation of plasma ketone body levels through oral intake of medium chain triglycerides (MCTs) may improve cognitive function. We aimed to examine the possible effects of single ketogenic diet on cognition in elderly nondemented subjects. Material and Method: Subjects were 20 non-demented adults over 60 years old (14 females, mean age; 66.3 ± 2.9 years) who underwent neurocognitive tests in 90 and 180 minutes after an oral intake of a diet (Meiji Ketonformula®) containing 20 g of MCTs and an isocaloric diet without MCTs on separate days. Results: Plasma levels of ketone bodies significantly increased in 60 through 180 minutes after the intake of MCTs compared to the placebo. Cognitive performance was also improved by the MCTs in working memory, executive function, and the composit cognitive score. The executive function improvement positively correlated with the increase of plasma β-hydroxybutyrate level. Discussion: Significant increase of plasma ketone concentration after 20g ingestion of MCTs may have a positive effect on cognitive functions, particularly working memory and executive function. The therapeutic potential of MCTs represents a promising new area of dementia research.Introduction: Glucose is the principal energy substrate for the brain, although ketone bodies are an effective alternative. Evidence suggests that elevation of plasma ketone body levels through oral intake of medium chain triglycerides (MCTs) may improve cognitive function. We aimed to examine the possible effects of single ketogenic diet on cognition in elderly nondemented subjects. Material and Method: Subjects were 20 non-demented adults over 60 years old (14 females, mean age; 66.3 ± 2.9 years) who underwent neurocognitive tests in 90 and 180 minutes after an oral intake of a diet (Meiji Ketonformula®) containing 20 g of MCTs and an isocaloric diet without MCTs on separate days. Results: Plasma levels of ketone bodies significantly increased in 60 through 180 minutes after the intake of MCTs compared to the placebo. Cognitive performance was also improved by the MCTs in working memory, executive function, and the composit cognitive score. The executive function improvement positively correlated with the increase of plasma β-hydroxybutyrate level. Discussion: Significant increase of plasma ketone concentration after 20g ingestion of MCTs may have a positive effect on cognitive functions, particularly working memory and executive function. The therapeutic potential of MCTs represents a promising new area of dementia research. EATING DISORDERS: PT600 – PT600 PT600 Oylethanolamide Modulates Human Neural Responses to Food Stimuli in Obesity Markus Leweke, Martin Grosshans, Falk Kiefer, Andreas MeyerLindenberg, Cathrin Rohleder, Carola Schaefer, Emanuel Schwarz, Heike Tost, Christian Vollmert, Sabine Vollstadt Central Institute of Mental Health, Germany Abstract Background: Obesity has emerged as a leading health threat and major risk factor for type 2 diabetes, cardiovascular disease, andBackground: Obesity has emerged as a leading health threat and major risk factor for type 2 diabetes, cardiovascular disease, and hypertension. The neurobiological basis of overeating remains insufficiently known, hampering sufficient intervention strategies. Here we investigate oleoylethanolamide, an agonist of PPAR-α. It has been implicated in weight regulation in animals but its respective role in humans is still unclear. Methods: Associations between plasma oleoylethanolamide, BMI and associated neurobiological impact (fMRi response to food stimuli) in 21 obese patients (BMI≥30) and 24 controls were investigated. We hypothesized that oleoylethanolamide interacts with BMI and fMRI response to food stimuli and may be affected in obese patients. Results: Associations between oleoylethanolamide and BMI differed significantly depending on whether subjects were obese or not (P=0.02). For obese individuals, oleoylethanolamide showed a trend towards a positive correlation with BMI (P=0.06, rho=0.42) while this relationship was inverse for controls (P=0.07, rho=0.34). We observed significant interactions between oleoylethanolamide and obesity on food-related brain activation in cortical areas associated with reward processing and interoceptive signaling (P=0.009). fMRI-investigation of food-craving suggests that identified brain areas may be involved in suppressing ‘liking’ of food, in non-obese subjects.