Precision weighting of cortical unsigned prediction error signals benefits learning, is mediated by dopamine, and is impaired in psychosis.

Recent theories of cortical function construe the brain as performing hierarchical Bayesian inference. According to these theories, the precision of prediction errors plays a key role in learning and decision-making, is controlled by dopamine and contributes to the pathogenesis of psychosis. To test these hypotheses, we studied learning with variable outcome-precision in healthy individuals after dopaminergic modulation with a placebo, a dopamine receptor agonist bromocriptine or a dopamine receptor antagonist sulpiride (dopamine study n = 59) and in patients with early psychosis (psychosis study n = 74: 20 participants with first-episode psychosis, 30 healthy controls and 24 participants with at-risk mental state attenuated psychotic symptoms). Behavioural computational modelling indicated that precision weighting of prediction errors benefits learning in health and is impaired in psychosis. FMRI revealed coding of unsigned prediction errors, which signal surprise, relative to their precision in superior frontal cortex (replicated across studies, combined n = 133), which was perturbed by dopaminergic modulation, impaired in psychosis and associated with task performance and schizotypy (schizotypy correlation in 86 healthy volunteers). In contrast to our previous work, we did not observe significant precision-weighting of signed prediction errors, which signal valence, in the midbrain and ventral striatum in the healthy controls (or patients) in the psychosis study. We conclude that healthy people, but not patients with first-episode psychosis, take into account the precision of the environment when updating beliefs. Precision weighting of cortical prediction error signals is a key mechanism through which dopamine modulates inference and contributes to the pathogenesis of psychosis.

Increased body mass index is associated with specific regional alterations in brain structure.

BACKGROUND: Although obesity is associated with structural changes in brain grey matter, findings have been inconsistent and the precise nature of these changes is unclear. Inconsistencies may partly be due to the use of different volumetric morphometry methods, and the inclusion of participants with comorbidities that exert independent effects on brain structure. The latter concern is particularly critical when sample sizes are modest. The purpose of the current study was to examine the relationship between cortical grey matter and body mass index (BMI), in healthy participants, excluding confounding comorbidities and using a large sample size. SUBJECTS: A total of 202 self-reported healthy volunteers were studied using surface-based morphometry, which permits the measurement of cortical thickness, surface area and cortical folding, independent of each other. RESULTS: Although increasing BMI was not associated with global cortical changes, a more precise, region-based analysis revealed significant thinning of the cortex in two areas: left lateral occipital cortex (LOC) and right ventromedial prefrontal cortex (vmPFC). An analogous region-based analysis failed to find an association between BMI and regional surface area or folding. Participants' age was also found to be negatively associated with cortical thickness of several brain regions; however, there was no overlap between the age- and BMI-related effects on cortical thinning. CONCLUSIONS: Our data suggest that the key effect of increasing BMI on cortical grey matter is a focal thinning in the left LOC and right vmPFC. Consistent implications of the latter region in reward valuation, and goal control of decision and action suggest a possible shift in these processes with increasing BMI.

Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects.

The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ≥ 30 kg m(-2) and binge eating scale scores ≥ 19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day(-1) GSK1521498, 5 mg day(-1) GSK1521498 or placebo (N=21 per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety and pharmacokinetics. The primary analysis was the comparison of change scores in the higher-dose treatment group versus placebo using analysis of covariance at each relevant time point. GSK1521498 (2 mg and 5 mg) was not different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, GSK1521498 5 mg day(-1) caused a significant reduction in hedonic responses to sweetened dairy products and reduced calorific intake, particularly of high-fat foods during ad libitum buffet meals, with some of these effects correlating with systemic exposure of GSK1521498. There were no significant effects of GSK1521498 2 mg day(-1) on eating behaviour, indicating dose dependency of pharmacodynamics. GSK1521498 was generally well tolerated and no previously unidentified safety signals were detected. The potential for these findings to translate into clinically significant effects in the context of binge eating and weight regain prevention requires further investigation.

Food images engage subliminal motivation to seek food.

Human eating behaviour is motivated and shaped by a complex interaction of internal drives such as hunger, external influences such as environmental cues and the sensory properties of food itself. Thus, as is demonstrated by the example of sensory-specific satiety (SSS), hunger may be reduced but particular foods (for example, desserts) retain their attraction and their ability to prompt consumption. In considering consumption, and overconsumption, it is therefore important to understand the interaction between internal and external drives to eat. Using grip force as a measure of motivation, we examined this interaction using an SSS manipulation. Critically, we sought to determine whether food stimuli would exert their influence even when they were subliminally presented (and thus not accessible to consciousness), and whether this unconscious influence would be flexibly updated in response to changes in food reward value with satiety. Demonstrating that the SSS effect remains when external stimuli are not consciously perceived, our data highlight the importance of even the most subtle, fleeting and even subliminal external events in shaping our motivation towards food.

Negative schizophrenic symptoms and the frontal lobe syndrome: one and the same?

The negative symptoms of schizophrenia have been considered to be a psychiatric form of the frontal lobe syndrome. However, no studies have compared these two disorders at the clinical level. In this study, 12 negative symptom schizophrenic patients and 11 patients with behavioural variant frontotemporal dementia (bv-FTD) were rated for negative symptoms and for occurrence of frontal lobe behaviours in everyday life. They were also rated for speech disorder and were given a series of executive tests. Both patient groups showed positive ratings on negative symptoms and frontal lobe behaviours in daily life; however, the schizophrenic patients had higher negative symptom scores and the bv-FTD patients had higher carer ratings on frontal behaviours in daily life. Both groups were impaired on the executive tests, but the bv-FTD patients showed significantly greater impairment on verbal fluency and a test requiring inhibition of prepotent responses. A minority of the bv-FTD patients unexpectedly showed speech abnormalities typically associated with schizophrenia. The findings indicate that the negative syndrome in schizophrenia and the frontal lobe syndrome resemble each other clinically in important respects. Some of the differences may be attributable to the additional presence of disinhibition in the frontal lobe syndrome.

Feeding the addiction: Narrowing of goals to habits.

Whilst the initiation of cocaine use is typically goal-directed and motivated by the rewarding effects of the drug, drug-taking can become habitual over time, rendering the user less sensitive to cocaine's hedonic value. Experimental studies suggest that patients with cocaine use disorder (CUD) are particularly prone to develop habits, even in non-drug related contexts. CUD patients have previously been shown to consume higher levels of high-calorie foods and report more uncontrolled eating, suggesting a tendency towards habitual or dysregulated food-related behaviours. We investigated this in CUD patients compared with healthy controls. Participants were presented with a series of food images and asked to rate their willingness to pay for, and their motivation to consume the foods. Self-reported motivations for food choices were collected using a validated questionnaire. Our data suggests CUD patients display goal-narrowing towards cocaine, as well as habitual tendencies towards both cocaine and food. These findings stress the importance of addressing non-drug related behaviours when treating CUD patients. Further, they suggest that habits may provide a novel and additional target for psychological interventions, for example, through the retraining of maladaptive habits. Whilst research into the feasibility and efficacy of habit retraining is certainly required, the potential for a new avenue of treatment should not be ignored.

Disrupted iron regulation in the brain and periphery in cocaine addiction.

Stimulant drugs acutely increase dopamine neurotransmission in the brain, and chronic use leads to neuroadaptive changes in the mesolimbic dopamine system and morphological changes in basal ganglia structures. Little is known about the mechanisms underlying these changes but preclinical evidence suggests that iron, a coenzyme in dopamine synthesis and storage, may be a candidate mediator. Iron is present in high concentrations in the basal ganglia and stimulant drugs may interfere with iron homeostasis. We hypothesised that morphological brain changes in cocaine addiction relate to abnormal iron regulation in the brain and periphery. We determined iron concentration in the brain, using quantitative susceptibility mapping, and in the periphery, using iron markers in circulating blood, in 44 patients with cocaine addiction and 44 healthy controls. Cocaine-addicted individuals showed excess iron accumulation in the globus pallidus, which strongly correlated with duration of cocaine use, and mild iron deficiency in the periphery, which was associated with low iron levels in the red nucleus. Our findings show that iron dysregulation occurs in cocaine addiction and suggest that it arises consequent to chronic cocaine use. Putamen enlargement in these individuals was unrelated to iron concentrations, suggesting that these are co-occurring morphological changes that may respectively reflect predisposition to, and consequences of cocaine addiction. Understanding the mechanisms by which cocaine affects iron metabolism may reveal novel therapeutic targets, and determine the value of iron levels in the brain and periphery as biomarkers of vulnerability to, as well as progression and response to treatment of cocaine addiction.

Atomoxetine effects on attentional bias to drug-related cues in cocaine dependent individuals.

RATIONALE: Biased attention towards drug-related cues and reduced inhibitory control over the regulation of drug-intake characterize drug addiction. The noradrenaline system has been critically implicated in both attentional and response inhibitory processes and is directly affected by drugs such as cocaine. OBJECTIVES: We examined the potentially beneficial effects of the noradrenaline reuptake inhibitor atomoxetine in improving cognitive control during two tasks that used cocaine- and non-cocaine-related stimuli. METHODS: A double-blind, placebo-controlled, and cross-over psycho-pharmacological design was employed. A single oral dose of atomoxetine (40 mg) was administered to 28 cocaine-dependent individuals (CDIs) and 28 healthy controls. All participants performed a pictorial attentional bias task involving both cocaine- and non-cocaine-related pictures as well as a verbal go/no-go task composed of cocaine- and food-related words. RESULTS: As expected, CDIs showed attentional bias to cocaine-related cues whilst controls did not. More importantly, however, atomoxetine, relative to placebo, significantly attenuated attentional bias in CDIs (F 26 = 6.73, P = 0.01). During the go/no-go task, there was a treatment × trial × group interaction, although this finding only showed a trend towards statistical significance (F 26 = 3.38, P = 0.07). CONCLUSIONS: Our findings suggest that atomoxetine reduces attentional bias to drug-related cues in CDIs. This may result from atomoxetine's modulation of the balance between tonic/phasic activity in the locus coeruleus and the possibly parallel enhancement of noradrenergic neurotransmission within the prefrontal cortex. Studying how cognitive enhancers such as atomoxetine influence key neurocognitive indices in cocaine addiction may help to develop reliable biomarkers for patient stratification in future clinical trials.

Is food addiction a valid and useful concept?

In this paper, we consider the concept of food addiction from a clinical and neuroscientific perspective. Food addiction has an established and growing currency in the context of models of overeating and obesity, and its acceptance shapes debate and research. However, we argue that the evidence for its existence in humans is actually rather limited and, in addition, there are fundamental theoretical difficulties that require consideration. We therefore review food addiction as a phenotypic description, one that is based on overlap between certain eating behaviours and substance dependence. To begin, we consider limitations in the general application of this concept to obesity. We share the widely held view that such a broad perspective is not sustainable and consider a more focused view: that it underlies particular eating patterns, notably binge eating. However, even with this more specific focus, there are still problems. Validation of food addiction at the neurobiological level is absolutely critical, but there are inconsistencies in the evidence from humans suggesting that caution should be exercised in accepting food addiction as a valid concept. We argue the current evidence is preliminary and suggest directions for future work that may provide more useful tests of the concept.