Association of Brain Reward Response With Body Mass Index and Ventral Striatal-Hypothalamic Circuitry Among Young Women With Eating Disorders.

Importance: Eating disorders are severe psychiatric disorders; however, disease models that cross subtypes and integrate behavior and neurobiologic factors are lacking. Objective: To assess brain response during unexpected receipt or omission of a salient sweet stimulus across a large sample of individuals with eating disorders and healthy controls and test for evidence of whether this brain response is associated with the ventral striatal-hypothalamic circuitry, which has been associated with food intake control, and whether salient stimulus response and eating disorder related behaviors are associated. Design, Setting, and Participants: In this cross-sectional functional brain imaging study, young adults across the eating disorder spectrum were matched with healthy controls at a university brain imaging facility and eating disorder treatment program. During a sucrose taste classic conditioning paradigm, violations of learned associations between conditioned visual and unconditioned taste stimuli evoked the dopamine-related prediction error. Dynamic effective connectivity during expected sweet taste receipt was studied to investigate hierarchical brain activation between food intake relevant brain regions. The study was conducted from June 2014 to November 2019. Data were analyzed from December 2019 to February 2020. Main Outcomes and Measures: Prediction error brain reward response across insula and striatum; dynamic effective connectivity between hypothalamus and ventral striatum; and demographic and behavior variables and their correlations with prediction error brain response and connectivity edge coefficients. Results: Of 317 female participants (197 with eating disorders and 120 healthy controls), the mean (SD) age was 23.8 (5.6) years and mean (SD) body mass index was 20.8 (5.4). Prediction error response was elevated in participants with anorexia nervosa (Wilks λ, 0.843; P = .001) and in participants with eating disorders inversely correlated with body mass index (left nucleus accumbens: r = -0.291; 95% CI, -0.413 to -0.167; P < .001; right dorsal anterior insula: r = -0.228; 95% CI, -0.366 to -0.089; P = .001), eating disorder inventory-3 binge eating tendency (left nucleus accumbens: r = -0.207; 95% CI, -0.333 to -0.073; P = .004; right dorsal anterior insula: r = -0.220; 95% CI, -0.354 to -0.073; P = .002), and trait anxiety (left nucleus accumbens: r = -0.148; 95% CI, -0.288 to -0.003; P = .04; right dorsal anterior insula: r = -0.221; 95% CI, -0.357 to -0.076; P = .002). Ventral striatal to hypothalamus directed connectivity was positively correlated with ventral striatal prediction error in eating disorders (r = 0.189; 95% CI, 0.045-0.324; P = .01) and negatively correlated with feeling out of control after eating (right side: r = -0.328; 95% CI, -0.480 to -0.164; P < .001; left side: r = -0.297; 95% CI, -0.439 to -0.142; P = .001). Conclusions and Relevance: The results of this cross-sectional imaging study support that body mass index modulates prediction error and food intake control circuitry in the brain. Once altered, this circuitry may reinforce eating disorder behaviors when paired with behavioral traits associated with overeating or undereating.

The Neural Processes Interlinking Social Isolation, Social Support, and Problem Alcohol Use.

BACKGROUND: Subjective feeling of social isolation, as can be measured by perceived burdensomeness (PB), is a major risk factor for alcohol misuse. Heightened PB is associated with elevated stress response and diminished cognitive control, both of which contribute to problem drinking. Here, we sought to identify the neural substrates underlying the relationship between PB and alcohol misuse. METHODS: We employed resting-state functional magnetic resonance imaging data collected from 61 problem drinkers to characterize the functional connectivity of the hypothalamus and ventral striatum (VS) in relation to PB. We specifically examined whether the connectivities of the hypothalamus and VS were differentially influenced by PB to produce contrasting effects on alcohol use. Finally, we evaluated how individual differences in social support modulate the inter-relationships of social isolation, neural connectivity, and the severity of problem drinking. RESULTS: Whole-brain multiple regressions show a positive relationship between PB and hypothalamic connectivity with the hippocampus and an inverse pattern for VS connectivity with the middle frontal gyrus. Difference in strength between the 2 connectivities predicted the severity of problem drinking, suggesting an imbalance involving elevated hypothalamic and diminished prefrontal cortical modulation in socially isolated problem drinkers. A path analysis further revealed that the lack of social support was associated with a bias toward low prefrontal connectivity, which in turn increased PB and facilitated problem drinking. CONCLUSIONS: Altered hypothalamus and VS connectivity may underlie problem drinking induced by social isolation. The current findings also highlight the important role of social support as a potential protective factor against alcohol misuse.

Alcohol Cue-Induced Ventral Striatum Activity Predicts Subsequent Alcohol Self-Administration.

BACKGROUND: Human laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory. METHODS: Non-treatment-seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm. RESULTS: Multilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2  = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes. CONCLUSIONS: Neuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.

Sex differences in serotonin-hypothalamic connections underpin a diminished sense of emotional well-being with increasing body weight.

BACKGROUND/OBJECTIVES: The neurobiological mechanisms linking obesity to emotional distress related to weight remain largely unknown. PARTICIPANTS/METHODS: Here we combined positron emission tomography, using the serotonin transporter (5-HTT) radiotracer [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, with functional connectivity magnetic resonance imaging, the Beck Depression Inventory (BDI-II) and the Impact of Weight on Quality of Life-Lite questionnaire (IWQOL-Lite) to investigate the role of central serotonin in the severity of depression (BDI-II), as well as in the loss of emotional well-being with body weight (IWQOL-Lite). RESULTS: In a group of lean to morbidly obese individuals (n=28), we found sex differences in the 5-HTT availability-related connectivity of the hypothalamus. Males (n=11) presented a strengthened connectivity to the lateral orbitofrontal cortex, whereas in females (n=17) we found strengethened projections to the ventral striatum. Both regions are known as reward regions involved in mediating the emotional response to food. Their resting-state activity correlated positively to the body mass index (BMI) and IWQOL-Lite scores, suggesting that each region in both sexes also underpins a diminished sense of emotional well-being with body weight. Contrarily to males, we found that in females also the BDI-II positively correlated with the BMI and by trend with the activity in ventral striatum, suggesting that in females an increased body weight may convey to other mood dimensions than those weight-related ones included in the IWQOL-Lite. CONCLUSIONS: This study suggests sex differences in serotonin-hypothalamic connections to brain regions of the reward circuitry underpinning a diminished sense of emotional well-being with an increasing body weight.

Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit.

Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were 'odor naive' to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology.

Ketamine Suppresses the Ventral Striatal Response to Reward Anticipation: A Cross-Species Translational Neuroimaging Study.

Convergent evidence implicates regional neural responses to reward anticipation in the pathogenesis of several psychiatric disorders, such as schizophrenia, where blunted ventral striatal responses to positive reward are observed in patients and at-risk populations. In vivo oxygen amperometry measurements in the ventral striatum in awake, behaving rats reveal reward-related tissue oxygen changes that closely parallel blood oxygen level dependent (BOLD) signal changes observed in human functional magnetic resonance imaging (fMRI), suggesting that a cross-species approach targeting this mechanism might be feasible in psychopharmacology. The present study explored modulatory effects of acute, subanaesthetic doses of ketamine-a pharmacological model widely used in psychopharmacological research, both preclinically and clinically-on ventral striatum activity during performance of a reward anticipation task in both species, using fMRI in humans and in vivo oxygen amperometry in rats. In a region-of-interest analysis conducted following a cross-over placebo and ketamine study in human subjects, an attenuated ventral striatal response during reward anticipation was observed following ketamine relative to placebo during performance of a monetary incentive delay task. In rats, a comparable attenuation of ventral striatal signal was found after ketamine challenge, relative to vehicle, in response to a conditioned stimulus that predicted delivery of reward. This study provides the first data in both species demonstrating an attenuating effect of acute ketamine on reward-related ventral striatal (O2) and fMRI signals. These findings may help elucidate a deeper mechanistic understanding of the potential role of ketamine as a model for psychosis, show that cross-species pharmacological experiments targeting reward signaling are feasible, and suggest this phenotype as a promising translational biomarker for the development of novel compounds, assessment of disease status, and treatment efficacy.

Variability and anatomical specificity of the orbitofrontothalamic fibers of passage in the ventral capsule/ventral striatum (VC/VS): precision care for patient-specific tractography-guided targeting of deep brain stimulation (DBS) in obsessive compulsive disorder (OCD).

Deep Brain Stimulation (DBS) is a neurosurgical procedure that can reduce symptoms in medically intractable obsessive-compulsive disorder (OCD). Conceptually, DBS of the ventral capsule/ventral striatum (VC/VS) region targets reciprocal excitatory connections between the orbitofrontal cortex (OFC) and thalamus, decreasing abnormal reverberant activity within the OFC-caudate-pallidal-thalamic circuit. In this study, we investigated these connections using diffusion magnetic resonance imaging (dMRI) on human connectome datasets of twenty-nine healthy young-adult volunteers with two-tensor unscented Kalman filter based tractography. We studied the morphology of the lateral and medial orbitofrontothalamic connections and estimated their topographic variability within the VC/VS region. Our results showed that the morphology of the individual orbitofrontothalamic fibers of passage in the VC/VS region is complex and inter-individual variability in their topography is high. We applied this method to an example OCD patient case who underwent DBS surgery, formulating an initial proof of concept for a tractography-guided patient-specific approach in DBS for medically intractable OCD. This may improve on current surgical practice, which involves implanting all patients at identical stereotactic coordinates within the VC/VS region.

Real-time functional magnetic resonance imaging neurofeedback can reduce striatal cue-reactivity to alcohol stimuli.

It has been shown that in alcoholic patients, alcohol-related cues produce increased activation of reward-related brain regions like the ventral striatum (VS), which has been proposed as neurobiological basis of craving. Modulating this activation might be a promising option in the treatment of alcohol addiction. One approach might be real-time functional magnetic resonance imaging neurofeedback (rtfMRI NF). This study was set up to implement and evaluate a rtfMRI approach in a group of non-addicted heavy social drinkers. Thirty-eight heavy drinking students were assigned to a real feedback group (rFB, n = 13), a yoke feedback group (yFB, n = 13) and a passive control group (noFB, n = 12). After conducting a reward task as functional localizer to identify ventral striatal regions, the participants viewed alcohol cues during three NF training blocks in a 3 T MRI scanner. The rFB group received feedback from their own and the yFB from another participants' VS. The noFB group received no feedback. The rFB and the yFB groups were instructed to downregulate the displayed activation. Activation of the VS and prefrontal control regions was compared between the groups. We found significant downregulation of striatal regions specifically in the rFB group. While the rFB and the yFB groups showed significant activation of prefrontal regions during feedback, this activation was only correlated to the reduction of striatal activation in the rFB group. We conclude that rtfMRI NF is a suitable method to reduce striatal activation to alcohol cues. It might be a promising supplement to the treatment of alcoholic patients.

DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS.

Obsessive-compulsive disorder (OCD) is a chronic, severe mental illness with up to 2-3% prevalence worldwide. In fact, OCD has been classified as one of the world's 10 leading causes of illness-related disability according to the World Health Organization, largely because of the chronic nature of disabling symptoms.([1]) Despite the severity and high prevalence of this chronic and disabling disorder, there is still relatively limited understanding of its pathophysiology. However, this is now rapidly changing due to development of powerful technologies that can be used to dissect the neural circuits underlying pathologic behaviors. In this article, we describe recent technical advances that have allowed neuroscientists to start identifying the circuits underlying complex repetitive behaviors using animal model systems. In addition, we review current surgical and stimulation-based treatments for OCD that target circuit dysfunction. Finally, we discuss how findings from animal models may be applied in the clinical arena to help inform and refine targeted brain stimulation-based treatment approaches.

Influence of dorsolateral prefrontal cortex and ventral striatum on risk avoidance in addiction: a mediation analysis.

BACKGROUND: Alterations in frontal and striatal function are hypothesized to underlie risky decision making in drug users, but how these regions interact to affect behavior is incompletely understood. We used mediation analysis to investigate how prefrontal cortex and ventral striatum together influence risk avoidance in abstinent drug users. METHOD: Thirty-seven abstinent substance-dependent individuals (SDI) and 43 controls underwent fMRI while performing a decision-making task involving risk and reward. Analyses of a priori regions-of-interest tested whether activity in dorsolateral prefrontal cortex (DLPFC) and ventral striatum (VST) explained group differences in risk avoidance. Whole-brain analysis was conducted to identify brain regions influencing the negative VST-risk avoidance relationship. RESULTS: Right DLPFC (RDLPFC) positively mediated the group-risk avoidance relationship (p < 0.05); RDLPFC activity was higher in SDI and predicted higher risk avoidance across groups, controlling for SDI vs. CONTROLS: Conversely, VST activity negatively influenced risk avoidance (p < 0.05); it was higher in SDI, and predicted lower risk avoidance. Whole-brain analysis revealed that, across group, RDLPFC and left temporal-parietal junction positively (p ≤ 0.001) while right thalamus and left middle frontal gyrus negatively (p < 0.005) mediated the VST activity-risk avoidance relationship. CONCLUSION: RDLPFC activity mediated less risky decision making while VST mediated more risky decision making across drug users and controls. These results suggest a dual pathway underlying decision making, which, if imbalanced, may adversely influence choices involving risk. Modeling contributions of multiple brain systems to behavior through mediation analysis could lead to a better understanding of mechanisms of behavior and suggest neuromodulatory treatments for addiction.

Exercise alters resting-state functional connectivity of motor circuits in parkinsonian rats.

Few studies have examined changes in functional connectivity after long-term aerobic exercise. We examined the effects of 4 weeks of forced running wheel exercise on the resting-state functional connectivity (rsFC) of motor circuits of rats subjected to bilateral 6-hydroxydopamine lesion of the dorsal striatum. Our results showed substantial similarity between lesion-induced changes in rsFC in the rats and alterations in rsFC reported in Parkinson's disease subjects, including disconnection of the dorsolateral striatum. Exercise in lesioned rats resulted in: (1) normalization of many of the lesion-induced alterations in rsFC, including reintegration of the dorsolateral striatum into the motor network; (2) emergence of the ventrolateral striatum as a new broadly connected network hub; and (3) increased rsFC among the motor cortex, motor thalamus, basal ganglia, and cerebellum. Our results showed for the first time that long-term exercise training partially reversed lesion-induced alterations in rsFC of the motor circuits, and in addition enhanced functional connectivity in specific motor pathways in the parkinsonian rats, which could underlie recovery in motor functions observed in these animals.