Ruiliang Wang

Gastric distention activates satiety circuitry in the human brain.

Gastric distention during meal ingestion activates vagal afferents, which send signals from the stomach to the brain and result in the perception of fullness and satiety. Distention is one of the mechanisms that modulates food intake. We measured regional brain activation during dynamic gastric balloon distention in 18 health subjects using functional magnetic resonance imaging and the blood oxygenation level-dependent (BOLD) responses. The BOLD signal was significantly changed by both inflow and outflow changes in the balloons volume. For lower balloon volumes, water inflow was associated with activation of sensorimotor cortices and right insula. The larger volume condition additionally activated left posterior amygdala, left posterior insula and the left precuneus. The response in the left amygdala and insula was negatively associated with changes in self-reports of fullness and positively with changes in plasma ghrelin concentration, whereas those in the right amygdala and insula were negatively associated with the subjects body mass index. The widespread activation induced by gastric distention corroborates the influence of vagal afferents on cortical and subcortical brain activity. These findings provide evidence that the left amygdala and insula process interoceptive signals of fullness produced by gastric distention involved in the controls of food intake.

Anterior cingulate cortex hypoactivations to an emotionally salient task in cocaine addiction

Anterior cingulate cortex (ACC) hypoactivations during cognitive processing characterize drug addicted individuals as compared with healthy controls. However, impaired behavioral performance or task disengagement may be crucial factors. We hypothesized that ACC hypoactivations would be documented in groups matched for performance on an emotionally salient task. Seventeen individuals with current cocaine use disorders (CUD) and 17 demographically matched healthy controls underwent functional magnetic resonance imaging during performance of a rewarded drug cue-reactivity task previously shown to engage the ACC. Despite lack of group differences in objective or subjective task-related performance, CUD showed more ACC hypoactivations throughout this emotionally salient task. Nevertheless, intensity of emotional salience contributed to results: (i) CUD with the largest rostroventral ACC [Brodmann Area (BA) 10, 11, implicated in default brain function] hypoactivations to the most salient task condition (drug words during the highest available monetary reward), had the least task-induced cocaine craving; (ii) CUD with the largest caudal-dorsal ACC (BA 32) hypoactivations especially to the least salient task condition (neutral words with no reward) had the most frequent current cocaine use; and (iii) responses to the most salient task condition in both these ACC major subdivisions were positively intercorrelated in the controls only. In conclusion, ACC hypoactivations in drug users cannot be attributed to task difficulty or disengagement. Nevertheless, emotional salience modulates ACC responses in proportion to drug use severity. Interventions to strengthen ACC reactivity or interconnectivity may be beneficial in enhancing top-down monitoring and emotion regulation as a strategy to reduce impulsive and compulsive behavior in addiction.

Impairment of Attentional Networks after 1 Night of Sleep Deprivation

Here, we assessed the effects of sleep deprivation (SD) on brain activation and performance to a parametric visual attention task. Fourteen healthy subjects underwent functional magnetic resonance imaging of ball-tracking tasks with graded levels of difficulty during rested wakefulness (RW) and after 1 night of SD. Self-reports of sleepiness were significantly higher and cognitive performance significantly lower for all levels of difficulty for SD than for RW. For both the RW and the SD sessions, task difficulty was associated with activation in parietal cortex and with deactivation in visual and insular cortices and cingulate gyrus but this pattern of activation/deactivation was significantly lower for SD than for RW. In addition, thalamic activation was higher for SD than for RW, and task difficulty was associated with increases in thalamic activation for the RW but not the SD condition. This suggests that thalamic resources, which under RW conditions are used to process increasingly complex tasks, are being used to maintain alertness with increasing levels of fatigue during SD. Thalamic activation was also inversely correlated with parietal and prefrontal activation. Thus, the thalamic hyperactivation during SD could underlie the reduced activation in parietal and blunted deactivation in cingulate cortices, impairing the attentional networks that are essential for accurate visuospatial attention performance.

Dopamine transporters in striatum correlate with deactivation in the default mode network during visuospatial attention.

Background Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task. Methodology/Principal Findings For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [11C]cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus. Conclusions/Significance These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN.

Disrupted functional connectivity with dopaminergic midbrain in cocaine abusers.

Background Chronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation) is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located) and cortical and subcortical brain regions during the performance of a sustained attention task. Methodology/Principal Findings We measured brain activation and functional connectivity with fMRI in 20 cocaine abusers and 20 matched controls. When compared to controls, cocaine abusers had lower positive functional connectivity of midbrain with thalamus, cerebellum, and rostral cingulate, and this was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate. Conclusions/Significance These findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.

Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.

Methylphenidate enhances brain activation and deactivation responses to visual attention and working memory tasks in healthy controls.

Methylphenidate (MPH) is a stimulant drug that amplifies dopamineric and noradrenergic signaling in the brain, which is believed to underlie its cognition enhancing effects. However, the neurobiological effects by which MPH improves cognition are still poorly understood. Here, functional magnetic resonance imaging (fMRI) was used together with working memory (WM) and visual attention (VA) tasks to test the hypothesis that 20mg oral MPH would increase activation in the dorsal attention network (DAN) and deactivation in the default mode network (DMN) as well as improve performance during cognitive tasks in healthy men. The group of subjects that received MPH (MPH group; N=16) had higher activation than the group of subjects who received no medication (control group: N=16) in DAN regions (parietal and prefrontal cortex, regions increasingly activated with increased cognitive load) and had increased deactivation in the insula and posterior cingulate cortex (regions increasingly deactivated with increased cognitive load) and these effects did not differ for the VA and the WM tasks. These findings provide the first evidence that MPH enhances activation of the DAN whereas it alters DMN deactivation. This suggests that MPH (presumably by amplifying dopamine and noradrenergic signaling) modulates cognition in part through its effects on DAN and DMN.

Gene x disease interaction on orbitofrontal gray matter in cocaine addiction.

CONTEXT Long-term cocaine use has been associated with structural deficits in brain regions having dopamine-receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. OBJECTIVE To examine variations in gray matter volume (GMV) as a function of lifetime drug use and the genotype of the monoamine oxidase A gene, MAOA, in men with cocaine use disorders (CUD) and healthy male controls. DESIGN Cross-sectional comparison. SETTING Clinical Research Center at Brookhaven National Laboratory. PATIENTS Forty individuals with CUD and 42 controls who underwent magnetic resonance imaging to assess GMV and were genotyped for the MAOA polymorphism (categorized as high- and low-repeat alleles). MAIN OUTCOME MEASURES The impact of cocaine addiction on GMV, tested by (1) comparing the CUD group with controls, (2) testing diagnosis × MAOA interactions, and (3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GMV beyond other factors. RESULTS (1) Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal, and temporal cortex and the hippocampus compared with controls. (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use. (3) The GMV in the dorsolateral prefrontal cortex and hippocampus was driven by lifetime alcohol use beyond the genotype and other pertinent variables. CONCLUSIONS Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, long-term alcohol use is a major contributor to gray matter loss in the dorsolateral prefrontal cortex and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.

Dopaminergic response to drug words in cocaine addiction.

When exposed to drug conditioned cues (stimuli associated with the drug), addicted individuals experience an intense desire for the drug, which is associated with increased dopamine cell firing. We hypothesized that drug-related words can trigger activation in the mesencephalon, where dopaminergic cells are located. During functional magnetic resonance imaging (fMRI), 15 individuals with cocaine use disorders and 15 demographically matched healthy control subjects pressed buttons for color of drug-related versus neutral words. Results showed that the drug words, but not neutral words, activated the mesencephalon in the cocaine users only. Further, in the cocaine users only, these increased drug-related mesencephalic responses were associated with enhanced verbal fluency specifically for drug words. Our results for the first time demonstrate fMRI response to drug words in cocaine-addicted individuals in mesencephalic regions as possibly associated with dopaminergic mechanisms and with conditioning to language (in this case drug words). The correlation between the brief verbal fluency test, which can be easily administered (crucial for clinical studies), and fMRI cue reactivity could be used as a biomarker of neurobiological changes in addiction.

Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: association to striatal D2/D3 receptors

Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [11C]raclopride and Positron emission tomography in 20 active cocaine abusers. Compared to neutral cues, food and cocaine cues increasingly engaged cerebellum, orbitofrontal, inferior frontal, and premotor cortices and insula and disengaged cuneus and default mode network (DMN). These fMRI signals were proportional to striatal D2/D3 receptors. Surprisingly cocaine and food cues also deactivated ventral striatum and hypothalamus. Compared to food cues, cocaine cues produced lower activation in insula and postcentral gyrus, and less deactivation in hypothalamus and DMN regions. Activation in cortical regions and cerebellum increased in proportion to the valence of the cues, and activation to food cues in somatosensory and orbitofrontal cortices also increased in proportion to body mass. Longer exposure to cocaine was associated with lower activation to both cues in occipital cortex and cerebellum, which could reflect the decreases in D2/D3 receptors associated with chronicity. These findings show that cocaine cues activate similar, though not identical, pathways to those activated by food cues and that striatal D2/D3 receptors modulate these responses, suggesting that chronic cocaine exposure might influence brain sensitivity not just to drugs but also to food cues. Hum Brain Mapp, 36:120–136, 2015.