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The role of sleep in brain physiology is poorly understood. Recently rodent studies have shown that the glymphatic system clears waste products from brain more efficiently during sleep compared to wakefulness due to the expansion of the interstitial fluid space facilitating entry of cerebrospinal fluid (CSF) into the brain. Here, we studied water diffusivity in the brain during sleep and awake conditions, hypothesizing that an increase in water diffusivity during sleep would occur concomitantly with an expansion of CSF volume - an effect that we predicted based on preclinical findings would be most prominent in cerebellum. We used MRI to measure slow and fast components of the apparent diffusion coefficient (ADC) of water in the brain in 50 healthy participants, in 30 of whom we compared awake versus sleep conditions and in 20 of whom we compared rested-wakefulness versus wakefulness following one night of sleep-deprivation. Sleep compared to wakefulness was associated with increases in slow-ADC in cerebellum and left temporal pole and with decreases in fast-ADC in thalamus, insula, parahippocampus and striatal regions, and the density of sleep arousals was inversely associated with ADC changes. The CSF volume was also increased during sleep and was associated with sleep-induced changes in ADCs in cerebellum. There were no differences in ADCs with wakefulness following sleep deprivation compared to rested-wakefulness. Although we hypothesized increases in ADC with sleep, our findings uncovered both increases in slow ADC (mostly in cerebellum) as well as decreases in fast ADC, which could reflect the distinct biological significance of fast- and slow-ADC values in relation to sleep. While preliminary, our findings suggest a more complex sleep-related glymphatic function in the human brain compared to rodents. On the other hand, our findings of sleep-induced changes in CSF volume provide preliminary evidence that is consistent with a glymphatic transport process in the human brain.

Dysfunctions in frontostriatal circuits have been associated with craving and cognitive control in smokers. However, the relevance of white matter (WM) diffusion properties of the ventral and dorsal frontostriatal tracts for behaviors associated with smoking remains relatively unknown, especially in young adulthood, a critical time period for the development and maintenance of addiction. Here, diffusion tensor imaging (DTI) and probabilistic tractography were used to investigate the WM tracts of the ventral and dorsal frontostriatal circuits in two independent studies (Study1: 36 male smokers (21.3 ± 1.3 years) vs. 35 male nonsmokers (21.2 ± 1.3 years); Study2: 29 male smokers (21.4 ± 1.1 years) vs. 25 male nonsmokers (21.0 ± 1.4 years)). Subjective craving was measured by the Questionnaire on Smoking Urges (QSU) and cognitive control ability was assessed with the Stroop task. In both studies, smokers committed more response errors than nonsmokers during the incongruent condition of the Stroop task. Relative to controls, smokers showed lower fractional anisotropy (FA) and higher radial diffusivity in left medial orbitofrontal cortex-to-nucleus accumbens fiber tracts (ventral frontostriatal path) and also lower FA in right dorsolateral prefrontal cortex-to-caudate fiber tracts (dorsal frontostriatal path). The FA values of the right dorsal fibers were negatively correlated with incongruent response Stroop errors in smokers, whereas the mean diffusivity values of the left ventral fibers were positively correlated with craving in smokers. Thus, WM diffusion properties of the dorsal and ventral frontostriatal tracts were associated with cognitive control and craving, respectively, in young male tobacco smokers. These data highlight the importance of studying WM in relation to neuropsychological changes underlying smoking.

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 20 mg 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.

Loss of control over drug taking is considered a hallmark of addiction and is critical in relapse. Dysfunction of frontal brain regions involved with inhibitory control may underlie this behavior. We evaluated whether addicted subjects when instructed to purposefully control their craving responses to drug-conditioned stimuli can inhibit limbic brain regions implicated in drug craving. We used PET and 2-deoxy-2[18F]fluoro-d-glucose to measure brain glucose metabolism (marker of brain function) in 24 cocaine abusers who watched a cocaine-cue video and compared brain activation with and without instructions to cognitively inhibit craving. A third scan was obtained at baseline (without video). Statistical parametric mapping was used for analysis and corroborated with regions of interest. The cocaine-cue video increased craving during the no-inhibition condition (pre 3+/-3, post 6+/-3; p

Methamphetamine is one of the most addictive and neurotoxic drugs of abuse. It produces large elevations in extracellular dopamine in the striatum through vesicular release and inhibition of the dopamine transporter. In the U.S. abuse prevalence varies by ethnicity with very low abuse among African Americans relative to Caucasians, differentiating it from cocaine where abuse rates are similar for the two groups. Here we report the first comparison of methamphetamine and cocaine pharmacokinetics in brain between Caucasians and African Americans along with the measurement of dopamine transporter availability in striatum. Methamphetamine’s uptake in brain was fast (peak uptake at 9 minutes) with accumulation in cortical and subcortical brain regions and in white matter. Its clearance from brain was slow (except for white matter which did not clear over the 90 minutes) and there was no difference in pharmacokinetics between Caucasians and African Americans. In contrast cocaine’s brain uptake and clearance were both fast, distribution was predominantly in striatum and uptake was higher in African Americans. Among individuals, those with the highest striatal (but not cerebellar) methamphetamine accumulation also had the highest dopamine transporter availability suggesting a relationship between METH exposure and DAT availability. Methamphetamine’s fast brain uptake is consistent with its highly reinforcing effects, its slow clearance with its long lasting behavioral effects and its widespread distribution with its neurotoxic effects that affect not only striatal but also cortical and white matter regions. The absence of significant differences between Caucasians and African Americans suggests that variables other than methamphetamine pharmacokinetics and bioavailability account for the lower abuse prevalence in African Americans.

Dopamine's role in inhibitory control is well recognized and its disruption may contribute to behavioral disorders of discontrol such as obesity. However, the mechanism by which impaired dopamine neurotransmission interferes with inhibitory control is poorly understood. We had previously documented a reduction in dopamine D2 receptors in morbidly obese subjects. To assess if the reductions in dopamine D2 receptors were associated with activity in prefrontal brain regions implicated in inhibitory control we assessed the relationship between dopamine D2 receptor availability in striatum with brain glucose metabolism (marker of brain function) in ten morbidly obese subjects (BMI>40 kg/m(2)) and compared it to that in twelve non-obese controls. PET was used with [(11)C]raclopride to assess D2 receptors and with [(18)F]FDG to assess regional brain glucose metabolism. In obese subjects striatal D2 receptor availability was lower than controls and was positively correlated with metabolism in dorsolateral prefrontal, medial orbitofrontal, anterior cingulate gyrus and somatosensory cortices. In controls correlations with prefrontal metabolism were not significant but comparisons with those in obese subjects were not significant, which does not permit to ascribe the associations as unique to obesity. The associations between striatal D2 receptors and prefrontal metabolism in obese subjects suggest that decreases in striatal D2 receptors could contribute to overeating via their modulation of striatal prefrontal pathways, which participate in inhibitory control and salience attribution. The association between striatal D2 receptors and metabolism in somatosensory cortices (regions that process palatability) could underlie one of the mechanisms through which dopamine regulates the reinforcing properties of food.

Decreased dopamine transporters (DAT) in the basal ganglia were shown in patients with human immunodeficiency virus (HIV) associated dementia. Therefore, we assessed the relationship between striatal DAT and dopamine D2 receptors (D2R) availability and cognitive performance, and whether cocaine abuse, a common co-morbid condition in HIV patients, would be associated with further decreases in DAT and D2 receptors.35 HIV-positive subjects [24 without (HIV) and 11 with a history of cocaine-dependence (HIV+Coc)] and 14 seronegative controls (SN) were evaluated with PET to measure DAT using [C-11]cocaine and D2R using [C-11]raclopride (availability of DAT or D2R estimated with Bmax/Kd), and a battery of neuropsychological tests.Compared to SN controls, both HIV subject groups had lower DAT in putamen (HIV+Coc: -16.7%, p = 0.003; HIV: -12.2%, p = 0.02) and only HIV+Coc showed lower DAT in caudate (-12.2%, p = 0.04). Lower D2R in both regions of both HIV groups were accounted by the greater nicotine use. Lower DAT, but not D2R, in putamen and caudate were associated with poorer performance on multiple neuropsychological tests, corrected for the effects of age, education, intelligence, mood, and nicotine use. Furthermore, a structural equation model (SEM) indicated that lower average dopamine function (both DAT and D2R) were related to poorer overall function on neuropsychological tests (p = 0.05).Reduced dopaminergic function may contribute to cognitive dysfunction in HIV patients with or without additional cocaine abuse. These findings suggest that these HIV patients may benefit from treatments that enhance dopamine function or protection from dopamine cell injury.

Imaging studies have shown an association between dopamine increases in striatum and cue induced craving in cocaine abusers. However, the extent to which dopamine increases reflect a primary rather than a secondary response to the cues remains unclear. Here we evaluated the extent to which dopamine increases by themselves can induce craving in cocaine abusers. Using PET and [11C]raclopride (D2 receptor radioligand sensitive to competition with endogenous dopamine) we show that in cocaine abusers (n = 20) oral methylphenidate (20 mg), which significantly increased dopamine in striatum, did not induce craving unless subjects were concomitantly exposed to cocaine cues (video scenes of subjects self-administering cocaine). This suggests that dopamine increases associated with conditioned cues are not primary responses but reflect downstream stimulation of dopamine cells (presumably glutamatergic afferents from prefrontal cortex and/or amygdala). Inasmuch as afferent stimulation of dopamine neurons results in phasic cell firing these findings suggest that “fast” dopamine increases, in contrast to the “slow” dopamine increases as achieved when using oral methylphenidate (mimicking tonic dopamine cell firing), are required for cues to trigger craving. The fact that methylphenidate induced craving only when given with the cocaine cues highlights the context dependency of methylphenidate’s effects and suggests that its use for the treatment of ADHD subjects with co-morbid drug abuse should not increase craving.

Methamphetamine's widepread abuse and concerns that it might increase Parkinson's disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [(11)C]cocaine to measure DAT, and with [(11)C]raclopride to measure dopamine release (assessed as changes in specific binding of [(11)C]raclopride between placebo and methylphenidate), which was used as a marker of dopamine neuronal function, we show that MA (n=16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum (except for a small decrease in left putamen), when compared to controls (n=15). In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p=0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n=9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p=0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of dopamine terminals.

Moderate doses of alcohol decrease glucose metabolism in the human brain, which has been interpreted to reflect alcohol-induced decreases in brain activity. Here, we measure the effects of two relatively low doses of alcohol (0.25 g/kg and 0.5 g/kg, or 5 to 10 mM in total body H2O) on glucose metabolism in the human brain. Twenty healthy control subjects were tested using positron emission tomography (PET) and FDG after placebo and after acute oral administration of either 0.25 g/kg, or 0.5 g/kg of alcohol, administered over 40 min. Both doses of alcohol significantly decreased whole-brain glucose metabolism (10% and 23% respectively). The responses differed between doses; whereas the 0.25 g/kg dose predominantly reduced metabolism in cortical regions, the 0.5 g/kg dose reduced metabolism in cortical as well as subcortical regions (i.e. cerebellum, mesencephalon, basal ganglia and thalamus). These doses of alcohol did not significantly change the scores in cognitive performance, which contrasts with our previous results showing that a 13% reduction in brain metabolism by lorazepam was associated with significant impairment in performance on the same battery of cognitive tests. This seemingly paradoxical finding raises the possibility that the large brain metabolic decrements during alcohol intoxication could reflect a shift in the substrate for energy utilization, particularly in light of new evidence that blood-borne acetate, which is markedly increased during intoxication, is a substrate for energy production by the brain.

Echo Planar imaging (EPI), the gold standard technique for functional MRI (fMRI), is based on fast magnetic field gradient switching. These time-varying magnetic fields induce electric (E) fields in the brain that could influence neuronal activity; but this has not been tested. Here we assessed the effects of EPI on brain glucose metabolism (marker of brain function) using PET and 18F 2-fluoro-2-deoxy-D-glucose (18FDG). Fifteen healthy subjects were in a 4 T magnet during the 18FDG uptake period twice: with (ON) and without (OFF) EPI gradients pulses along the z-axis (Gz: 23 mT/m; 250 microsecond rise-time; 920 Hz). The E-field from these EPI pulses is non-homogeneous, increasing linearly from the gradient’s isocenter (radial and z directions), which allowed us to assess the correlation between local strength of the E-field and the regional metabolic differences between ON and OFF sessions. Metabolic images were normalized to metabolic activity in the plane positioned at the gradient’s isocenter where E=0 for both ON and OFF conditions. Statistical parametric analyses used to identify regions that differed between ON versus OFF (p

Sleep deprivation interferes with cognitive performance but the mechanisms are poorly understood. We recently reported that one night of sleep deprivation increased dopamine in striatum (measured with [(11)C]raclopride, a PET radiotracer that competes with endogenous dopamine for binding to D2 receptors) and that these increases were associated with impaired performance in a visual attention task. To better understand this association here we evaluate the relationship between changes in striatal dopamine (measured as changes in D2 receptor availability using PET and [(11)C]raclopride) and changes in brain activation to a visual attention task (measured with BOLD and fMRI) when performed during sleep deprivation versus during rested wakefulness. We find that sleep induced changes in striatal dopamine were associated with changes in cortical brain regions modulated by dopamine (attenuated deactivation of anterior cingulate gyrus and insula) but also in regions that are not recognized targets of dopaminergic modulation (attenuated activation of inferior occipital cortex and cerebellum). Moreover, the increases in striatal dopamine as well as its associated regional activation and deactivation patterns correlated negatively with performance accuracy. These findings therefore suggest that hyperstimulation of D2 receptors in striatum may contribute to the impairment in visual attention during sleep deprivation. Thus, while dopamine increases in prefrontal regions (including stimulation of D1 receptors) may facilitate attention our findings suggest that hyperstimulation of D2 receptors in striatum may impair it. Alternatively, these associations may reflect a compensatory striatal dopamine response (to maintain arousal) that is superimposed on a larger response to sleep deprivation.

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 balloon's 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 subject's 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.

Objective: The increased incidence of obesity most likely reflects changes in the environment that had made food more available and palatable. Here we assess the response of the human brain to the presentation of appetitive food stimuli during food presentation using PET and FDG. Method: Metabolic changes in response to food presentation were done in 12 healthy normal body weight subjects who were food deprived before the study. Results: Food presentation significantly increased metabolism in the whole brain (24%, P < 0.01) and these changes were largest in superior temporal, anterior insula, and orbitofrontal cortices. The increases in the right orbitofrontal cortex were the ones that correlated significantly with the increases in self-reports of hunger and desire for food. Discussion: The marked increase in brain metabolism by the presentation of food provides evidence of the high sensitivity of the human brain to food stimuli. This high sensitivity coupled with the ubiquitousness of food stimuli in the environment is likely to contribute to the epidemic of obesity. In particular, the activation of the right orbitofrontal cortex, a brain region involved with drive, may underlie the motivation to procure food, which may be subjectively experienced as “desire for food” and “hunger” when exposed to food stimuli.