Cannabis use is rising, yet there is poor understanding of biological processes that might link chronic cannabis use to brain structural abnormalities. To lend insight into this topic, we examined ...white matter microstructural integrity and gray matter cortical thickness/density differences between 89 individuals with cannabis dependence (CD) and 89 matched controls (64 males, 25 females in each group) from the Human Connectome Project. We tested whether cortical patterns for expression of genes relevant for cannabinoid signaling (from Allen Human Brain Atlas postmortem tissue) were associated with spatial patterns of cortical thickness/density differences in CD. CD had lower fractional anisotropy than controls in white matter bundles innervating posterior cingulate and parietal cortex, basal ganglia, and temporal cortex. The CD group also had significantly less gray matter thickness and density in precuneus, relative to controls. Sibling-pair analysis found support for causal and graded liability effects of cannabis on precuneus structure. Spatial patterns of gray matter differences in CD were significantly associated with regional differences in monoacylglycerol lipase (MAGL) expression in postmortem brain tissue, such that regions with higher MAGL expression (but not fatty-acid amide hydrolase or FAAH) were more vulnerable to cortical thinning. In sum, chronic cannabis use is associated with structural differences in white and gray matter, which was most prominent in precuneus and associated white matter tracts. Regions with high MAGL expression, and therefore with potentially physiologically restricted endogenous cannabinoid signaling, may be more vulnerable to the effects of chronic cannabis use on cortical thickness.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The correspondence between cerebral glucose metabolism (indexing energy utilization) and synchronous fluctuations in blood oxygenation (indexing neuronal activity) is relevant for neuronal ...specialization and is affected by brain disorders. Here, we define novel measures of relative power (rPWR, extent of concurrent energy utilization and activity) and relative cost (rCST, extent that energy utilization exceeds activity), derived from FDG-PET and fMRI. We show that resting-state networks have distinct energetic signatures and that brain could be classified into major bilateral segments based on rPWR and rCST. While medial-visual and default-mode networks have the highest rPWR, frontoparietal networks have the highest rCST. rPWR and rCST estimates are generalizable to other indexes of energy supply and neuronal activity, and are sensitive to neurocognitive effects of acute and chronic alcohol exposure. rPWR and rCST are informative metrics for characterizing brain pathology and alternative energy use, and may provide new multimodal biomarkers of neuropsychiatric disorders.
Opioid receptors are expressed throughout the brain and play a major role in regulating striatal dopamine (DA) release. Clinical studies have shown that naloxone (NAL, a nonspecific opioid ...antagonist) in individuals with opioid use disorder and morphine (MRP, a nonspecific opioid agonist) in healthy controls, resulted in DA release in the dorsal and ventral striatum, respectively. It is not known whether the underlying patterns of striatal DA release are associated with the striatal distribution of opioid receptors. We leveraged previously published PET datasets (collected in independent cohorts) to study the brain‐wide distribution of opioid receptors and to compare striatal opioid receptor availability with striatal DA release patterns. We identified three major gray matter segments based on availability maps of DA and opioid receptors: striatum, and primary and secondary opioid segments with high and intermediate opioid receptor availability, respectively. Patterns of DA release induced by NAL and MRP were inversely associated and correlated with kappa (NAL: r(68) = −0.81, MRP: r(68) = 0.54), and mu (NAL: r(68) = −0.62, MRP: r(68) = 0.46) opioid receptor availability. Kappa opioid receptor availability accounted for a unique part of variance in NAL‐ and MRP‐DA release patterns (ΔR2 >0.14, p <.0001). In sum, distributions of opioid receptors distinguished major cortical and subcortical regions. Patterns of NAL‐ and MRP‐induced DA release had inverse associations with striatal opioid receptor availability. Our approach provides a pattern‐based characterization of drug‐induced DA targets and is relevant for modeling the role of opioid receptors in modulating striatal DA release.
We characterized the brain‐wide distribution of opioid receptors and, within the striatum, studied their association with drug‐induced dopamine release patterns. There was highest opioid receptor availability in a brain primary opioid segment including frontal, temporal, limbic, thalamic, cerebellar vermis, and periaqueductal gray regions. Patterns of dopamine release induced by naloxone and morphine were inversely related and were both associated with mu and uniquely with kappa opioid receptor availability. The data revealed major brain opioid segments and showed that striatal DA release patterns were related to the pharmacology of opioid drugs.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Obese individuals exhibit brain alterations of resting-state functional connectivity (RSFC) integrity of resting-state networks (RSNs) related to food intake. Bariatric surgery is currently the most ...effective treatment for combating morbid obesity. How bariatric surgery influences neurocircuitry is mostly unknown. Functional connectivity density (FCD) mapping was employed to calculate local (lFCD)/global (gFCD) voxelwise connectivity metrics in 22 obese participants who underwent functional magnetic resonance imaging before and 1 month after sleeve gastrectomy (SG), and in 19 obese controls (Ctr) without surgery but tested twice (baseline and 1-month later). Two factor (group, time) repeated measures ANOVA was used to assess main and interaction effects in lFCD/gFCD; regions of interest were identified for subsequent seed to voxel connectivity analyses to assess resting-state functional connectivity and to examine association with weight loss. Bariatric surgery significantly decreased lFCD in VMPFC, posterior cingulate cortex (PCC)/precuneus, and dorsal anterior cingulate cortex (dACC)/dorsomedial prefrontal cortex (DMPFC) and decreased gFCD in VMPFC, right dorsolateral prefrontal cortex (DLPFC) and right insula (p
< .05). lFCD decreased in VMPFC and PCC/precuneus correlated with reduction in BMI after surgery. Seed to voxel connectivity analyses showed the VMPFC had stronger connectivity with left DLPFC and weaker connectivity with hippocampus/parahippocampus, and PCC/precuneus had stronger connectivity with right caudate and left DLPFC after surgery. Bariatric surgery significantly decreased FCD in regions involved in self-referential processing (VMPFC, DMPFC, dACC, and precuneus), and interoception (insula), and changes in VMPFC/precuneus were associated with reduction in BMI suggesting a role in improving control of eating behaviors following surgery.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Obesity is associated with impaired inhibitory control over food intake. We hypothesized that the neural circuitry underlying inhibition of food craving would be impaired in obesity. Here we assessed ...whether obese men show altered brain responses during attempted cognitive inhibition of craving when exposed to food cues.
Sixteen obese men (32 ± 8.7 years old, BMI = 38.6 ± 7.2) were compared with 11 age-matched non-obese men (BMI 24.2 ± 2.5) using PET and FDG. Brain glucose metabolism was evaluated in a food deprived state: no food stimulation, food stimulation with no inhibition (NI), and food stimulation with attempted inhibition (AI), each on a separate day. Individualized favorite food items were presented prior to and after FDG injection for 40 min. For AI, participants were asked to attempt to inhibit their desire for the food presented. Self-reports for hunger and food desire were recorded.
Food stimulation compared with no stimulation increased glucose metabolism in inferior and superior frontal gyrus, default mode network and cerebellum, in both groups. For both groups, AI compared with NI-suppressed metabolism in right subgenual anterior cingulate, orbitofrontal areas, bilateral insula, and temporal gyri. There was a stimulation-by-group interaction effect in obese (but not in non-obese) men showing increased metabolism in pregenual anterior cingulate cortex (pgACC) and caudate during AI relative to NI. Changes in the food desire from NI to AI correlated negatively with changes in metabolism in pgACC/caudate in obese but not in non-obese men.
Obese men showed higher activation in pgACC/caudate, which are regions involved with self-regulation and emotion/reward during AI. Behavioral associations suggest that successful AI is an active process requiring more energy in obese but not in non-obese men. The additional required effort to increase cognitive control in response to food stimulation in obese compared with non-obese men may contribute to their uncontrolled eating behavior.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Dopamine (DA) neurotransmission is critical in the neurobiology of reward and aversion, but its contribution to the aversive state of opioid withdrawal remains unknown in humans. To address this, we ...used updated voxelwise methods and retrospectively analyzed a
Craclopride-PET dataset to measure D
receptor availability and relative cerebral blood flow (R1) in male opioid use disorder (OUD) participants (n = 10) during placebo and acute opioid withdrawal conditions. We found that acute withdrawal precipitated by the opioid antagonist naloxone significantly increased dorsal striatal DA release in OUD participants (p
< 0.05). Net changes in striatal DA were significantly correlated with a subjective index of withdrawal aversion such that greater DA increases were associated with more aversive responses (r(8) = 0.82, p < 0.005). Withdrawal also affected brain function, as indexed by increases in relative cerebral blood flow in the insula and putamen (p
< 0.05). Our findings are different from preclinical studies that have primarily reported decreases in ventral striatal DA during naloxone precipitated withdrawal, whereas this effect was not significant in OUD participants (p = 0.79). In sum, we provide evidence for the contribution of increases in dorsal striatal DA to the aversive state of naloxone precipitated withdrawal in humans.
During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this ...energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-(18)FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal.
Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there ...are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent
Craclopride PET brain imaging studies that measured methylphenidate-induced dopamine increases in the striatum using different routes of administration (Cohort A = oral 60 mg; Cohort B = intravenous 0.5 mg/kg; total n = 95; 65 male, 30 female), in blinded placebo-controlled designs. Females when compared to males reported stronger feeling of "drug effects" and showed significantly greater dopamine release in the ventral striatum (where nucleus accumbens is located) to both oral and intravenous methylphenidate. In contrast, there were no significant differences in methylphenidate-induced increases in dorsal striatum for either oral or intravenous administration nor were there differences in levels of methylphenidate in plasma. The greater dopamine increases with methylphenidate in ventral but not dorsal striatum in females compared to males suggests an enhanced sensitivity specific to the dopamine reward system that might underlie sex differences in the vulnerability to substance use disorders and to attention-deficit/hyperactivity disorder (ADHD).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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