Examining the role of dopamine in methylphenidate's effects on resting brain function.

The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI (Functional MRI) metrics widely used to assess resting brain function. However, their differential sensitivity to stimulant-induced dopamine (DA) increases, including the rate of DA rise and the relationship between them, have not been investigated. Here we used, simultaneous PET-fMRI to examine the association between dynamic changes in striatal DA and brain activity as assessed by ALFF and gFCD, following placebo, intravenous (IV), or oral methylphenidate (MP) administration, using a within-subject double-blind placebo-controlled design. In putamen, MP significantly reduced D2/3 receptor availability and strongly reduced ALFF and increased gFCD in the brain for IV-MP (Cohen's d > 1.6) but less so for oral-MP (Cohen's d < 0.6). Enhanced gFCD was associated with both the level and the rate of striatal DA increases, whereas decreased ALFF was only associated with the level of DA increases. These findings suggest distinct representations of neurovascular activation with ALFF and gFCD by stimulant-induced DA increases with differential sensitivity to the rate and the level of DA increases. We also observed an inverse association between gFCD and ALFF that was markedly enhanced during IV-MP, which could reflect an increased contribution from MP's vasoactive properties.

Seasonality in regional brain glucose metabolism.

BACKGROUND: Daylength and the rates of changes in daylength have been associated with seasonal fluctuations in psychiatric symptoms and in cognition and mood in healthy adults. However, variations in human brain glucose metabolism in concordance with seasonal changes remain under explored. METHODS: In this cross-sectional study, we examined seasonal effects on brain glucose metabolism, which we measured using 18F-fluorodeoxyglucose-PET in 97 healthy participants. To maximize the sensitivity of regional effects, we computed relative metabolic measures by normalizing the regional measures to white matter metabolism. Additionally, we explored the role of rest-activity rhythms/sleep-wake activity measured with actigraphy in the seasonal variations of regional brain metabolic activity. RESULTS: We found that seasonal variations of cerebral glucose metabolism differed across brain regions. Glucose metabolism in prefrontal regions increased with longer daylength and with greater day-to-day increases in daylength. The cuneus and olfactory bulb had the maximum and minimum metabolic values around the summer and winter solstice respectively (positively associated with daylength), whereas the temporal lobe, brainstem, and postcentral cortex showed maximum and minimum metabolic values around the spring and autumn equinoxes, respectively (positively associated with faster daylength gain). Longer daylength was associated with greater amplitude and robustness of diurnal activity rhythms suggesting circadian involvement. CONCLUSIONS: The current findings advance our knowledge of seasonal patterns in a key indicator of brain function relevant for mood and cognition. These data could inform treatment interventions for psychiatric symptoms that peak at specific times of the year.

Sex differences in methylphenidate-induced dopamine increases in ventral striatum.

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 [11C]raclopride 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).

Brain opioid segments and striatal patterns of dopamine release induced by naloxone and morphine.

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.

Accelerated Aging of the Amygdala in Alcohol Use Disorders: Relevance to the Dark Side of Addiction.

Here we assessed changes in subcortical volumes in alcohol use disorder (AUD). A simple morphometry-based classifier (MC) was developed to identify subcortical volumes that distinguished 32 healthy controls (HCs) from 33 AUD patients, who were scanned twice, during early and later withdrawal, to assess the effect of abstinence on MC-features (Discovery cohort). We validated the novel classifier in an independent Validation cohort (19 AUD patients and 20 HCs). MC-accuracy reached 80% (Discovery) and 72% (Validation). MC features included the hippocampus, amygdala, cerebellum, putamen, corpus callosum, and brain stem, which were smaller and showed stronger age-related decreases in AUD than HCs, and the ventricles and cerebrospinal fluid, which were larger in AUD and older participants. The volume of the amygdala showed a positive association with anxiety and negative urgency in AUD. Repeated imaging during the third week of detoxification revealed slightly larger subcortical volumes in AUD patients, consistent with partial recovery during abstinence. The steeper age-associated volumetric reductions in stress- and reward-related subcortical regions in AUD are consistent with accelerated aging, whereas the amygdalar associations with negative urgency and anxiety in AUD patients support its involvement in the "dark side of addiction".

Brain structural changes in cannabis dependence: association with MAGL.

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.

Reduced Segregation Between Cognitive and Emotional Processes in Cannabis Dependence.

Addiction is characterized by an erosion of cognitive control toward drug taking that is accentuated by negative emotional states. Here we tested the hypothesis that enhanced interference on cognitive control reflects a loss of segregation between cognition and emotion in addiction. We analyzed Human Connectome Project data from 1206 young adults, including 89 with cannabis dependence (CD). Two composite factors, one for cognition and one for emotion, were derived using principal component (PC) analyses. Component scores for these PCs were significantly associated in the CD group, such that negative emotionality correlated with poor cognition. However, the corresponding component scores were uncorrelated in matched controls and nondependent recreational cannabis users (n = 87). In CD, but not controls or recreational users, functional magnetic resonance imaging activations to emotional stimuli (angry/fearful faces > shapes) correlated with activations to cognitive demand (working memory; 2-back > 0-back). Canonical correlation analyses linked individual differences in cognitive and emotional component scores with brain activations. In CD, there was substantial overlap between cognitive and emotional brain-behavior associations, but in controls, associations were more restricted to the cognitive domain. These findings support our hypothesis of impaired segregation between cognitive and emotional processes in CD that might contribute to poor cognitive control under conditions of increased emotional demand.

Brain Network Segregation and Glucose Energy Utilization: Relevance for Age-Related Differences in Cognitive Function.

The human brain is organized into segregated networks with strong within-network connections and relatively weaker between-network connections. This "small-world" organization may be essential for maintaining an energetically efficient system, crucial to the brain which consumes 20% of the body's energy. Brain network segregation and glucose energy utilization both change throughout the lifespan. However, it remains unclear whether these processes interact to contribute to differences in cognitive performance with age. To address this, we examined fluorodeoxyglucose-positron emission tomography and resting-state functional magnetic resonance imaging from 88 participants aged 18-73 years old. Consistent with prior work, brain network segregation showed a negative association with age across both sensorimotor and association networks. However, relative glucose metabolism demonstrated an interaction with age, showing a negative slope in association networks but a positive slope in sensorimotor networks. Overall, brain networks with lower segregation showed significantly steeper age-related differences in glucose metabolism, compared with highly segregated networks. Sensorimotor network segregation mediated the association between age and poorer spatial cognition performance, and sensorimotor network metabolism mediated the association between age and slower response time. These data provide evidence that sensorimotor segregation and glucose metabolism underlie some age-related changes in cognition. Interventions that stimulate somatosensory networks could be important for treatment of age-related cognitive decline.

ß-Amyloid accumulation in the human brain after one night of sleep deprivation.

The effects of acute sleep deprivation on ß-amyloid (Aß) clearance in the human brain have not been documented. Here we used PET and 18F-florbetaben to measure brain Aß burden (ABB) in 20 healthy controls tested after a night of rested sleep (baseline) and after a night of sleep deprivation. We show that one night of sleep deprivation, relative to baseline, resulted in a significant increase in Aß burden in the right hippocampus and thalamus. These increases were associated with mood worsening following sleep deprivation, but were not related to the genetic risk (APOE genotype) for Alzheimer's disease. Additionally, baseline ABB in a range of subcortical regions and the precuneus was inversely associated with reported night sleep hours. APOE genotyping was also linked to subcortical ABB, suggesting that different Alzheimer's disease risk factors might independently affect ABB in nearby brain regions. In summary, our findings show adverse effects of one-night sleep deprivation on brain ABB and expand on prior findings of higher Aß accumulation with chronic less sleep.

Inhibition of food craving is a metabolically active process in the brain in obese men.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Apparent diffusion coefficient changes in human brain during sleep - Does it inform on the existence of a glymphatic system?

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.

Association Between Reduced Brain Glucose Metabolism and Cortical Thickness in Alcoholics: Evidence of Neurotoxicity.

BACKGROUND: Excessive alcohol consumption is associated with reduced cortical thickness (CT) and lower cerebral metabolic rate of glucose (CMRGlu), but the correlation between these 2 measures has not been investigated. METHODS: We tested the association between CT and cerebral CMRGlu in 19 participants with alcohol use disorder (AUD) and 20 healthy controls. Participants underwent 2-Deoxy-2-[18F]fluoroglucose positron emission tomography to map CMRGlu and magnetic resonance imaging to assess CT. RESULTS: Although performance accuracy on a broad range of cognitive domains did not differ significantly between AUD and HC, AUD had widespread decreases in CT and CMRGlu. CMRGlu, normalized to cerebellum (rCMRGlu), showed significant correlation with CT across participants. Although there were large group differences in CMRGlu (>17%) and CT (>6%) in medial orbitofrontal and BA 47, the superior parietal cortex showed large reductions in CMRGlu (~17%) and minimal CT differences (~2.2%). Though total lifetime alcohol (TLA) was associated with CT and rCMRGlu, the causal mediation analysis revealed significant direct effects of TLA on rCMRGlu but not on CT, and there were no significant mediation effects of TLA, CT, and rCMRGlu. CONCLUSIONS: The significant correlation between decrements in CT and CMRGlu across AUD participants is suggestive of alcohol-induced neurotoxicity, whereas the findings that the most metabolically affected regions in AUD had minimal atrophy and vice versa indicates that changes in CT and CMRGlu reflect distinct responses to alcohol across brain regions.

An Autonomic Network: Synchrony Between Slow Rhythms of Pulse and Brain Resting State Is Associated with Personality and Emotions.

The sympathetic system's role in modulating vasculature and its influence on emotions and personality led us to test the hypothesis that interactions between brain resting-state networks (RSNs) and pulse amplitude (indexing sympathetic activity) would be associated with emotions and personality. In 203 participants, we characterized RSN spatiotemporal characteristics, and phase-amplitude associations of RSN fluctuations with pulse and respiratory recordings. We found that RSNs are spatially reproducible within participants and were temporally associated with low frequencies (LFs < 0.1 Hz) in physiological signals. LF fluctuations in pulse amplitude were not related to cardiac electrical activity and preceded LF fluctuations in RSNs, while LF respiratory amplitude fluctuations followed LF fluctuations in RSNs. LF phase dispersion (PD) (lack of synchrony) between RSNs and pulse (PDpulse) (not respiratory) correlated with the common variability in measures of personality and emotions, with more synchrony being associated with more positive temperamental characteristics. Voxel-level PDpulse mapping revealed an "autonomic brain network," including sensory cortices and dorsal attention stream, with significant interactions with peripheral signals. Here, we uncover associations between pulse signal amplitude (presumably of sympathetic origin) and brain resting state, suggesting that interactions between central and autonomic nervous systems are important for characterizing personality and emotions.

New Repeat Polymorphism in the AKT1 Gene Predicts Striatal Dopamine D2/D3 Receptor Availability and Stimulant-Induced Dopamine Release in the Healthy Human Brain.

The role of the protein kinase Akt1 in dopamine neurotransmission is well recognized and has been implicated in schizophrenia and psychosis. However, the extent to which variants in the AKT1 gene influence dopamine neurotransmission is not well understood. Here we investigated the effect of a newly characterized variant number tandem repeat (VNTR) polymorphism in AKT1 [major alleles: L- (eight repeats) and H- (nine repeats)] on striatal dopamine D2/D3 receptor (DRD2) availability and on dopamine release in healthy volunteers. We used PET and [11C]raclopride to assess baseline DRD2 availability in 91 participants. In 54 of these participants, we also measured intravenous methylphenidate-induced dopamine release to measure dopamine release. Dopamine release was quantified as the difference in specific binding of [11C]raclopride (nondisplaceable binding potential) between baseline values and values following methylphenidate injection. There was an effect of AKT1 genotype on DRD2 availability at baseline for the caudate (F(2,90) = 8.2, p = 0.001) and putamen (F(2,90) = 6.6, p = 0.002), but not the ventral striatum (p = 0.3). For the caudate and putamen, LL showed higher DRD2 availability than HH; HL were in between. There was also a significant effect of AKT1 genotype on dopamine increases in the ventral striatum (F(2,53) = 5.3, p = 0.009), with increases being stronger in HH > HL > LL. However, no dopamine increases were observed in the caudate (p = 0.1) or putamen (p = 0.8) following methylphenidate injection. Our results provide evidence that the AKT1 gene modulates both striatal DRD2 availability and dopamine release in the human brain, which could account for its association with schizophrenia and psychosis. The clinical relevance of the newly characterized AKT1 VNTR merits investigation.SIGNIFICANCE STATEMENT The AKT1 gene has been implicated in schizophrenia and psychosis. This association is likely to reflect modulation of dopamine signaling by Akt1 kinase since striatal dopamine hyperstimulation is associated with psychosis and schizophrenia. Here, using PET with [11C]raclopride, we identified in the AKT1 gene a new variable number tandem repeat (VNTR) marker associated with baseline striatal dopamine D2/D3 receptor availability and with methylphenidate-induced striatal dopamine increases in healthy volunteers. Our results confirm the involvement of the AKT1 gene in modulating striatal dopamine signaling in the human brain. Future studies are needed to assess the association of this new VNTR AKT1 variant in schizophrenia and drug-induced psychoses.

Abnormal frontostriatal tracts in young male tobacco smokers.

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 ±â€¯1.3 years) vs. 35 male nonsmokers (21.2 ±â€¯1.3 years); Study2: 29 male smokers (21.4 ±â€¯1.1 years) vs. 25 male nonsmokers (21.0 ±â€¯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.

Bariatric surgery in obese patients reduced resting connectivity of brain regions involved with self-referential processing.

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 (pFWE < .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.

Temporal Evolution of Brain Functional Connectivity Metrics: Could 7 Min of Rest be Enough?

Unaccounted temporal dynamics of resting-state functional connectivity (FC) metrics challenges their potential as biomarkers for clinical applications in neuroscience. Here we studied the scan time required to reach stable values for various FC metrics including seed-voxel correlations and spatial independent component analyses (sICA), and for the local functional connectivity density (lFCD), a graph theory metric. By increasing the number of time points included in the analysis, we assessed the effects of scan time on convergence of accuracy, sensitivity, specificity, reproducibility, and reliability of these FC metrics. The necessary scan time to attenuate the effects of the temporal dynamics by 80% varied across connectivity metrics and was shorter for lFCD (7 min) than for FC (11 min) or for sICA (10 min). Findings suggest that the scan time required to achieve stable FC is metric-dependent, with lFCD being the most resilient metric to the effects of temporal dynamics. Thus, the lFCD metric could be particularly useful for pediatric and patient populations who may not tolerate long scans.

High-Resolution Functional Connectivity Density: Hub Locations, Sensitivity, Specificity, Reproducibility, and Reliability.

Brain regions with high connectivity have high metabolic cost and their disruption is associated with neuropsychiatric disorders. Prior neuroimaging studies have identified at the group-level local functional connectivity density ( L: FCD) hubs, network nodes with high degree of connectivity with neighboring regions, in occipito-parietal cortices. However, the individual patterns and the precision for the location of the hubs were limited by the restricted spatiotemporal resolution of the magnetic resonance imaging (MRI) measures collected at rest. In this work, we show that MRI datasets with higher spatiotemporal resolution (2-mm isotropic; 0.72 s), collected under the Human Connectome Project (HCP), provide a significantly higher precision for hub localization and for the first time reveal L: FCD patterns with gray matter (GM) specificity >96% and sensitivity >75%. High temporal resolution allowed effective 0.01-0.08 Hz band-pass filtering, significantly reducing spurious L: FCD effects in white matter. These high spatiotemporal resolution L: FCD measures had high reliability [intraclass correlation, ICC(3,1) > 0.6] but lower reproducibility (>67%) than the low spatiotemporal resolution equivalents. GM sensitivity and specificity benchmarks showed the robustness of L: FCD to changes in model parameter and preprocessing steps. Mapping individual's brain hubs with high sensitivity, specificity, and reproducibility supports the use of L: FCD as a biomarker for clinical applications in neuropsychiatric disorders.

Correlation between Traits of Emotion-Based Impulsivity and Intrinsic Default-Mode Network Activity.

Negative urgency (NU) and positive urgency (PU) are implicated in several high-risk behaviors, such as eating disorders, substance use disorders, and nonsuicidal self-injury behavior. The current study aimed to explore the possible link between trait of urgency and brain activity at rest. We assessed the amplitude of low-frequency fluctuations (ALFF) of the resting-state functional magnetic resonance imaging (fMRI) signal in 85 healthy volunteers. Trait urgency measures were related to ALFF in the lateral orbitofrontal cortex, dorsolateral prefrontal cortex, ventral and dorsal medial frontal cortex, anterior cingulate, and posterior cingulate cortex/precuneus. In addition, trait urgency measures showed significant correlations with the functional connectivity of the posterior cingulate cortex/precuneus seed with the thalamus and midbrain region. These findings suggest an association between intrinsic brain activity and impulsive behaviors in healthy humans.

Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases.

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.