Association of genetic ancestry with striatal dopamine D2/D3 receptor availability.

Despite ethnic differences in allele frequencies of variants in dopaminergic genes associated with dopamine D2/D3 receptor availability (D2R), no study to date has investigated the relationship between genetic ancestry and striatal D2R. Here, we show that ancestry-informative markers significantly predict dorsal striatal D2R in 117 healthy ethnically diverse residents of the New York metropolitan area using Positron Emission Tomography (PET) with [11C]raclopride (P<0.0001), while correcting for age, sex, BMI, education, smoking status, and estimated socioeconomic status (ZIP codes). Effects of ethnicity on D2R were not driven by variation in dopaminergic candidate genes. Instead, candidate gene associations with striatal D2R were diminished when correcting for ancestry. These findings imply that future studies investigating D2 receptor genes should covary for genetic ancestry or study homogeneous populations. Moreover, ancestry studies on human neurobiology should control for socioeconomic differences between ethnic groups.

Alcohol affects brain functional connectivity and its coupling with behavior: greater effects in male heavy drinkers.

Acute and chronic alcohol exposure significantly affect behavior but the underlying neurobiological mechanisms are still poorly understood. Here, we used functional connectivity density (FCD) mapping to study alcohol-related changes in resting brain activity and their association with behavior. Heavy drinkers (HD, N=16, 16 males) and normal controls (NM, N=24, 14 males) were tested after placebo and after acute alcohol administration. Group comparisons showed that NM had higher FCD in visual and prefrontal cortices, default mode network regions and thalamus, while HD had higher FCD in cerebellum. Acute alcohol significantly increased FCD within the thalamus, impaired cognitive and motor functions, and affected self-reports of mood/drug effects in both groups. Partial least squares regression showed that alcohol-induced changes in mood/drug effects were associated with changes in thalamic FCD in both groups. Disruptions in motor function were associated with increases in cerebellar FCD in NM and thalamus FCD in HD. Alcohol-induced declines in cognitive performance were associated with connectivity increases in visual cortex and thalamus in NM, but in HD, increases in precuneus FCD were associated with improved cognitive performance. Acute alcohol reduced 'neurocognitive coupling', the association between behavioral performance and FCD (indexing brain activity), an effect that was accentuated in HD compared with NM. Findings suggest that reduced cortical connectivity in HD contribute to decline in cognitive abilities associated with heavy alcohol consumption, whereas increased cerebellar connectivity in HD may have compensatory effects on behavioral performance. The results reveal how drinking history alters the association between brain FCD and individual differences in behavioral performance.

Recovery of brain structural abnormalities in morbidly obese patients after bariatric surgery.

BACKGROUND/OBJECTIVES: Obesity-related brain structural abnormalities have been reported extensively, and bariatric surgery (BS) is currently the most effective intervention to produce sustained weight reduction in overtly obese (OB) people. It is unknown whether BS can repair the brain circuitry abnormalities concomitantly with long-term weight loss. SUBJECTS/METHODS: In order to investigate whether BS promotes neuroplastic structural recovery in morbidly OB patients, we quantified fractional anisotropy (FA), mean diffusivity (MD) and gray (GM) and white (WM) matter densities in 15 morbidly OB patients and in 18 normal weight (NW) individuals. OB patients were studied at baseline and also 1 month after laparoscopic sleeve gastrectomy surgery. RESULTS: Two-sample t-test between OB (baseline) and NW groups showed decreased FA values, GM/WM densities and increased MD value in brain regions associated with food intake control (that is, caudate, orbitofrontal cortex, body and genu of corpus callosum) and cognitive-emotion regulation (that is, inferior frontal gyrus, hippocampus, insula, external capsule) (P<0.05, family-wise error correction). Paired t-test in the OB group between before and after surgery showed that BS generated partial neuroplastic structural recovery in the OB group, but the differences had relative less strength and smaller volume (P<0.001). CONCLUSIONS: This study provides the first anatomical evidence for BS-induced acute neuroplastic recovery that might in part mediate the long-term benefit of BS in weight reduction. It also highlights the importance of this line of gut-brain axis research employing the combined BS and neuroimaging model for identifying longitudinal changes in brain structure that correlated with obesity status.

Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers.

Dopamine signaling in nucleus accumbens is essential for cocaine reward. Interestingly, imaging studies have reported blunted dopamine increases in striatum (assessed as reduced binding of [(11)C]raclopride to D2/D3 receptors) in detoxified cocaine abusers. Here, we evaluate whether the blunted dopamine response reflected the effects of detoxification and the lack of cocaine-cues during stimulant exposure. For this purpose we studied 62 participants (43 non-detoxified cocaine abusers and 19 controls) using positron emission tomography and [(11)C]raclopride (radioligand sensitive to endogenous dopamine) to measure dopamine increases induced by intravenous methylphenidate and in 24 of the cocaine abusers, we also compared dopamine increases when methylphenidate was administered concomitantly with a cocaine cue-video versus a neutral-video. In controls, methylphenidate increased dopamine in dorsal (effect size 1.4; P<0.001) and ventral striatum (location of accumbens) (effect size 0.89; P<0.001), but in cocaine abusers methylphenidate's effects did not differ from placebo and were similar whether cocaine-cues were present or not. In cocaine abusers despite the markedly attenuated dopaminergic effects, the methylphenidate-induced changes in ventral striatum were associated with intense drug craving. Our findings are consistent with markedly reduced signaling through D2 receptors during intoxication in active cocaine abusers regardless of cues exposure, which might contribute to compulsive drug use.

Effect of combined naltrexone and bupropion therapy on the brain's reactivity to food cues.

OBJECTIVE: The significant weight loss observed with combination naltrexone-sustained release (SR) 32 mg and bupropion SR 360 mg (NB32) therapy is thought to be due, in part, to bupropion stimulation of hypothalamic pro-opiomelanocortin (POMC) neurons, and naltrexone blockade of opioid receptor-mediated POMC autoinhibition, but the neurobiological mechanisms are not fully understood. We assessed changes in brain reactivity to food cues before and after NB32 treatment. METHODS: Forty women (31.1±8.1 years; body mass index: 32.5±3.9) received 4 weeks of NB32 or placebo, and were instructed to maintain their dietary and exercise habits. Functional magnetic resonance imaging responses (analyzed using SPM2 and clusters (>100 pixels)) to a 5-min food video (preparation of the subject's favorite food) and a 5-min neutral video (manipulation of neutral objects) under conditions of mild food deprivation (∼14 h) were assessed before and after treatment. RESULTS: The food cues video induced positive brain activation in visual and prefrontal cortices, insula and subcortical brain regions. The group-by-treatment interaction on regional brain activation was significant and showed that whereas NB32 attenuated the activation in the hypothalamus in response to food cues (P<0.01), it enhanced activation in regions involved in inhibitory control (anterior cingulate), internal awareness (superior frontal, insula, superior parietal) and memory (hippocampal) regions (whole-brain analysis; P<0.05). CONCLUSIONS: Blunting the hypothalamic reactivity to food cues while enhancing the activation of regions involved with self-control and internal awareness by NB32 might underlie its therapeutic benefits in obesity.

Aging and functional brain networks.

Aging is associated with changes in human brain anatomy and function and cognitive decline. Recent studies suggest the aging decline of major functional connectivity hubs in the 'default-mode' network (DMN). Aging effects on other networks, however, are largely unknown. We hypothesized that aging would be associated with a decline of short- and long-range functional connectivity density (FCD) hubs in the DMN. To test this hypothesis, we evaluated resting-state data sets corresponding to 913 healthy subjects from a public magnetic resonance imaging database using functional connectivity density mapping (FCDM), a voxelwise and data-driven approach, together with parallel computing. Aging was associated with pronounced long-range FCD decreases in DMN and dorsal attention network (DAN) and with increases in somatosensory and subcortical networks. Aging effects in these networks were stronger for long-range than for short-range FCD and were also detected at the level of the main functional hubs. Females had higher short- and long-range FCD in DMN and lower FCD in the somatosensory network than males, but the gender by age interaction effects were not significant for any of the networks or hubs. These findings suggest that long-range connections may be more vulnerable to aging effects than short-range connections and that, in addition to the DMN, the DAN is also sensitive to aging effects, which could underlie the deterioration of attention processes that occurs with aging.

Resting functional connectivity of language networks: characterization and reproducibility.

The neural basis of language comprehension and production has been associated with superior temporal (Wernicke's) and inferior frontal (Broca's) cortical areas, respectively. However, recent resting-state functional connectivity (RSFC) and lesion studies have implicated a more extended network in language processing. Using a large RSFC data set from 970 healthy subjects and seed regions in Broca's and Wernicke's, we recapitulate this extended network that includes not only adjoining prefrontal, temporal and parietal regions but also bilateral caudate and left putamen/globus pallidus and subthalamic nucleus. We also show that the language network has predominance of short-range functional connectivity (except posterior Wernicke's area that exhibited predominant long-range connectivity), which is consistent with reliance on local processing. Predominantly, long-range connectivity was left lateralized (except anterior Wernicke's area that exhibited rightward lateralization). The language network also exhibited anti-correlated activity with auditory (only for Wernicke's area) and visual cortices that suggests integrated sequential activity with regions involved with listening or reading words. Assessment of the intra-subject's reproducibility of this network and its characterization in individuals with language dysfunction is required to determine its potential as a biomarker for language disorders.

Decreased dopamine activity predicts relapse in methamphetamine abusers.

Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [(11)C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

Positive emotionality is associated with baseline metabolism in orbitofrontal cortex and in regions of the default network.

Positive emotionality (PEM) (personality construct of well-being, achievement/motivation, social and closeness) has been associated with striatal dopamine D2 receptor availability in healthy controls. As striatal D2 receptors modulate activity in orbitofrontal cortex (OFC) and cingulate (brain regions that process natural and drug rewards), we hypothesized that these regions underlie PEM. To test this, we assessed the correlation between baseline brain glucose metabolism (measured with positron emission tomography and [(18)F]fluoro-deoxyglucose) and scores on PEM (obtained from the multidimensional personality questionnaire or MPQ) in healthy controls (n = 47). Statistical parametric mapping (SPM) analyses revealed that PEM was positively correlated (P(c)<0.05, voxel corrected) with metabolism in various cortical regions that included orbitofrontal (Brodman area, BA 11, 47) and cingulate (BA 23, 32) and other frontal (BA 10, 9), parietal (precuneus, BA 40) and temporal (BA 20, 21) regions that overlap with the brain's default mode network (DMN). Correlations with the other two main MPQ personality dimensions (negative emotionality and constraint) were not significant (SPM P(c)<0.05). Our results corroborate an involvement of orbitofrontal and cingulate regions in PEM, which is considered a trait that protects against substance use disorders. As dysfunction of OFC and cingulate is a hallmark of addiction, these findings support a common neural basis underlying protective personality factors and brain dysfunction underlying substance use disorders. In addition, we also uncovered an association between PEM and baseline metabolism in regions from the DMN, which suggests that PEM may relate to global cortical processes that are active during resting conditions (introspection, mind wandering).

Effects of irrigation on the seasonal abundance of Empoasca vitis in north-Italian vineyards.

The effect of irrigation on the abundance of Empoasca vitis (Göthe) populations was investigated in four vineyards located in northeastern Italy. In two experiments, we compared leafhopper population densities in plots irrigated (micro-spray irrigation system) or nonirrigated. In another experiment, we studied the effect of various irrigation systems on E. vitis populations over two successive seasons. In particular, five treatments were compared: control (not irrigated), traditional drip system, three types of subirrigation varying in distance from the row (40, 135, and 95 cm). In this vineyard, stem water potential was monitored with a pressure chamber. E. vitis population densities were affected by irrigation, with higher densities of this pest recorded on irrigated vines. Highest E. vitis densities were detected in drip irrigation plots compared with nonirrigated plots where water stress was highest. Moderate water stress (subirrigation plots) was associated with intermediate leafhopper densities. Implications for integrated pest management are discussed.

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.

Fever, abdominal pain, and lymphocytic ascites in a young immigrant from western Africa.

Tuberculous peritonitis is an uncommon disease in countries with low tuberculosis (TB) incidence, most often affecting non-white race, foreign-born individuals. We describe a case of TB with peritoneal involvement in a 32-year-old man immigrated to Italy from Burkina Faso, who presented with a history of fever, malaise, abdominal pain and abdominal swelling. Due to its nonspecific clinical presentation and paucibacillary nature, diagnosis of tuberculous peritonitis can be challenging, and requires a high index of suspicion. This report highlights the diagnostic challenges posed by tuberculous peritonitis and emphasizes the importance of imaging (computed tomography, CT) in identifying typical findings, and the value of histological examination of tissue specimens from peritoneum or any site of suspected TB as a tool for diagnosis confirmation.

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.

Habenula-prefrontal resting-state connectivity in reactive aggressive men - A pilot study.

Disproportionate anger and reactive aggression in response to provocation are core symptoms of intermittent-explosive disorder (IED). Previous research shows a link between the propensity for aggression in healthy individuals and altered functioning of prefrontal-limbic and default-mode networks (DMN) at rest when no provocation is present. In a pilot study, we used resting-state functional magnetic resonance imaging to investigate the effects of pronounced reactive aggression in men, exemplified by IED, on the functional organization of resting-state brain networks including subcortical nodes such as the habenula previously implicated in aggression in preclinical models. Graph theory was applied to resting-state networks to determine alterations in global efficiency and clustering in high reactive aggressive men compared to low reactive aggressive men (controls). Further, we computed within-group correlations between trait aggression and graph measures, as well as within-group whole-brain seed-to-voxel regression analyses between trait aggression and habenula resting-state functional connectivity (rsFC). Reactive aggressive men compared to controls showed higher global efficiency in the left habenula, the left pulvinar in the thalamus, the left dorso-lateral prefrontal cortex, and the right temporal pole, as well as a trend for decreased clustering in DMN nodes. In the reactive aggressive group, high levels of trait aggression were linked to lower global efficiency of the left habenula, and to lower rsFC between the left habenula and the left ventro-lateral prefrontal cortex, a core region involved in inhibitory control. Together with preclinical evidence, our findings in men underline the relevance of aberrant habenula-prefrontal connectivity for the severity of aggressive behavior. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

Sex differences in sensory gating of the thalamus during auditory interference of visual attention tasks.

Men and women have different cognitive abilities that might reflect sex-specific neural organization. Here we studied sex effects on brain function using functional magnetic resonance imaging (fMRI) with variable acoustic noise (AN) to modulate the cognitive challenge and enhance the sensitivity for the detection of sex differences in brain activation. During the performance of a visual attention (VA) task that requires the tracking of multiple moving objects and has graded levels of difficulty, women (n=15) but not men (n=13) had shorter reaction times for "Loud" than for "Quiet" scans. Men activated more than women in the superior prefrontal and occipital cortices and the anterior thalamus. The latent connectivity of the prefrontal cortex was higher with the anterior thalamus but lower with the auditory cortex for men than for women. Increases in activation with visual attention load were larger for men than for women in the superior parietal and auditory cortices. Increased AN reduced brain activation in the parietal cortex and the anterior thalamus for men but not for women. Together, these sex-specific differences in brain activation during the VA task, at different cognitive and acoustic levels suggest differences in auditory gating of the thalamus for men and women.

Role of the anterior cingulate and medial orbitofrontal cortex in processing drug cues in cocaine addiction.

Our goal in the current report was to design a new functional magnetic resonance imaging (fMRI) task to probe the role of the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) in processing of salient symptom-related cues during the simultaneous performance of an unrelated task in drug-addicted persons. We used a novel fMRI color-word drug Stroop task in 14 individuals with cocaine use disorders; subjects had to press for color of drug vs. matched neutral words. Although there were no accuracy or speed differences between the drug and neutral conditions in the current sample of subjects, drug words were more negatively valenced than the matched neutral words. Further, consistent with prior reports in individuals with other psychopathologies using different Stroop fMRI paradigms, our more classical color-word Stroop design revealed bilateral activations in the caudal-dorsal anterior cingulate cortex (cdACC) and hypoactivations in the rostro-ventral anterior cingulate cortex/medial orbitofrontal cortex (rACC/mOFC). A trend for larger rACC/mOFC hypoactivations to the drug than neutral words did not survive whole-brain corrections. Nevertheless, correlation analyses indicated that (1) the more the cdACC drug-related activation, the more negative the valence attributed to the drug words (r=-0.86, P<0.0001) but not neutral words; and (2) the more the rACC/mOFC hypoactivation to drug minus neutral words, the more the errors committed specifically to the drug minus neutral words (r=0.85, P<0.0001). Taken together, results suggest that this newly developed drug Stroop fMRI task may be a sensitive biobehavioral assay of the functions recruited for the regulation of responses to salient symptom-related stimuli in drug-addicted individuals.

Different activation patterns for working memory load and visual attention load.

Attention is a basic component of cognition, and is modulated by cognitive load. We aimed to map the common network that supports attentional load across different tasks using functional magnetic resonance imaging (fMRI). Twenty-two healthy volunteers performed two sets of tasks with graded levels of cognitive load: verbal working memory (WM) and visual attention (VA) tasks. For both tasks, increased cognitive load (WM-load and VA-load) activated a common network comprising parietal and occipital cortices, thalamus, and the cerebellum, indicating that these brain regions are involved in higher level of attention. The fMRI signals in the prefrontal cortices increased with WM-load but not with VA-load, suggesting that executive function is involved for the more demanding WM tasks but not for the more difficult VA tasks. Conversely, VA tasks activated more strongly an occipito-parietal network comprising the postcentral (PostCG) and the superior occipital (SOG) gyri, suggesting complex visual processing in this network.

Widespread disruption in brain activation patterns to a working memory task during cocaine abstinence.

Cocaine abstinence is associated with impaired performance in cognitive functions including attention, vigilance and executive function. Here we test the hypothesis that cognitive dysfunction during cocaine abstinence reflects in part impairment of cortical and subcortical regions modulated by dopamine. We used functional magnetic resonance imaging (fMRI) to study brain activation to a verbal working memory task in cocaine abusers (n=16) and healthy controls (n=16). Compared to controls, cocaine abusers showed: (1) hypoactivation in the mesencephalon, where dopamine neurons are located, as well as the thalamus, a brain region involved in arousal; (2) larger deactivation in dopamine projection regions (putamen, anterior cingulate, parahippocampal gyrus, and amygdala); and (3) hyperactivation in cortical regions involved with attention (prefrontal and parietal cortices), which probably reflects increased attention and control processes as compensatory mechanisms. Furthermore, the working memory load activation was lower in the prefrontal and parietal cortices in cocaine abusers when compared with controls, which might reflect limited network capacity. These abnormalities were accentuated in the cocaine abusers with positive urines for cocaine at time of study (as compared to cocaine abusers with negative urines) suggesting that the deficits may reflect in part early cocaine abstinence. These findings provide evidence of impaired function of regions involved with executive control, attention and vigilance in cocaine abusers. This widespread neurofunctional disruption is likely to underlie the cognitive deficits during early cocaine abstinence and to reflect involvement of dopamine as well as other neurotransmitters.