The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence.

The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.

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.

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.

Simultaneous TMS-fMRI of the Visual Cortex Reveals Functional Network, Even in Absence of Phosphene Sensation.

Phosphene sensation is commonly used to measure cortical excitability during transcranial magnetic stimulation (TMS) of the occipital cortex. However, some individuals lack this perception, and the reason for it is still unknown. In this work, we used functional magnetic resonance imaging (fMRI) to detect brain activation during local TMS of the occipital cortex in twelve healthy subjects. We found that TMS modulated brain activity in areas connected to the stimulation site, even in people unable to see phosphene. However, we observed a trend for a lower blood-oxygenation-level dependent (BOLD) signal, and smaller brain-activation clusters near the stimulated site than in the interconnected brain areas, suggesting that TMS pulse is more effective downstream than at its application site. Furthermore, we noted prominent differences in brain activation/deactivation patterns between subjects who perceived phosphene and those who did not, implying a functional distinction in their neuronal networks that might explain the origin of differences in phosphene generation.

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.

K-space spatial low-pass filters can increase signal loss artifacts in Echo-Planar Imaging.

Effective transverse relaxation rate (T(2)*)-weighted echo-planar imaging (EPI) is extensively used for functional magnetic resonance imaging (fMRI), because of its high speed and good sensitivity to the blood oxygenation level-dependent (BOLD) signal. Nevertheless, its use is limited in areas with severe static magnetic field inhomogeneities that cause frequency shifts and T(2)* relaxation-related distortions of the MR signal along the time-domain (k-space) trajectory, resulting in disperse time-domain signals and generating susceptibility-induced signal losses. Echo planar images are commonly smoothed with k-space spatial low-pass filters to improve the signal-to-noise ratio (SNR) and reduce reconstruction artifacts. Here, we show that when such filters are applied to the dispersed echo-signals (not perfectly centered in k-space), part of the image information from the object is removed, thereby enhancing signal-loss artifacts in the images. To avoid this artifact, the dispersed echo signal has to be refocused before k-space filtering.

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.

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.

fMRI-acoustic noise alters brain activation during working memory tasks.

Scanner noise during functional magnetic resonance imaging (fMRI) may interfere with brain function and change blood oxygenation level dependent (BOLD) signals, a problem that generally worsens at the higher field strengths. Therefore, we studied the effect of increased acoustic noise on fMRI during verbal working memory (WM) processing. The sound pressure level of scanner noise was increased by 12 dBA from "Quiet" to "Loud" echo planar imaging (EPI) scans by utilizing resonant vibration modes of the gradient coil. A WM paradigm with graded levels of task difficulty was used to further access WM load. Increased scanner noise produced increased BOLD responses (percent signal change) bilaterally in the cerebellum, inferior (IFG), medial (medFG), and superior (SFG) frontal, fusiform (FusG), and the lingual (LG) gyri, and decreased BOLD responses bilaterally in the anterior cingulate gyrus (ACG) and the putamen. This finding suggests greater recruitment of attention resources in these brain regions, probably to compensate for interference due to louder scanner noise. Increased working memory load increased the BOLD signals in IFG and the cerebellum, but decreased the BOLD signals in the putamen and the LG. These findings also support the idea that brain function requires additional attention resources under noisier conditions. Load- and acoustic-noise-related changes in BOLD responses correlated negatively in the WM network. This study demonstrates that MR noise affects brain activation pattern. Future comparisons between studies performed under different acoustic conditions (due to differing magnetic field strengths, pulse sequences, or scanner manufacturers) might require knowledge of the sound pressure level of acoustic noise during fMRI.

Practice-induced changes of brain function during visual attention: a parametric fMRI study at 4 Tesla.

A parametric functional MRI (fMRI) study with three levels of task difficulty was performed to determine the effect of practice and attentional load on brain activation during visual attention tasks. Brief practice during repeat fMRI scanning (20 min) did not change performance accuracy or reaction times (RT), but decreased activation bilaterally in the inferior, middle, and superior frontal gyri, superior temporal gyrus, thalamus, and cerebellum. Increased attentional load decreased performance accuracy but not RT, and increased activation bilaterally in the inferior, posterior, and superior parietal cortices, thalamus, cerebellum, and frontal gyri. These changes suggest that practice decreases dependency on thalamus, cerebellum, and the frontal cortices for controlled task processing possibly due to increased efficiency of the attentional network. Since short-term practice-effects in the prefrontal cortex may be similar to attentional load-effects, studies of attentional load need to take practice effects into account.

Fast optimization of a biplanar gradient coil set.

This work presents an approach for fast optimization of gradient coils, using the simulated annealing method. The shielding condition derived from a target field method and the analytical evaluation of the fields produced by simple geometries were used to reduce the computing time. This method is applied to the optimization of a shielded biplanar gradient coil set. Efficiency, inductance, and homogeneity of the gradient fields produced by the optimized geometries were studied as a function of the number of wires, for the longitudinal and transverse gradient coils. A prototype of the gradient set was made to test the proposed design method. The resulting experimental values of coil efficiency, inductance, field linearity, and shielding performance exhibit good agreement between theory and experiment.

Shielded biplanar gradient coil design.

An application of the target field method to the design of shielded biplanar gradient coils for magnetic resonance imaging electromagnets is presented. Some specific cases are studied, and optimized geometries are proposed for the axial and transverse gradient coils that eliminate the third- and minimize the fifth-order terms in the magnetic field expansion.