Dopamine-dependent architecture of cortico-subcortical network connectivity.

Maladaptive dopaminergic mediation of reward processing in humans is thought to underlie multiple neuropsychiatric disorders, including addiction, Parkinson's disease, and schizophrenia. Mechanisms responsible for the development of such disorders may depend on individual differences in neural signaling within large-scale cortico-subcortical circuitry. Using a combination of functional neuroimaging and pharmacological challenges in healthy volunteers, we identified opposing dopamine agonistic and antagonistic neuromodulatory effects on distributed functional interactions between specific subcortical regions and corresponding neocortical "resting-state" networks, known to be involved in distinct aspects of cognition and reward processing. We found that, relative to a placebo, levodopa and haloperidol challenges, respectively, increased or decreased the functional connectivity between (1) the midbrain and a "default mode" network, (2) the right caudate and a right-lateralized frontoparietal network, and (3) the ventral striatum and a fronto-insular network. Further, we found drug-specific associations between brain circuitry reactivity to dopamine modulation and individual differences in trait impulsivity, revealing dissociable drug-personality interaction effects across distinct dopamine-dependent cortico-subcortical networks. Our findings identify possible systems underlying pathogenesis and treatment efficacy in disorders of dopamine deficiency.

Manipulating brain connectivity with δ9-tetrahydrocannabinol: a pharmacological resting state FMRI study.

Resting state-functional magnetic resonance imaging (RS-FMRI) is a neuroimaging technique that allows repeated assessments of functional connectivity in resting state. While task-related FMRI is limited to indirectly measured drug effects in areas affected by the task, resting state can show direct CNS effects across all brain networks. Hence, RS-FMRI could be an objective measure for compounds affecting the CNS. Several studies on the effects of cannabinoid receptor type 1 (CB(1))-receptor agonist δ(9)-tetrahydrocannabinol (THC) on task-dependent FMRI have been performed. However, no studies on the effects of cannabinoids on resting state networks using RS-FMRI have been published. Therefore, we investigated the effects of THC on functional brain connectivity using RS-FMRI. Twelve healthy volunteers (9 male, 3 female) inhaled 2, 6 and 6 mg THC or placebo with 90-minute intervals in a randomized, double blind, cross-over trial. Eight RS-FMRI scans of 8 min were obtained per occasion. Subjects rated subjective psychedelic effects on a visual analog scale after each scan, as pharmacodynamic effect measures. Drug-induced effects on functional connectivity were examined using dual regression with FSL software (FMRIB Analysis Group, Oxford). Eight maps of voxel-wise connectivity throughout the entire brain were provided per RS-FMRI series with eight predefined resting-state networks of interest. These maps were used in a mixed effects model group analysis to determine brain regions with a statistically significant drug-by-time interaction. Statistical images were cluster-corrected, and results were Bonferroni-corrected across multiple contrasts. THC administration increased functional connectivity in the sensorimotor network, and was associated with dissociable lateralized connectivity changes in the right and left dorsal visual stream networks. The brain regions showing connectivity changes included the cerebellum and dorsal frontal cortical regions. Clear increases were found for feeling high, external perception, heart rate and cortisol, whereas prolactin decreased. This study shows that THC induces both increases and (to a lesser extent) decreases in functional brain connectivity, mainly in brain regions with high densities of CB(1)-receptors. Some of the involved regions could be functionally related to robust THC-induced CNS-effects that have been found in previous studies (Zuurman et al., 2008), such as postural stability, feeling high and altered time perception.

Effects of morphine and alcohol on functional brain connectivity during "resting state": a placebo-controlled crossover study in healthy young men.

A major challenge in central nervous system (CNS) drug research is to develop a generally applicable methodology for repeated measurements of drug effects on the entire CNS, without task-related interactions and a priori models. For this reason, data-driven resting-state fMRI methods are promising for pharmacological research. This study aimed to investigate whether different psychoactive substances cause drug-specific effects in functional brain connectivity during resting-state. In this double blind placebo-controlled (double dummy) crossover study, seven resting-state fMRI scans were obtained in 12 healthy young men in three different drug sessions (placebo, morphine and alcohol; randomized). Drugs were administered intravenously based on validated pharmacokinetic protocols to minimize the inter- and intra-subject variance in plasma drug concentrations. Dual-regression was used to estimate whole-brain resting-state connectivity in relation to eight well-characterized resting-state networks, for each data set. A mixed effects analysis of drug by time interactions revealed dissociable changes in both pharmacodynamics and functional connectivity resulting from alcohol and morphine. Post hoc analysis of regions of interest revealed adaptive network interactions in relation to pharmacokinetic and pharmacodynamic curves. Our results illustrate the applicability of resting-state functional brain connectivity in CNS drug research.

Reduced functional brain connectivity prior to and after disease onset in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is characterised by both regional and generalised neuronal cell loss in the brain. Investigating functional brain connectivity patterns in rest in HD has the potential to broaden the understanding of brain functionality in relation to disease progression. This study aims to establish whether brain connectivity during rest is different in premanifest and manifest HD as compared to controls. METHODS: At the Leiden University Medical Centre study site of the TRACK-HD study, 20 early HD patients (disease stages 1 and 2), 28 premanifest gene carriers and 28 healthy controls underwent 3 T MRI scanning. Standard and high-resolution T1-weighted images and a resting state fMRI scan were acquired. Using FSL, group differences in resting state connectivity were examined for eight networks of interest using a dual regression method. With a voxelwise correction for localised atrophy, group differences in functional connectivity were examined. RESULTS: Brain connectivity of the left middle frontal and pre-central gyrus, and right post central gyrus with the medial visual network was reduced in premanifest and manifest HD as compared to controls (0.05 > p > 0.0001). In manifest HD connectivity of numerous widespread brain regions with the default mode network and the executive control network were reduced (0.05 > p > 0.0001). DISCUSSION: Brain regions that show reduced intrinsic functional connectivity are present in premanifest gene carriers and to a much larger extent in manifest HD patients. These differences are present even when the potential influence of atrophy is taken into account. Resting state fMRI could potentially be used for early disease detection in the premanifest phase of HD and for monitoring of disease modifying compounds.

Dopamine modulates reward system activity during subconscious processing of sexual stimuli.

Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive-compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the 'reward system'. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n=53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate 'wanting' in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication.

Pseudocontinuous arterial spin labeling reveals dissociable effects of morphine and alcohol on regional cerebral blood flow.

We have examined sensitivity and specificity of pseudocontinuous arterial spin labeling (PCASL) to detect global and regional changes in cerebral blood flow (CBF) in response to two different psychoactive drugs. We tested alcohol and morphine in a placebo-controlled, double-blind randomized study in 12 healthy young men. Drugs were administered intravenously. Validated pharmacokinetic protocols achieved minimal intersubject and intrasubject variance in plasma drug concentration. Permutation-based statistical testing of a mixed effect repeated measures model revealed a widespread increase in absolute CBF because of both morphine and alcohol. Conjunction analysis revealed overlapping effects of morphine and alcohol on absolute CBF in the left anterior cingulate, right hippocampus, right insula, and left primary sensorimotor areas. Effects of morphine and alcohol on relative CBF (obtained from z-normalization of absolute CBF maps) were significantly different in the left putamen, left frontoparietal network, cerebellum, and the brainstem. Corroborating previous PET results, our findings suggest that PCASL is a promising tool for central nervous system drug research.