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Dopamine (DA) mediated brain activity is intimately linked to reward‐driven cerebral responses, while aberrant reward processing has been implicated in several psychiatric disorders. fMRI has been a valuable tool in understanding the mechanism by which DA modulators alter reward‐driven responses and how they may exert their therapeutic effect. However, the potential effects of a pharmacological compound on aspects of neurovascular coupling may cloud the interpretability of the BOLD contrast. Here, we assess the effects of risperidone on reward driven BOLD signals produced by reward anticipation and outcome, while attempting to control for potential drug effects on regional cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). Healthy male volunteers (n = 21) each received a single oral dose of either 0.5 mg, 2 mg of risperidone or placebo in a double‐blind, placebo‐controlled, randomised, three‐period cross‐over study design. Participants underwent fMRI scanning while performing the widely used Monetary Incentive Delay (MID) task to assess drug impact on reward function. Measures of CBF (Arterial Spin Labelling) and breath‐hold challenge induced BOLD signal changes (as a proxy for CVR) were also acquired and included as covariates. Risperidone produced divergent, dose‐dependent effects on separate phases of reward processing, even after controlling for potential nonneuronal influences on the BOLD signal. These data suggest the D2 antagonist risperidone has a wide‐ranging influence on DA‐mediated reward function independent of nonneuronal factors. We also illustrate that assessment of potential vascular confounds on the BOLD signal may be advantageous when investigating CNS drug action and advocate for the inclusion of these additional measures into future study designs., Single dose risperidone produces dose‐response and divergent effects on different phases of reward‐related brain activity in healthy human volunteers in a placebo‐controlled fMRI study. These effects persist after accounting for potential nonneuronal effects of the drug on cerebral blood flow and cerebrovascular reactivity (as measured by a breath hold challenge).

Background Ketamine as an antidepressant improves anhedonia as early as 2 hours after infusion. These drug effects are thought to be exerted via actions on reward-related brain areas—yet these actions remain largely unknown. Our study investigates ketamine’s effects during the anticipation and receipt of an expected reward, after the psychotomimetic effects of ketamine have passed, when early antidepressant effects are reported. Methods We examined ketamine’s effects during the anticipation and receipt of expected rewards on predefined brain areas, namely, the dorsal and ventral striatum, ventral tegmental area, amygdala, and insula. We recruited 37 male and female participants with remitted depression who were free from symptoms and antidepressant treatments at the time of the scan. Participants were scanned 2 hours after drug administration in a double-blind crossover design (ketamine: 0.5 mg/kg and placebo) while performing a monetary reward task. Results A significant main effect of ketamine was observed across all regions of interest during the anticipation and feedback phases of win and no-win trials. The drug effects were particularly prominent in the nucleus accumbens and putamen, which showed increased activation on the receipt of smaller rewards compared with neutral. The levels of (2R,6R)-hydroxynorketamine 2 hours after infusion significantly correlated with the activation observed in the ventral tegmental area for that contrast. Conclusions These findings demonstrate that ketamine can produce detectable changes in reward-related brain areas 2 hours after infusion, which occur without symptom changes and support the idea that ketamine might improve reward-related symptoms via modulation of response to feedback.

Background: Cognitive flexibility deficits are present in patients with schizophrenia and are strong predictors of functional outcome but, as yet, have no pharmacological treatments. Aims: The purpose of this study was to investigate whether the phosphodiesterase type-4 inhibitor, roflumilast, can improve cognitive flexibility performance and functional brain activity in patients with schizophrenia. Methods: This was a within-subject, randomised, double-blind, placebo-controlled, three-period crossover study using a version of the Intradimensional/Extradimensional (ID/ED) task, optimised for functional magnetic resonance imaging (fMRI), in 10 patients with schizophrenia who were scanned after receiving placebo, 100 µg or 250 µg roflumilast for 8 consecutive days. Data from an additional fMRI ID/ED study of 18 healthy participants on placebo was included to contextualise the schizophrenia-related performance and activations. The fMRI analyses included a priori driven region of interest (ROI) analysis of the dorsal frontoparietal attention network. Results: Patients on placebo demonstrated broad deficits in task performance compared to the healthy comparison group, accompanied by preserved network activity for solution search, but reduced activity in left ventrolateral prefrontal cortex (VLPFC) and posterior parietal cortex for attentional set-shifting and reduced activity in left dorsolateral prefrontal cortex (DLPFC) for reversal learning. These ROI deficits were ameliorated by 250 µg roflumilast, whereas during solution search 100 µg roflumilast reduced activity in the left orbitofrontal cortex, right DLPFC and bilateral PPC, which was associated with an improvement in formation of attentional sets. Conclusions: The results suggest roflumilast has dose-dependent cognitive enhancing effects on the ID/ED task in patients with schizophrenia, and provides sufficient support for larger studies to test roflumilast’s role in improving cognitive flexibility deficits in this clinical population.

Chronic administration of antipsychotic drugs has been linked to structural brain changes observed in patients with schizophrenia. Recent MRI studies have shown rapid changes in regional brain volume following just a single dose of these drugs. However, it is not clear if these changes represent real volume changes or are artefacts ("apparent" volume changes) due to drug-induced physiological changes, such as increased cerebral blood flow (CBF). To address this, we examined the effects of a single, clinical dose of three commonly prescribed antipsychotics on quantitative measures of T1 and regional blood flow of the healthy human brain. Males (n = 42) were randomly assigned to one of two parallel groups in a double-blind, placebo-controlled, randomized, three-period cross-over study design. One group received a single oral dose of either 0.5 or 2 mg of risperidone or placebo during each visit. The other received olanzapine (7.5 mg), haloperidol (3 mg), or placebo. MR measures of quantitative T1, CBF, and T1-weighted images were acquired at the estimated peak plasma concentration of the drug. All three drugs caused localized increases in striatal blood flow, although drug and region specific effects were also apparent. In contrast, all assessments of T1 and brain volume remained stable across sessions, even in those areas experiencing large changes in CBF. This illustrates that a single clinically relevant oral dose of an antipsychotic has no detectable acute effect on T1 in healthy volunteers. We further provide a methodology for applying quantitative imaging methods to assess the acute effects of other compounds on structural MRI metrics. Hum Brain Mapp 39:319-331, 2018. © 2017 Wiley Periodicals, Inc.

As a result of neuro-vascular coupling, the functional effects of antipsychotics in human brain have been investigated in both healthy and clinical populations using haemodynamic markers such as regional Cerebral Blood Flow (rCBF). However, the relationship between observed haemodynamic effects and the pharmacological action of these drugs has not been fully established. Here, we analysed MRI-based rCBF data from a placebo-controlled study in healthy volunteers, who received a single dose of three different D2 receptor antagonists and tested the association of the main effects of the drugs on rCBF against normative population maps of D2R protein density and gene-expression data. In particular, we correlated CBF changes after antipsychotic administration with non-displaceable binding potential (BPND) template maps of the high affinity D2-antagonist Positron Emission Tomography (PET) ligand [18F]Fallypride and brain post-mortem microarray mRNA expression data for the DRD2 gene. For all antipsychotics, rCBF changes were directly proportional to brain D2R densities and DRD2 mRNA expression measures, although PET BPND spatial profiles explained more variance as compared with mRNA profiles (PET R2 range= 0.20-0.60, mRNA PET R2 range 0.04-0.20, pairwise-comparisons all p2R profiles varied between the different antipsychotics tested, possibly reflecting differential affinities. Overall, these results indicate that the functional effects of antipsychotics as measured with rCBF are tightly correlated with the distribution of their target receptors in striatal and extra-striatal regions. Our results further demonstrate the link between neurotransmitter targets and haemodynamic changes reinforcing rCBF as a robust in-vivo marker of drug effects. This work is important in bridging the gap between pharmacokinetic and pharmacodynamics of novel and existing compounds.

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.

Background Previous studies measuring cerebral blood flow (CBF) with magnetic resonance sequences like Arterial Spin Labelling (ASL) showed that patients with schizophrenia (SCZ) have increased CBF in basal ganglia and reduced blood flow in cortical areas like the prefrontal cortex. It is still not clear whether these abnormalities are related to antipsychotic treatment or rather they reflect a disease trait independent from medication. Interestingly, administration of single dose of antipsychotics in healthy volunteers produce marked functional effects that are in the same region reported as altered in SCZ. These effects are thought to depend on dopamine D2 receptor (D2R) blockade, although their relationship with antipsychotic pharmacodynamics has not been fully established yet. In fact, the haemodynamic nature of CBF measures makes difficult to interpret drug effects in terms of altered neurotransmission function. Here, we tested whether CBF changes induced by different antipsychotics mirror receptor distribution profiles of D2R. We evaluated the correlation of CBF variation with receptor density as measured with PET and brain mRNA expression extracted from the Allen Human Brain Atlas (ABA). Methods Forty-two healthy male subjects were enrolled in a double blind, randomized, placebo-controlled, crossover study. Participants were randomized in two equal parallel groups to receive a single dose of antipsychotic/placebo in three separate sessions. In Group 1 placebo, olanzapine 7.5mg (OLA) or haloperidol 3mg (HAL) were administered before the MRI scan. In Group 2 participants received placebo, 0.5mg (lowRIS) or 2mg (highRIS) of risperidone. Regional CBF was assessed with pseudo-continuous ASL (pCASL) sequence. For each antipsychotic, a paired T-test was performed in SPM12 with global CBF values as covariate of no interest. A template image of dopamine D2 receptor density was derived from 6 PET scans in healthy volunteers using the high affinity D2/D3 antagonist ligand [18F]-Fallypride. Brain mRNA expression values for DRD2 gene (coding for D2R) were extracted from the ABA dataset by using the MENGA toolbox. CBF contrast images and the [18F]Fallypride BPND template were segmented into 83 ROIs by using the Desikan-Killiany Atlas. The regional changes in CBF against placebo (∆CBF) were compared with regional BPND values and gene expression maps using multivariate correlations. Results For all antipsychotics, CBF changes in each ROI were directly proportional to [18F]Fallypride non displaceable binding potential (BPND) values (OLA R2= 0.24, HAL R2= 0.61, lowRIS R2= 0.54, highRIS R2= 0.52, all p

White matter disruption is an important determinant of cognitive impairment after brain injury, but conventional neuroimaging underestimates its extent. In contrast, diffusion tensor imaging provides a validated and sensitive way of identifying the impact of axonal injury. The relationship between cognitive impairment after traumatic brain injury and white matter damage is likely to be complex. We applied a flexible technique - tract-based spatial statistics - to explore whether damage to specific white matter tracts is associated with particular patterns of cognitive impairment. The commonly affected domains of memory, executive function and information processing speed were investigated in 28 patients in the post-acute/chronic phase following traumatic brain injury and in 26 age-matched controls. Analysis of fractional anisotropy and diffusivity maps revealed widespread differences in white matter integrity between the groups. Patients showed large areas of reduced fractional anisotropy, as well as increased mean and axial diffusivities, compared with controls, despite the small amounts of cortical and white matter damage visible on standard imaging. A stratified analysis based on the presence or absence of microbleeds (a marker of diffuse axonal injury) revealed diffusion tensor imaging to be more sensitive than gradient-echo imaging to white matter damage. The location of white matter abnormality predicted cognitive function to some extent. The structure of the fornices was correlated with associative learning and memory across both patient and control groups, whilst the structure of frontal lobe connections showed relationships with executive function that differed in the two groups. These results highlight the complexity of the relationships between white matter structure and cognition. Although widespread and, sometimes, chronic abnormalities of white matter are identifiable following traumatic brain injury, the impact of these changes on cognitive function is likely to depend on damage to key pathways that link nodes in the distributed brain networks supporting high-level cognitive functions. © 2011 The Author.

Recent studies have shown that drug‐induced spatial alteration patterns in resting state functional activity as measured using magnetic resonance imaging (rsfMRI) are associated with the distribution of specific receptor systems targeted by respective compounds. Based on this approach, we introduce a toolbox (JuSpace) allowing for cross‐modal correlation of MRI‐based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma‐aminobutric acid) neurotransmission. We apply JuSpace to two datasets covering Parkinson's disease patients (PD) and risperidone‐induced changes in rsfMRI and cerebral blood flow (CBF). Consistently with the predominant neurodegeneration of dopaminergic and serotonergic system in PD, we find significant spatial associations between rsfMRI activity alterations in PD and dopaminergic (D2) and serotonergic systems (5‐HT1b). Risperidone induced CBF alterations were correlated with its main targets in serotonergic and dopaminergic systems. JuSpace provides a biologically meaningful framework for linking neuroimaging to underlying neurotransmitter information., Here, we introduce the JuSpace toolbox allowing for cross‐modal correlation of MRI‐based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma‐aminobutric acid) neurotransmission. The toolbox provides a biologically meaningful framework for linking neuroimaging to underlying neurotransmitter information.