Brain Glutamate Dynamics Predict Positive Agency in Healthy Women: Insights from Combined Application of Pharmacological Challenge, Comprehensive Affective Assessment, and Magnetic Resonance Spectroscopy.

Contributions of brain glutamate (Glu) to conscious emotion are not well understood. Here, we evaluate the relationship of experimentally induced change in neocortical Glu (ΔGlu) and subjective states in well individuals, using combined application of pharmacological challenge, magnetic resonance spectroscopy (MRS), and comprehensive affective assessment. Drug challenge with d-amphetamine (AMP) (20 mg oral), methamphetamine (MA) (Desoxyn, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton MRS quantified neurometabolites in the right dorsal anterior cingulate cortex 140-150 min post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5 h on each session, yielding 3792 responses per participant (91,008 responses overall, N = 24 participants), with self-reports reduced by principal components analysis (PCA). PCA produced a primary factor score of AMP- and MA-induced positive agency (ΔPA). MRS indicated drug-induced ΔGlu related positively to ΔPA (ΔGluMA r = +0.44, p < 0.05, N = 21), with large effects in females (ΔGluMA r = +0.52, p < 0.05; ΔGluAMP r = +0.61, p < 0.05, N = 11). Subjective states related to ΔGlu included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect (r's = +0.51 to +0.74, p < 0.05), and alleviation of anxiety in females (r = -0.61, p < 0.05, N = 11). These self-reports correlated with ΔGlu to the extent they loaded on ΔPA (r = 0.95 AMP, p = 5 × 10-10; r = 0.63 MA, p = 0.0015, N = 11), indicating the coherence of ΔGlu effects on emotional states. Timing data indicated Glu shaped positive emotion both concurrently and prospectively, with no relationship with pre-MRS emotion (ΔGluAMP r = +0.59 to +0.65, p's < 0.05; ΔGluMA r = +0.53, p < 0.05, N = 11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, which are most readily observed in women. The findings illustrate the promise of combined application of pharmacological challenge, comprehensive affective assessment, and MRS neuroimaging techniques in basic and clinical studies.

Exposure to a sensory functional ingredient in the pig model modulates the blood-oxygen-level dependent brain responses to food odor and acute stress during pharmacological MRI in the frontostriatal and limbic circuits.

Introduction: In the present study, we examined the effects of a supplementation with a sensory functional ingredient (FI, D16729, Phodé, France) containing vanillin, furaneol, diacetyl and a mixture of aromatic fatty acids on the behavioural and brain responses of juvenile pigs to acute stress. Methods: Twenty-four pigs were fed from weaning with a standard granulated feed supplemented with the functional ingredient D16729 (FS animals, N = 12) or a control formulation (CT animals, N = 12). After a feed transition (10 days after weaning), the effects of FI were investigated on eating behaviour during two-choice feed preference tests. Emotional reactivity to acute stress was then investigated during openfield (OF), novel suddenly moving object (NSO), and contention tests. Brain responses to the FI and the two different feeds' odour, as well as to an acute pharmacological stressor (injection of Synacthen®) were finally investigated with functional magnetic resonance imaging (fMRI). Results: FS animals tended to spend more time above the functional feed (p = 0.06) and spent significantly more time at the periphery of the arena during NSO (p < 0.05). Their latency to contact the novel object was longer and they spent less time exploring the object compared to CT animals (p < 0.05 for both). Frontostriatal and limbic responses to the FI were influenced by previous exposure to FI, with higher activation in FS animals exposed to the FI feed odor compared to CT animals exposed to a similarly familiar feed odor without FI. The pharmacological acute stress provoked significant brain activations in the prefrontal and thalamic areas, which were alleviated in FS animals that also showed more activity in the nucleus accumbens. Finally, the acute exposure to FI in naive animals modulated their brain responses to acute pharmacological stress. Discussion: Overall, these results showed how previous habituation to the FI can modulate the brain areas involved in food pleasure and motivation while alleviating the brain responses to acute stress.

Intragastric fructose administration interacts with emotional state in homeostatic and hedonic brain regions.

Background: Interoceptive properties of food may influence emotional state and its neural basis, as shown for fatty acids but remains unstudied for carbohydrates.Objectives: To study the effects of fructose and its interaction with sad emotion on brain activity in homeostatic and hedonic regions and investigate whether gut hormone responses can explain effects.Design: In 15 healthy subjects, brain activity for 40min after intragastric infusion of fructose (25g) or water was recorded using a cross-over pharmacological magnetic resonance imaging (phMRI) paradigm. Sad or neutral emotional states were induced by classical music and emotional facial expressions. Emotional state was assessed using the Self-Assessment Manikin. Blood samples were taken to assess gut hormone levels. Brain responses to fructose versus placebo, sad versus neutral emotion, and their interaction were analyzed over time in a single mask of a priori defined regions of interest at a voxel-level threshold of pFWEcorrected <0.05. Effects on emotion and hormones were tested using linear mixed models.Results: No main effects of fructose, emotion, or fructose-by-emotion interaction on emotional ratings were observed. Main effects of fructose, emotion and aninteraction effect were found on brain activity (medulla, midbrain, hypothalamus, basal ganglia, anterior insula, orbitofrontal cortex, anterior cingulate cortex and amygdala). An increase in circulating GLP-1 after fructose in neutral emotion was abolished during sad emotion (fructose-by-emotion-by-time, p=0.041). Ghrelin levels were higher in sad emotion (time-by-emotion, p=0.037).Conclusions: Emotional state interacts with brain and endocrine responses to intragastric infusion of 25 g of fructose, however such an effect was not found at behavioral level.Trial registration: ClinicalTrials.gov identifier: NCT02946983.

Pharmacological MRI with Simultaneous Measurement of Cerebral Perfusion and Blood-Cerebrospinal Fluid Barrier Function using Interleaved Echo-Time Arterial Spin Labelling.

Pharmacological MRI (phMRI) studies seek to capture changes in brain haemodynamics in response to a drug. This provides a methodological platform for the evaluation of novel therapeutics, and when applied to disease states, may provide diagnostic or mechanistic information pertaining to common brain disorders such as dementia. Changes to brain perfusion and blood-cerebrospinal fluid barrier (BCSFB) function can be probed, non-invasively, by arterial spin labelling (ASL) and blood-cerebrospinal fluid barrier arterial spin labelling (BCSFB-ASL) MRI respectively. Here, we introduce a method for simultaneous recording of pharmacological perturbation of brain perfusion and BCSFB function using interleaved echo-time ASL, applied to the anesthetized mouse brain. Using this approach, we capture an exclusive decrease in BCSFB-mediated delivery of arterial blood water to ventricular CSF, following anti-diuretic hormone, vasopressin, administration. The commonly used vasodilatory agent, CO2, induced similar increases (~21%) in both cortical perfusion and the BCSFB-ASL signal. Furthermore, we present evidence that caffeine administration triggers a marked decrease in BCSFB-mediated labelled water delivery (41%), with no significant changes in cortical perfusion. Finally, we demonstrate a marked decrease in the functional response of the BCSFB to, vasopressin, in the aged vs adult brain. Together these data, the first of such kind, highlight the value of this translational approach to capture simultaneous and differential pharmacological modulation of vessel tone at the blood brain barrier and BCSFB and how this relationship may be modified in the ageing brain.

Imaging of the dopamine system with focus on pharmacological MRI and neuromelanin imaging.

The dopamine system in the brain is involved in a variety of neurologic and psychiatric disorders, such as Parkinson's disease, attention-deficit/hyperactivity disorder and psychosis. Different aspects of the dopamine system can be visualized and measured with positron emission tomography (PET) and single photon emission computed tomography (SPECT), including dopamine receptors, dopamine transporters, and dopamine release. New developments in MR imaging also provide proxy measures of the dopamine system in the brain, offering alternatives with the advantages MR imaging, i.e. no radiation, lower costs, usually less invasive and time consuming. This review will give an overview of these developments with a focus on the most developed techniques: pharmacological MRI (phMRI) and neuromelanin sensitive MRI (NM-MRI). PhMRI is a collective term for functional MRI techniques that administer a pharmacological challenge to assess its effects on brain hemodynamics. By doing so, it indirectly assesses brain neurotransmitter function such as dopamine function. NM-MRI is an upcoming MRI technique that enables in vivo visualization and semi-quantification of neuromelanin in the substantia nigra. Neuromelanin is located in the cell bodies of dopaminergic neurons of the nigrostriatal pathway and can be used as a proxy measure for long term dopamine function or degeneration of dopaminergic neurons. Both techniques are still primarily used in clinical research, but there is promise for clinical application, in particular for NM-MRI in dopaminergic neurodegenerative diseases like Parkinson's disease.

Neurochemical underpinning of hemodynamic response to neuropsychiatric drugs: A meta- and cluster analysis of preclinical studies.

Functional magnetic resonance imaging (fMRI) is an extensively used method for the investigation of normal and pathological brain function. In particular, fMRI has been used to characterize spatiotemporal hemodynamic response to pharmacological challenges as a non-invasive readout of neuronal activity. However, the mechanisms underlying regional signal changes are yet unclear. In this study, we use a meta-analytic approach to converge data from microdialysis experiments with relative cerebral blood volume (rCBV) changes following acute administration of neuropsychiatric drugs in adult male rats. At whole-brain level, the functional response patterns show very weak correlation with neurochemical alterations, while for numerous brain areas a strong positive correlation with noradrenaline release exists. At a local scale of individual brain regions, the rCBV response to neurotransmitters is anatomically heterogeneous and, importantly, based on a complex interplay of different neurotransmitters that often exert opposing effects, thus providing a mechanism for regulating and fine tuning hemodynamic responses in specific regions.

Targeting migraine treatment with neuroimaging-Pharmacological neuroimaging in headaches.

PURPOSE: The current review provides a recapitulation of recent advances in pharmacological neuroimaging in headache, a promising tool to understanding of how a drug works in the brain and how it may lead to new insights of disease mechanisms of headache. RESULTS: Pharmacological positron emission tomography with radioligand-labeled medication may provide evidence whether and where a medication binds in the brain but is still mostly restricted to animal work. Pharmacological functional MRI using task-specific approaches identified central modulation patterns as a consequence of attack and preventative headache medication, which may be distinct to a specific drug mechanism. Pharmacological neuroimaging and specifically in combination with functional imaging is a promising tool to better understand not only certain medications but also certain disease mechanisms. SUMMARY: Pharmacological imaging techniques have advanced over the last few years and showed great potential of providing new insights into drug pharmacodynamics and disease mechanism. There are still limitations and challenges to be overcome.

Pharmacological MRI responses of raclopride in rats: The relationship with D2 receptor occupancy and cataleptic behavior.

Pharmacological magnetic resonance imaging (phMRI) allows the visualization of brain pharmacological effects of drugs using functional MRI (fMRI). phMRI can help us facilitate central nervous system (CNS) drug development. However, there have been few studies demonstrating the dose relationship of the fMRI response induced by CNS drugs to underlying target engagement or behavioral efficacy. To clarify these relationships, we examined receptor occupancy measurements using positron emission tomography (PET) (n = 3~5), fMRI (n = 5~8) and a cataleptic behavior (n = 6) with raclopride, a dopamine D2 receptor antagonist (8, 20, and 200 µg/kg) on Wistar rats. Dopamine D2 receptor occupancy was increased dose dependently by raclopride (41.8 ± 2.7%, 8 µg/kg; 64.9 ± 2.8%, 20 µg/kg; 83.1 ± 3.0%, 200 µg/kg). phMRI study revealed significant positive responses to raclopride at 200 µg/kg specifically in the striatum and nucleus accumbens, related to dopaminergic system. Slight fMRI responses were observed at 20 µg/kg in some areas corresponding to the striatum and nucleus accumbens. There were no noticeable fMRI responses at 8 µg/kg raclopride administration. Raclopride at 200 µg/kg significantly increased the cataleptic score, although, at 8 and 20 µg/kg, raclopride had no significant effects. These findings showed that raclopride-induced fMRI responses were observed at doses inducing cataleptic behavior and high D2 receptor occupancy, suggesting that phMRI can be useful for dose selection in clinical trial as an evaluation method of brain activity, which reflects behavioral responses induced by target engagements.

(R)- and (S)-ketamine induce differential fMRI responses in conscious rats.

(R,S)-ketamine exerts robust antidepressant effects in patients with depression when given at sub-anesthetic doses. Each of the enantiomers in this racemic mixture, (R)-ketamine and (S)-ketamine, have been reported to exert antidepressant effects individually. However, the neuropharmacological effects of these enantiomers and the mechanisms underlying their antidepressive actions have not yet been fully elucidated. Therefore, we investigated the effect of (R,S)-, (R)-, and (S)-ketamine on brain activity by functional MRI (fMRI) in conscious rats and compared these with that of N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 (n = 5~7). We also assessed their pharmacokinetic profiles (n = 4) and their behavioral effects (n = 7~9). This pharmacological MRI study revealed a significant positive response to (S)-ketamine specifically in the cortex, nucleus accumbens and striatum. In contrast, negative fMRI responses were observed in various brain regions after (R)-ketamine administration. (R,S)-ketamine, evoked significant positive fMRI responses specifically in the cortex, nucleus accumbens and striatum, and this fMRI response pattern was comparable with that of (S)-ketamine. MK-801-induced similar fMRI response pattern to (S)-ketamine. The fMRI responses to (S)-ketamine and MK-801 showed differential temporal profiles, which corresponded with brain concentration profiles. (S)-ketamine and MK-801 significantly increased locomotor activity, while (R)-ketamine produced no noticeable change. (R,S)-ketamine tended to increase locomotor activity. Our novel fMRI findings show that (R)-ketamine and (S)-ketamine induce completely different fMRI response patterns on rat, and that the response produced by the latter is similar to that elicited by an NMDAR antagonist. Our findings provide insight into the antidepressant mechanism of (R,S)-ketamine.

Effects of ketamine treatment on cocaine-induced reinstatement and disruption of functional connectivity in unanesthetized rhesus monkeys.

RATIONALE: Substance use disorders are characterized by a loss of executive control over reward-based decision-making, and disruption of fronto-striatal connectivity has been implicated in this process. Sub-anesthetic ketamine has recently been shown to bolster fronto-striatal connectivity in drug-naïve subjects. OBJECTIVES: The influence of ketamine treatment was examined on the disruptive effects of cocaine on functional connectivity (FC) and on cocaine-seeking behavior in female rhesus monkeys. METHODS: Three female rhesus were trained for unanesthetized MRI scanning. Each received three drug-naïve/abstinent pharmacological MRI scans with acute injections of saline, cocaine (0.3 mg/kg i.v.), and cocaine (0.3 mg/kg i.v.) 48-h after a ketamine treatment (low dose = 0.345 mg/kg bolus + 0.256 mg/kg/h for 1 h; i.v.), and a fourth scan with saline injection following 2 months of daily cocaine self-administration. A separate cohort of five rhesus (4 female), all with extensive histories of cocaine exposure, underwent reinstatement testing 48 h after ketamine (or vehicle) treatment. Two sub-anesthetic doses were tested: low dose and high dose = 0.69 mg/kg + 0.512 mg/kg/h for 1 h. RESULTS: Ketamine treatment attenuated the effects of cocaine on both global and fronto-striatal FC in drug-naïve/abstinent subjects. Two months of daily cocaine self-administration led to prolonged disruption of both global and fronto-striatal FC. Cocaine-seeking behavior during reinstatement was reduced following ketamine treatment at the low dose, but not high dose. CONCLUSION: These findings illustrate the disruptive effects of cocaine on functional connectivity and provide evidence for the potential efficacy of ketamine as a treatment for stimulant use disorder.

Validations of apomorphine-induced BOLD activation correlations in hemiparkinsonian rhesus macaques.

Identification of Parkinson's disease at the earliest possible stage of the disease may provide the best opportunity for the use of disease modifying treatments. However, diagnosing the disease during the pre-symptomatic period remains an unmet goal. To that end, we used pharmacological MRI (phMRI) to assess the function of the cortico-basal ganglia circuit in a non-human primate model of dopamine deficiency to determine the possible relationships between phMRI signals with behavioral, neurochemical, and histological measurements. Animals with unilateral treatments with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), that expressed stable, long-term hemiparkinsonism were challenged with the dopaminergic receptor agonist, apomorphine, and structure-specific phMRI blood oxygen level-dependent (BOLD) activation responses were measured. Behavioral, histopathological, and neurochemical measurements were obtained and correlated with phMRI activation of structures of the cortico-basal ganglia system. Greater phMRI activations in the basal ganglia and cortex were associated with slower movement speed, decreased daytime activity, or more pronounced parkinsonian features. Animals showed decreased stimulus-evoked dopamine release in the putamen and substantia nigra pars compacta and lower basal glutamate levels in the motor cortex on the MPTP-lesioned hemisphere compared to the contralateral hemisphere. The altered neurochemistry was significantly correlated with phMRI signals in the motor cortex and putamen. Finally, greater phMRI activations in the caudate nucleus correlated with fewer tyrosine hydroxylase-positive (TH+) nigral cells and decreased TH+ fiber density in the putamen. These results reveal the correlation of phMRI signals with the severity of the motor deficits and pathophysiological changes in the cortico-basal ganglia circuit.

Temporal dynamics of the pharmacological MRI response to subanaesthetic ketamine in healthy volunteers: A simultaneous EEG/fMRI study.

BACKGROUND: Pharmacological magnetic resonance imaging has been used to investigate the neural effects of subanaesthetic ketamine in healthy volunteers. However, the effect of ketamine has been modelled with a single time course and without consideration of physiological noise. AIMS: This study aimed to investigate ketamine-induced alterations in resting neural activity using conventional pharmacological magnetic resonance imaging analysis techniques with physiological noise correction, and a novel analysis utilising simultaneously recorded electroencephalography data. METHODS: Simultaneous electroencephalography/functional magnetic resonance imaging and physiological data were collected from 30 healthy male participants before and during a subanaesthetic intravenous ketamine infusion. RESULTS: Consistent with previous literature, we show widespread cortical blood-oxygen-level dependent signal increases and decreased blood-oxygen-level dependent signals in the subgenual anterior cingulate cortex following ketamine. However, the latter effect was attenuated by the inclusion of motion regressors and physiological correction in the model. In a novel analysis, we modelled the pharmacological magnetic resonance imaging response with the power time series of seven electroencephalography frequency bands. This showed evidence for distinct temporal time courses of neural responses to ketamine. No electroencephalography power time series correlated with decreased blood-oxygen-level dependent signal in the subgenual anterior cingulate cortex. CONCLUSIONS: We suggest the decrease in blood-oxygen-level dependent signals in the subgenual anterior cingulate cortex typically seen in the literature is the result of physiological noise, in particular cardiac pulsatility. Furthermore, modelling the pharmacological magnetic resonance imaging response with a single temporal model does not completely capture the full spectrum of neuronal dynamics. The use of electroencephalography regressors to model the response can increase confidence that the pharmacological magnetic resonance imaging is directly related to underlying neural activity.

Intragastric quinine administration decreases hedonic eating in healthy women through peptide-mediated gut-brain signaling mechanisms.

Objectives: Intragastric bitter tastants may decrease appetite and food intake. We aimed to investigate the gut-brain signaling and brain mechanisms underlying these effects.Methods: Brain responses to intragastric quinine-hydrochloride (QHCl, 10 µmol/kg) or placebo infusion were recorded using functional magnetic resonance imaging in 15 healthy women. Appetite-related sensations, plasma levels of gastrointestinal hormones and hedonic food intake (ad libitum drink test) were assessed.Results: Lower octanoylated ghrelin (P<0.04), total ghrelin (P<0.01), and motilin (P<0.01) plasma levels were found after QHCl administration, along with lower prospective food consumption ratings (P<0.02) and hedonic food intake (P<0.05). QHCl increased neural activity in the hypothalamus and hedonic (anterior insula, putamen, caudate, pallidum, amygdala, anterior cingulate cortex, orbitofrontal cortex, midbrain) regions, but decreased activity in the homeostatic medulla (all pFWE-corrected<0.05). Differential brain responses to QHCl versus placebo covaried with subjective and hormonal responses and predicted differences in hedonic food intake.Discussion: Intragastric QHCl decreases prospective and actual food intake in healthy women by interfering with homeostatic and hedonic brain circuits in a ghrelin- and motilin-mediated fashion. These findings suggest a potential of bitter tastants to reduce appetite and food intake, through the gut-brain axis.

Effects of dexamphetamine-induced dopamine release on resting-state network connectivity in recreational amphetamine users and healthy controls.

Dexamphetamine (dAMPH) is not only used for the treatment of attention deficit hyperactivity disorder (ADHD), but also as a recreational drug. Acutely, dAMPH induces release of predominantly dopamine (DA) in the striatum, and in the cortex both DA and noradrenaline. Recent animal studies have shown that chronic dAMPH administration can induce changes in the DA system following long-term exposure, as evidenced by reductions in DA transporters, D2/3 receptors and endogenous DA levels. However, only a limited number of studies have investigated the effects of dAMPH in the human brain. We used a combination of resting-state functional magnetic resonance imaging (rs-fMRI) and [(123)I]IBZM single-photon emission computed tomography (SPECT) (to assess baseline D2/3 receptor binding and DA release) in 15 recreational AMPH users and 20 matched healthy controls to investigate the short-, and long-term effects of AMPH before and after an acute intravenous challenge with dAMPH. We found that acute dAMPH administration reduced functional connectivity in the cortico-striatal-thalamic network. dAMPH-induced DA release, but not DA D2/3 receptor binding, was positively associated with connectivity changes in this network. In addition, acute dAMPH reduced connectivity in default mode networks and salience-executive-networks networks in both groups. In contrast to our hypothesis, no significant group differences were found in any of the rs-fMRI networks investigated, possibly due to lack of sensitivity or compensatory mechanisms. Our findings thus support the use of ICA-based resting-state functional connectivity as a tool to investigate acute, but not chronic, alterations induced by dAMPH on dopaminergic processing in the striatum.

Ketamine-induced brain activation in awake female nonhuman primates: a translational functional imaging model.

RATIONALE: There is significant interest in the NMDA receptor antagonist ketamine due to its efficacy in treating depressive disorders and its induction of psychotic-like symptoms that make it a useful tool for modeling psychosis. OBJECTIVE: The present study extends the successful development of an apparatus and methodology to conduct pharmacological MRI studies in awake rhesus monkeys in order to evaluate the CNS effects of ketamine. METHODS: Functional MRI scans were conducted in four awake adult female rhesus monkeys during sub-anesthetic intravenous (i.v.) infusions of ketamine (0.345 mg/kg bolus followed by 0.256 mg/kg/h constant infusion) with and without risperidone pretreatment (0.06 mg/kg). Statistical parametric maps of ketamine-induced blood oxygenation level-dependent (BOLD) activation were obtained with appropriate general linear regression models (GLMs) incorporating motion and hemodynamics of ketamine infusion. RESULTS: Ketamine infusion induced and sustained robust BOLD activation in a number of cortical and subcortical regions, including the thalamus, cingulate gyrus, and supplementary motor area. Pretreatment with the antipsychotic drug risperidone markedly blunted ketamine-induced activation in many brain areas. CONCLUSIONS: The results are remarkably similar to human imaging studies showing ketamine-induced BOLD activation in many of the same brain areas, and pretreatment with risperidone or another antipsychotic blunting the ketamine response to a similar extent. The strong concordance of the functional imaging data in humans with these results from nonhuman primates highlights the translational value of the model and provides an excellent avenue for future research examining the CNS effects of ketamine. This model may also be a useful tool for evaluating the efficacy of novel antipsychotic drugs.

Estimating multivariate similarity between neuroimaging datasets with sparse canonical correlation analysis: an application to perfusion imaging.

An increasing number of neuroimaging studies are based on either combining more than one data modality (inter-modal) or combining more than one measurement from the same modality (intra-modal). To date, most intra-modal studies using multivariate statistics have focused on differences between datasets, for instance relying on classifiers to differentiate between effects in the data. However, to fully characterize these effects, multivariate methods able to measure similarities between datasets are needed. One classical technique for estimating the relationship between two datasets is canonical correlation analysis (CCA). However, in the context of high-dimensional data the application of CCA is extremely challenging. A recent extension of CCA, sparse CCA (SCCA), overcomes this limitation, by regularizing the model parameters while yielding a sparse solution. In this work, we modify SCCA with the aim of facilitating its application to high-dimensional neuroimaging data and finding meaningful multivariate image-to-image correspondences in intra-modal studies. In particular, we show how the optimal subset of variables can be estimated independently and we look at the information encoded in more than one set of SCCA transformations. We illustrate our framework using Arterial Spin Labeling data to investigate multivariate similarities between the effects of two antipsychotic drugs on cerebral blood flow.

Pharmacological MRI (phMRI) of the Human Central Nervous System.

Pharmacological magnetic resonance imaging (phMRI) of the central nervous system (CNS) addresses the increasing demands in the biopharma industry for new methods that can accurately predict, as early as possible, whether novel CNS agents will be effective and safe. Imaging of physiological and molecular-level function can provide a more direct measure of a drug mechanism of action, enabling more predictive measures of drug activity. The availability of phMRI of the nervous system within the professional infrastructure of the Clinical Research Center (CRC) Hannover as proof of concept center ensures that advances in basic science progress swiftly into benefits for patients. Advanced standardized MRI techniques including quantitative MRI, kurtosis determination, functional MRI, and spectroscopic imaging of the entire brain are necessary for phMRI. As a result, MR scanners will evolve into high-precision measuring instruments for assessment of desirable and undesirable effects of drugs as the basic precondition for individually tailored therapy. The CRC's Imaging Unit with high-end large-scale equipment will allow the following unique opportunities: for example, identification of MR-based biomarkers to assess the effect of drugs (surrogate parameters), establishment of normal levels and reference ranges for MRI-based biomarkers, evaluation of the most relevant MRI sequences for drug monitoring in outpatient care. Another very important prerequisite for phMRI is the MHH Core Facility as the scientific and operational study unit of the CRC partner Hannover Medical School. This unit is responsible for the study coordination, conduction, complete study logistics, administration, and application of the quality assurance system based on required industry standards.

Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain.

The development of pharmacological magnetic resonance imaging (phMRI) has presented the opportunity for investigation of the neurophysiological effects of drugs in vivo. Psilocin, a hallucinogen metabolised from psilocybin, was recently reported to evoke brain region-specific, phMRI signal changes in humans. The present study investigated the effects of psilocin in a rat model using phMRI and then probed the relationship between neuronal and haemodynamic responses using a multimodal measurement preparation. Psilocin (2 mg/kg or 0.03 mg/kg i.v.) or vehicle was administered to rats (N=6/group) during either phMRI scanning or concurrent imaging of cortical blood flow and recording of local field potentials. Compared to vehicle controls psilocin (2 mg/kg) evoked phMRI signal increases in a number of regions including olfactory and limbic areas and elements of the visual system. PhMRI signal decreases were seen in other regions including somatosensory and motor cortices. Investigation of neurovascular coupling revealed that whilst neuronal responses (local field potentials) to sensory stimuli were decreased in amplitude by psilocin administration, concurrently measured haemodynamic responses (cerebral blood flow) were enhanced. The present findings show that psilocin evoked region-specific changes in phMRI signals in the rat, confirming recent human data. However, the results also suggest that the haemodynamic signal changes underlying phMRI responses reflect changes in both neuronal activity and neurovascular coupling. This highlights the importance of understanding the neurovascular effects of pharmacological manipulations for interpreting haemodynamic neuroimaging data.

"Domain gauges": A reference system for multivariate profiling of brain fMRI activation patterns induced by psychoactive drugs in rats.

Pharmacological magnetic resonance imaging (phMRI) of the brain has become a widely used tool in both preclinical and clinical drug research. One of its challenges is to condense the observed complex drug-induced brain-activation patterns into semantically meaningful metrics that can then serve as a basis for informed decision making. To aid interpretation of spatially distributed activation patterns, we propose here a set of multivariate metrics termed "domain gauges", which have been calibrated based on different classes of marketed or validated reference drugs. Each class represents a particular "domain" of interest, i.e., a specific therapeutic indication or mode of action. The drug class is empirically characterized by the unique activation pattern it evokes in the brain-the "domain profile". A domain gauge provides, for any tested intervention, a "classifier" as a measure of response strength with respect to the domain in question, and a "differentiator" as a measure of deviation from the domain profile, both along with error ranges. Capitalizing on our in-house database with an unprecedented wealth of standardized perfusion-based phMRI data obtained from rats subjected to various validated treatments, we exemplarily focused on 3 domains based on therapeutic indications: an antipsychotic, an antidepressant and an anxiolytic domain. The domain profiles identified as part of the gauge definition process, as well as the outputs of the gauges when applied to both reference and validation data, were evaluated for their reconcilability with prior biological knowledge and for their performance in drug characterization. The domain profiles provided quantitative activation patterns with high biological plausibility. The antipsychotic profile, for instance, comprised key areas (e.g., cingulate cortex, nucleus accumbens, ventral tegmental area, substantia nigra) which are believed to be strongly involved in mediating an antipsychotic effect, and which are in line with network-level dysfunctions observed in schizophrenia. The domain gauges plausibly positioned the vast majority of the pharmacological and even non-pharmacological treatments. The results also suggest the segregation of sub-domains based on, e.g., the mode of action. Upon judicious selection of domains and careful calibration of the gauges, our approach represents a valuable analytical tool for biological interpretation and decision making in drug discovery.

Pharmacological MRI response to a selective dopamine transporter inhibitor, GBR12909, in awake and anesthetized rats.

Pharmacological magnetic resonance imaging (phMRI) is a powerful tool for imaging the effects of drugs on brain activity. In preclinical phMRI studies, general anesthesia used for minimizing head movements is thought to influence the phMRI responses to drugs. In this study we investigated the phMRI responses to a selective dopamine transporter (DAT) inhibitor, GBR12909, and a dopamine (DA) releaser, d-amphetamine (AMPH), in the isoflurane anesthetized and awake rats using a relative cerebral blood volume (rCBV) method. AMPH (1 mg/kg i.p.) caused an increase in rCBV in the dopaminergic circuitry in the both anesthetized and awake rats. The striatal rCBV change was correlated with the change of the striatal DA concentration induced by AMPH in the both anesthetized and awake rats. GBR12909 (10 mg/kg i.p.) caused a positive rCBV response and showed a similar regional pattern of rCBV response to AMPH in the awake rats, and the correlation between the change of the striatal rCBV and the striatal DA concentration was observed. However, in the anesthetized rats, GBR12909 induced a widespread negative rCBV response, whereas an increase in striatal DA concentration was observed. These findings indicate that phMRI responses to activation of DA neurotransmission by GBR12909 or AMPH are overall identical in the awake state, while the phMRI response to a DAT inhibitor, GBR12909 but not to AMPH was changed by isoflurane anesthesia. For the evaluation of neuroactive drugs using phMRI, isoflurane anesthesia might be complicated the interpretation of pharmacodynamic effects of drugs in preclinical studies.