Pharmacological fMRI Study Research Articles

Alcohol induced region-dependent alterations of hemodynamic response: implications for the statistical interpretation of pharmacological fMRI studies

Worldwide, ethanol abuse causes thousands of fatal accidents annually as well as innumerable social dysfunctions and severe medical disorders. Yet, few studies have used the blood oxygenation level dependent functional magnetic resonance imaging method (BOLD fMRI) to map how alcohol alters brain functions, as fMRI relies on neurovascular coupling, which may change due to the vasoactive properties of alcohol. We monitored the hemodynamic response function (HRF) with a high temporal resolution. In both motor cortices and the visual cortex, alcohol prolonged the time course of the HRF, indicating an overall slow-down of neurovascular coupling rather than an isolated reduction in neuronal activity. However, in the supplementary motor area, alcohol-induced changes to the HRF suggest a reduced neuronal activation. This may explain why initiating and coordinating complex movements, including speech production, are often impaired earlier than executing basic motor patterns. Furthermore, the present study revealed a potential pitfall associated with the statistical interpretation of pharmacological fMRI studies based on the general linear model: if the functional form of the HRF is changed between the conditions data may be erroneously interpreted as increased or decreased neuronal activation. Thus, our study not only presents an additional key to how alcohol affects the network of brain functions but also implies that potential changes to neurovascular coupling have to be taken into account when interpreting BOLD fMRI. Therefore, measuring individual drug-induced HRF changes is recommended for pharmacological fMRI.

Neuromodulation of Performance Monitoring

Event Abstract Back to Event Neuromodulation of Performance Monitoring Markus Ullsperger1* 1 Radboud University Nijmegen, Donders Institute for Brain, Netherlands For goal-directed behavior it is essential to continuously monitor action outcomes that in turn guide subsequent decision making. After a short overview of the functional neuroanatomy I will present recent data on the role of neuromodulators such as dopamine in performance monitoring and resulting subsequent adjustments. The posterior mesial frontal cortex (pMFC) has been consistently implicated in monitoring action outcomes for deviations from the goals and in signaling the need for adjustments. Recent evidence suggests that adjustments are not just driven by one negative action outcome but are a function of reinforcement history. It appears that the pMFC encodes the updating of action values based on the statistical properties of a changeable reward environment. In reinforcement learning, action values are updated based on the prediction error, which has been shown to be coded by phasic responses of the dopaminergic system. To study the role of dopamine (DA) in performance monitoring we investigated the influence of a genetic polymorphism of the DA D2 receptor gene on behavior and brain activity in reinforcement learning tasks with fMRI. Carriers of an allele associated with lower striatal D2 receptor density showed decreased responses of the pMFC to negative action outcomes, less interaction of this region with the ventral striatum and the hippocampus, and reduced learning to avoid actions with negative consequences. In reversal learning, this allele was associated with increased switching behavior, reduced increase of pMFC activity with accumulating evidence for a rule switch, and reduced ventral striatal and orbitofrontal switch-related activity. In a recent pharmacological fMRI study, treatment with the D2 antagonist amisulpride modulated reward-based learning and associated activity in the ventromedial prefrontal cortex. Increased value-related activity in this region under amisulpride was associated with enhanced discrimination of competing positive choices. In the presentation, I will integrate these findings in a larger framework of performance monitoring and resulting learning and discuss the interactions of the pMFC with the ventral striatum and the ventromedial prefrontal cortex and their modulation by DA in this context. Keywords: Decision Making, Performance monitoring, Posterior mesial frontal cortex (pMFC) Conference: Decision Neuroscience From Neurons to Societies, Berlin, Germany, 23 Sep - 25 Sep, 2010. Presentation Type: Speaker Topic: Abstracts Citation: Ullsperger M (2010). Neuromodulation of Performance Monitoring. Front. Neurosci. Conference Abstract: Decision Neuroscience From Neurons to Societies. doi: 10.3389/conf.fnins.2010.82.00027 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Aug 2010; Published Online: 07 Sep 2010. * Correspondence: Dr. Markus Ullsperger, Radboud University Nijmegen, Donders Institute for Brain, Nijmegen, Netherlands, m.ullsperger@donders.ru.nl Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Markus Ullsperger Google Markus Ullsperger Google Scholar Markus Ullsperger PubMed Markus Ullsperger Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Evidence for glutamatergic neurotransmission in cognitive control in an auditory attention task

There is little knowledge regarding the underlying mediating factors for cognitive control at the synaptic level, especially the role played by glutamatergic neurotransmission. In the current study the effect of the NMDA receptor antagonist memantine was examined in a pharmacological fMRI study. Thirty-one healthy adults were scanned twice in a counter-balanced design, either drug naïve or after administration of memantine for 21 days, to build up a steady-state plasma concentration in all participants. The participants performed an auditory attention control task while in the MR scanner. The results showed significant reduction in activation in prefrontal cortex and anterior cingulate cortex after memantine administration compared to the drug naïve session. We suggest that the present results may have implications for the understanding of deficits in cognitive control in psychiatric disorders, like schizophrenia, through altered glutamatergic neurotransmission.

Switching schizophrenia patients from typical neuroleptics to olanzapine: Effects on BOLD response during attention and working memory

Dysfunctional activation of the dorsolateral prefrontal cortex (DLPFC) during working memory (WM) in schizophrenia patients has repeatedly been observed, however little is known about specific medication effects on the modulation of DLPFC activation. We measured activation of DLPFC during a WM task in a longitudinal fMRI study in ten schizophrenia patients first when they received conventional antipsychotics (T1) and a second time after they had been switched to olanzapine (T2). A healthy control group matched for age, handedness and gender was investigated at two corresponding time points. We analyzed the fMRI data with SPM5 in a 2 × 2 × 2 design (group × session × task). Schizophrenia patients showed fewer correct responses compared to healthy controls at both time points. The fMRI data revealed a significant group by task interaction in the bilateral DLPFC and the right parietal cortex, indicating a reduced BOLD response in the patient group. After switching to olanzapine, schizophrenia patients displayed a significant increase in the BOLD response during the 0-back condition in the DLPFC. This study showed that switching patients from conventional neuroleptics to olanzapine did not significantly alter the frontal or parietal BOLD response during working memory task. However, medication status had influences on the activation during attentional task (0-back), emphasizing the importance of baseline selection in pharmacological fMRI studies.

The effect of a serotonine agonist on neural activity and BOLD activity in monkey primary visual cortex, a pharmacological fMRI (PhMRI) study

The effect of a serotonine agonist on neural activity and BOLD activity in monkey primary visual cortex, a pharmacological fMRI (PhMRI) study

Regional brain activity after prolonged cholinergic enhancement in early Alzheimer's disease

This functional magnetic resonance imaging (fMRI) study examined changes in brain activation after prolonged (20 weeks) and stabilized treatment with the cholinesterase inhibitor galantamine in a small group of patients with very mild Alzheimer's disease (AD). Two cognitive activation paradigms were chosen: one requiring semantic association and the other relying on attention and requiring target detection. A group of age- and education-matched healthy controls was also scanned for comparison. A modest (but not statistically significant) improvement in behavioral scores after treatment was observed in both fMRI tasks. There were brain activation increases in the semantic association task after treatment, and the differences in brain activation present in the comparison of AD patients' baseline images with those of controls were not detectable after treatment. In the target detection task, regions that were activated in the elderly controls but not in the baseline images of the AD group also showed significant activation after treatment. Overall, however, the increases were modest and might reflect the heterogeneity of clinical response to treatment in this small group. Future pharmacological fMRI studies should include clinical response as a factor in the analysis of cholinergic enhancement effects in AD patients.

The role of fMRI in drug discovery

Pharmacological functional (phMRI) studies are making a significant contribution to our understanding of drug-effects on brain systems. Pharmacological fMRI has an additional contribution to make in the translation of disease models and candidate compounds from preclinical to clinical investigation and in the early clinical stages of drug development. Here it can demonstrate a proof-of-concept of drug action in a small human cohort and thus contribute substantially to decision-making in drug development. We review the methods underlying pharmacological fMRI studies and the links that can be made between animal and human investigations. We discuss the potential fMRI markers of drug effect, experimental designs and caveats in interpreting hemodynamic fMRI data as reflective of changes in neuronal activity. Although there are no current published examples of fMRI applied to novel compounds, we illustrate the potential of fMRI across a range of applications and with specific reference to processing of pain in the human brain and pharmacological analgesia. Pharmacological fMRI is developing to meet the neuroscientific challenges. Electrophysiological methods can be used to corroborate the drug effects measured hemodynamically with fMRI. In future, pharmacological fMRI is likely to extend to examinations of the spinal cord and into pharmacogenetics to relate genetic polymorphisms to differential responses of the brain to drugs.

Raloxifene Treatment Enhances Brain Activation during Recognition of Familiar Items: a Pharmacological fMRI Study in Healthy Elderly Males

Raloxifene is a selective estrogen receptor modulator that may delay the onset of mild cognitive impairment in elderly women. Effects of raloxifene treatment on mental performance in males remain to be investigated. In a previous functional magnetic resonance imaging (fMRI) study, we showed that raloxifene treatment enhanced brain activation in elderly males during encoding of new information (faces) into memory. The current study used fMRI in the same group of subjects to screen for effects of raloxifene treatment on brain function during face recognition. Healthy elderly males (n=28; mean age 63.6 years, SD 2.4) were scanned at baseline and after 3 months of treatment with either raloxifene 120 mg (n=14) or placebo (n=14) in a randomized, double-blind, placebo-controlled study design. Functional data were analyzed in an event-related fashion with respect to correct hits and correct rejections using FSL software. Performance data were analyzed with respect to recognition accuracy, latency, and response bias. Functional effects of treatment were found on brain activation related to correct hits only. When compared to placebo treatment, raloxifene treatment enhanced brain activation in the left posterior parahippocampal area (Z=3.9) and right inferior prefrontal cortex (Z=3.5). Recognition accuracy scores remained stable in the raloxifene group, whereas the placebo group showed a small but significant decrease in accuracy scores (p=0.02). No significant effects were found on response bias or latency. In conclusion, raloxifene treatment affects brain function during memory performance in a way that may reflect increased arousal during initial encoding, with downstream effects on brain function during retrieval of information. Behaviorally, such neurofunctional effects may actively block decreased memory performance as a result of context-dependency. The validity of these predictions can be tested in large-scale clinical trials.

Cholinergic challenge in Alzheimer patients and mild cognitive impairment differentially affects hippocampal activation—a pharmacological fMRI study

Pharmacological functional MRI (phMRI) examines the impact of pharmacologically induced neurochemical changes on brain function at a system level. The current phMRI study directly compared effects of cholinergic stimulation on brain function between patients with Alzheimer's disease and mild cognitive impairment, a disease stage preceding the development of Alzheimer's disease. Brain function during recognition of (un)familiar information was examined for changes after exposure to galantamine, a cholinesterase inhibitor used for treating memory deficits in Alzheimer's disease. Alzheimer patients [n = 18; age 74.5 years +/- 8.2; Mini-Mental State Examination (MMSE) 22.5 +/- 2.4] and patients with mild cognitive impairment (n = 28; mean age 73.6 +/- 7.5; MMSE 27.0 +/- 1.2) were scanned during face recognition under three different conditions: at baseline, and after acute (single dose) and prolonged exposure (5 days) to galantamine. Functional data were analysed in an event-related fashion. In both groups, acute exposure produced strong increases in brain activation (Z > 3.1). Prolonged exposure produced less strong effects that mainly involved decreases in activation (Z > 3.1). In mild cognitive impairment, acute exposure increased activation in posterior cingulate, left inferior parietal, and anterior temporal lobe. Prolonged exposure decreased activation in similar posterior cingulate areas, and in bilateral prefrontal areas. Effects were stronger for positive ('familiar') than for negative ('unfamiliar') decisions, indicating that the effect was specific to memory retrieval. In Alzheimer patients, acute exposure increased activation bilaterally in hippocampal areas, whereas prolonged exposure decreased activation in these areas. Effects were more pronounced for negative than for positive decisions, suggesting a preferential effect on memory encoding. Unique profiles of signal reactivity were found in a number of areas, including left inferior parietal lobe and left hippocampus proper. The reactivity of posterior cingulate and hippocampal structures to cholinergic challenge suggests a key role of the cholinergic system in the functional processes that lead to Alzheimer's disease. The differential response to cholinergic challenge in mild cognitive impairment and Alzheimer patients may reflect a difference in the functional status of the cholinergic system between both groups, which is in line with recent results showing a differential clinical response to cholinergic treatment.

Effects of dopaminergic and serotonergic manipulation on emotional processing: A pharmacological fMRI study

Recent neuroimaging studies have demonstrated abnormal central emotional processing in psychiatric disorders. The dopamine (DA) systems and serotonin (5-HT) systems are the main target of psychopharmacotherapy. DA D 2 receptor antagonists and selective serotonin reuptake inhibitors (SSRIs) are widely used in psychiatric practice. Investigating the effects of these drugs on emotional processing should lead to a better understanding of the pathophysiology and pharmacotherapy of neuropsychiatric disorders. We aimed to examine effects of dopaminergic and serotonergic manipulation on neural responses to unpleasant pictures in healthy volunteers using pharmacological fMRI. Thirteen healthy male subjects participated in a single-blind, randomized, placebo-controlled design study. Each subject participated in three fMRI sessions. In each session, participants were orally administered either 25 mg of sultopride or 50 mg of fluvoxamine or placebo prior to scanning, and neural responses to unpleasant and neutral pictures were recorded. Despite no significant differences being found in the subjective ratings of affective pictures across three sessions, compared to placebo, acute treatments of DA D 2 receptor antagonists and SSRIs commonly attenuated the amygdala activity, although both treatments had slightly different modulatory effects on other components of the neural circuit of emotional processing. This study has shown that even acute treatment of drugs that manipulate neurotransmitter systems could affect brain activation associated with emotional processing in human brain. At the same time, our findings suggest that pharmacological fMRI could be a powerful tool for investigating the neurophysiological properties of drugs targeting neuropsychiatric disorders.

Individual capacity differences predict working memory performance and prefrontal activity following dopamine receptor stimulation

Dopamine receptors are abundant in the prefrontal cortex (PFC), a critical region involved in working memory. This pharmacological fMRI study tested the relationships between dopamine, PFC function, and individual differences in working memory capacity. Subjects performed a verbal delayed-recognition task after taking either the dopamine receptor agonist bromocriptine or a placebo. Behavioral effects of bromocriptine treatment depended on subjects' working memory spans, with the greatest behavioral benefit for lower span subjects. After bromocriptine, PFC activity was positively correlated with a measure of cognitive efficiency (RT slope) during the probe period of the task. Less efficient subjects with slower memory retrieval rates had greater PFC activity, whereas more efficient subjects had less activity. After placebo, these measures were uncorrelated. These results support the role of dopamine in verbal working memory and suggest that dopamine may modulate the efficiency of retrieval of items from the contents of working memory. Individual differences in PFC dopamine receptor concentration may thus underlie the behavioral effects of dopamine stimulation on working memory function.

Challenging the cholinergic system in mild cognitive impairment: a pharmacological fMRI study

Mild cognitive impairment (MCI) often represents an early form of Alzheimer disease (AD). In both MCI and AD, characteristic cholinergic changes may occur. Functional magnetic resonance imaging (fMRI) may help to examine neurochemical changes in early disease by studying signal reactivity to pharmacological challenge. In this study, MCI patients [n=28; mean age 73.6+/-7.5; mini mental state examination (MMSE) 27.0+/-1.2] were scanned during task performance in a randomized trial under three different medication regimes: at baseline [BL; no galantamine (GAL)], after a single oral dose of GAL (SD), and after prolonged exposure (steady state: SS). Memory tasks included an episodic face-encoding task and a parametric n-letter back working memory (WM) task. Alterations in brain activation patterns before and after treatment were analyzed for both tasks using multilevel statistical analysis. Significant increases in brain activation from BL were observed after prolonged exposure only. For face encoding (n=28), these involved left prefrontal areas, the anterior cingulate gyrus, left occipital areas, and left posterior hippocampus. For working memory (n=28), increased activation was found in right precuneus and right middle frontal gyrus, coinciding with increased accuracy scores after GAL treatment. In conclusion, cholinergic challenge produces alterations in brain activation patterns in elderly MCI patients that can be detected with fMRI. This should encourage further functional imaging studies to examine the status of neurotransmitter systems in disease.

Acute effects of corticosterone on BOLD signal: A pharmacological fMRI study in rats at 7 tesla

Thirteen adrenalectomized rats were examined by phMRI at 7 Tesla in order to map local changes in BOLD signal after an acute stress challenge with corticosterone (CORT, n=7) compared to vehicle injection (CON, n=6). Regional time courses of CORT versus CON showed a relative increase (1.0–1.2%) in BOLD signal in medial prefrontal cortex/anterior cingulate (mPFC/ACC). Averaged time courses of volume of interests identified post hoc in SPM map confirmed a positive response difference of CORT/CON in orbitofrontal cortex, caudate-putamen and mPFC/ACC. Acute rises of CORT appear to regionally increase BOLD signal being in line with stress-related activation of prefrontal circuits.