Using fMRI to quantify the time dependence of remifentanil analgesia in the human brain.

To understand and exploit centrally acting drugs requires reliable measures of their time course of action in the human brain. Functional magnetic resonance imaging (fMRI) is able to measure noninvasively, drug-induced changes in task-related brain activity. Here, we have characterized, in a specific region of the brain, the time of onset of action and the half-life of action of a clinically relevant dose of a potent opioid analgesic agent, remifentanil. These times were established from the temporal variation of the amplitude of the blood oxygen level-dependent response in the insular cortex contralateral to a painfully hot thermal stimulus, in volunteers receiving a remifentanil infusion. The insular cortex has repeatedly been reported as activated by noxious thermal stimulation. The times of onset and offset of drug action were each characterized by a half-life for changes in fMRI signal from within the insula. These characteristic times agreed with the observed drug-induced analgesia and previous pharmacokinetic-pharmacodynamic measurements for remifentanil. We have successfully measured, for the first time using fMRI, temporal pharmacological parameters for a CNS-active drug based on its effect on task-related activity in a specific brain region. Comparison of the time course of regional brain activity with pain perception could reveal those regions engaged in drug-induced analgesia.     

The application of functional magnetic resonance imaging to neuropharmacology

The technique of functional magnetic resonance imaging (fMRI) has the capacity to acquire data with spatial and temporal resolution that far exceeds other currently available methods of non-invasive investigation of brain function. This coupled with its ability for serial studies makes it an attractive prospect for investigating the effects of pharmacological agents in the brain. Recent advances in fMRI have been made in the areas of reward and dependence, brain trauma and injury, psychotropic drugs and pain using small animals. Although the use of fMRI in pharmacological studies is becoming popular, there are various associated complications, such as the possible interference of drugs with the mechanisms that give rise to the pharmacological fMRI signal, and local or global cardiovascular changes that might produce functional responses unrelated to neural activity. Consideration of these concerns, coupled with careful attention to experimental detail and verification procedures, promises to make pharmacological fMRI use a valuable tool for understanding the actions of drugs in the brain.     

Hemodynamic and metabolic changes induced by cocaine in anesthetized rat observed with multimodal functional MRI

Rationale Physiological changes (such as heart rate and respiration rate) associated with strong pharmacological stimuli could change the blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) mapping signals, independent of neural activity.Objectives This study investigates whether the physiological changes per se associated with systemic cocaine administration (1 mg/kg) contaminate the BOLD fMRI signals by measuring BOLD and cerebral blood flow (CBF) fMRI and estimating the cerebral metabolic rate of oxygen (CMRO₂) changes.Materials and methods BOLD and CBF fMRI was performed, and changes in CMRO₂ were estimated using the BOLD biophysical model.Results After systemic cocaine administration, blood pressure, heart rate, and respiration rate increased, fMRI signals remained elevated after physiological parameters had returned to baseline. Cocaine induced changes in the BOLD signal within regions of the reward pathway that were heterogeneous and ranged from −1.2 to 5.4%, and negative changes in BOLD were observed along the cortical surface. Changes in CBF and estimated CMRO₂ were heterogeneous and positive throughout the brain, ranging from 14 to 150% and 10 to 55%, respectively.Conclusions This study demonstrates a valuable tool to investigate the physiological and biophysical basis of drug action on the central nervous system, offering the means to distinguish the physiological from neural sources of the BOLD fMRI signal.     

Functional imaging and neurochemical correlates of stimulant self-administration in primates

Abstract Rationale. Recent advances in neuroimaging and in vivo neurochemistry have documented drug-induced functional changes in brain activity under physiologically relevant conditions. These approaches have significant strengths and important limitations that should be considered. Objectives. The present review describes current in vivo approaches to characterize drug effects as they relate to behavior, and highlights key contributions derived from each approach in the context of stimulant self-administration in primates. Methods. Techniques relating in vitro neurochemistry to behavioral pharmacology are compared to several in vivo approaches, including microdialysis, positron emission tomography (PET) neuroimaging and functional magnetic resonance imaging (fMRI). Results. In vitro neurochemical correlates of behavioral pharmacology established a significant relationship between dopamine and the reinforcing effects of abused stimulants. Subsequent in vivo microdialysis studies in behaving animals supported a critical role for nucleus accumbens dopamine in the reinforcing effects of stimulants. PET neuroimaging in monkeys and humans documented a close relationship between dopamine transporter (DAT) occupancy in vivo and the reinforcing effects of stimulants. The effectiveness of selective DAT inhibitors to reduce cocaine self-administration also was linked to DAT occupancy in vivo. Lastly, the measurement of cerebral blood flow and metabolism with PET and fMRI has begun to define the neuronal circuitry influenced by acute and chronic stimulant exposure. Conclusions. Collectively, in vivo neurochemistry and functional imaging have complemented in vitro approaches and have enhanced our current understanding of the neurobiology of abused stimulants. Electronic Publication     

Effect of <Emphasis Type="Italic">Thunbergia laurifolia</Emphasis>, a Thai natural product used to treat drug addiction,on cerebral activity detected by functional magnetic resonance imaging in the rat

Rationale Thunbergia laurifolia Linn. (TL) is an herbal medicine used to treat alcohol and drug addiction in Thai traditional medicine. A previous study demonstrated that an extract of TL increases rat striatal dopamine release in vitro. Objectives This study determined whether a methanol extract of TL altered rat brain region activity using in vivo functional nuclear magnetic resonance imaging (fMRI) in a manner consistent with the observed effects in vitro on dopamine release. Methods fMRI was performed on a 2.35-T Bruker MR system. MR images were acquired from rat brain using the rapid acquisition relaxation enhanced sequence (field of view 50 mm). The imaging parameters used for the anatomical scan yielded an in-plane spatial resolution of 0.2×0.2 mm. Consecutive single-slice functional imaging over the rat brain investigated the changes in signal intensity in various parts of the brains induced by TL (200 mg/kg, i.p.) or vehicle administration. Results These demonstrate that TL increased signal intensity in various brain areas such as nucleus accumbens, globus pallidus, amygdala, frontal cortex, caudate putamen and hippocampus. These are similar to those reported previously to show effects after either cocaine or amphetamine administration. Physiological variables were not affected by the injection of TL (200 mg/kg, i.p.), but there was a small decrease in arterial blood pressure. Conclusions The results indicate that TL increases significant neuronal activity in specific brain regions responsible for reward and locomotor behaviour (fixed-effect analysis); however, there is no significant difference between TL and vehicle-treated groups with random-effect analysis (population statistic). The active compound(s) in TL responsible for the pharmacological effects of TL remain to be identified.     

Effect of Thunbergia laurifolia, a Thai natural product used to treat drug addiction, on cerebral activity detected by functional magnetic resonance imaging in the rat

RATIONALE: Thunbergia laurifolia Linn. (TL) is an herbal medicine used to treat alcohol and drug addiction in Thai traditional medicine. A previous study demonstrated that an extract of TL increases rat striatal dopamine release in vitro. OBJECTIVES: This study determined whether a methanol extract of TL altered rat brain region activity using in vivo functional nuclear magnetic resonance imaging (fMRI) in a manner consistent with the observed effects in vitro on dopamine release. METHODS: fMRI was performed on a 2.35-T Bruker MR system. MR images were acquired from rat brain using the rapid acquisition relaxation enhanced sequence (field of view 50 mm). The imaging parameters used for the anatomical scan yielded an in-plane spatial resolution of 0.2x0.2 mm. Consecutive single-slice functional imaging over the rat brain investigated the changes in signal intensity in various parts of the brains induced by TL (200 mg/kg, i.p.) or vehicle administration. RESULTS: These demonstrate that TL increased signal intensity in various brain areas such as nucleus accumbens, globus pallidus, amygdala, frontal cortex, caudate putamen and hippocampus. These are similar to those reported previously to show effects after either cocaine or amphetamine administration. Physiological variables were not affected by the injection of TL (200 mg/kg, i.p.), but there was a small decrease in arterial blood pressure. CONCLUSIONS: The results indicate that TL increases significant neuronal activity in specific brain regions responsible for reward and locomotor behaviour (fixed-effect analysis); however, there is no significant difference between TL and vehicle-treated groups with random-effect analysis (population statistic). The active compound(s) in TL responsible for the pharmacological effects of TL remain to be identified.     

Detection of cannabinoid agonist evoked increase in BOLD contrast in rats using functional magnetic resonance imaging

BOLD-contrast functional magnetic resonance imaging (fMRI) was used to investigate the effects of the synthetic cannabinoid agonist HU210 on the rat brain in order to determine potential CNS sites of action for the functional effects of cannabinoids. After obtaining basal data, rats (n=8) were given the cannabinoid agonist HU210 (10 microg/kg i.v.) and volume data sets collected for 85 mins. Significant increases in functional BOLD activity were observed in specific brain regions including those important in pain (PAG), reward (VTA and accumbens) and motor function (striatum). In order to confirm cannabinoid receptor involvement in the HU210 evoked functional BOLD activity, rats (n=8) were pre-treated with the CB1 cannabinoid receptor antagonist SR141716A (100 microg/kg i.v.) prior to HU210. Pretreatment with SR141716A abolished all significant evoked HU210 functional BOLD activity. To exclude the involvement of potential systemic effects induced by the cannabinoid agonist administration on the observed evoked functional BOLD activity a separate experiment investigated the effect of HU210 (10 microg/kg i.v.) on mean arterial pressure and showed that HU210 had no significant effect on pressure under chloral hydrate anaesthesia. In summary, this study demonstrates that the cannabinoid agonist HU210 evokes a significant increase in BOLD functional activity in specific regions and that this was cannabinoid receptor mediated. Furthermore the study indicates the potential value of fMRI in rodents to delineate pharmacologically induced changes in regional brain function.     

Paradigm shift in translational neuroimaging of CNS disorders

During the last two decades, functional neuroimaging technology, especially functional magnetic resonance imaging (fMRI), has improved tremendously, with new attention towards resting-state functional connectivity of the brain. This development has allowed scientists to study changes in brain structure and function, and probe these two properties under conditions of evoked stimulation, disease and drug administration. In the domain of functional imaging, the identification and characterization of central nervous system (CNS) functional networks have emerged as potential biomarkers for CNS disorders in humans. Recent attempts to translate clinical neuroimaging methodology to preclinical studies have also been carried out, which offer new opportunities in translational neuroscience research. In this paper, we review recent developments in structural and functional MRI and their use to probe functional connectivity in various CNS disorders such as schizophrenia, mood disorders, Alzheimer's disease (AD) and pain.     

Pharmacological applications of magnetic resonance imaging

Magnetic resonance imaging (MRI) techniques are capable of spatial and temporal resolution and within subject repeatability that far exceed other currently available methods of noninvasively investigating brain functioning. While functional MRI (fMRI) techniques have traditionally been used to investigate sensory, motor, and cognitive functions, they are also very attractive for investigating the effects of pharmacological agents in the brain. However, because pharmacological agents may interfere with the very mechanisms that give rise to the fMRI signal, careful attention to experimental design and data analysis issues must be exercised. Specifically, introducing a drug into the system could potentially alter the coupling of neural activity with regional cerebral blood flow and/or the extraction of oxygen from blood, or may cause local or global cardiovascular changes unrelated to neural activity. These concerns notwithstanding, careful attention to experimental detail and verification procedures promises to make pharmacological MRI a valuable tool for understanding the actions of drugs on the brain at many levels. The physiological and biophysical bases of blood oxygen level-dependent, arterial spin labeling, cerebral blood flow, cerebral blood volume, and spectroscopy acquisition methods are presented to illustrate where confounds may arise when a drug is added to the system. Selected studies combining administration of pharmacological agents with MRI techniques are critically reviewed to illustrate both the challenges inherent in these applications and some possible solutions. Included are studies of acute direct effects of drugs, effects of drugs on task-related activation, chronic effects of drugs, effects of drugs on cerebral metabolism, and variable effects of drugs in different populations.     

Lithium and valproate attenuate dextroamphetamine-induced changes in brain activation

BACKGROUND: Previous studies have suggested that both lithium and valproate may decrease phosphoinositol second messenger system (PI-cycle) activity. There is also evidence that dextroamphetamine may increase PI cycle activity. It was previously demonstrated that dextroamphetamine administration in volunteers causes a region and task dependent decrease in brain activation in healthy volunteers. The current study assessed the effect of 14 days pretreatment with lithium and valproate on these dextroamphetamine-induced changes in regional brain activity in healthy volunteers. METHODS: This was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n = 12), 900 mg lithium (n = 9) or placebo (n = 12). Functional images were acquired using functional magnetic resonance imaging (fMRI) while subjects performed three cognitive tasks, a word generation paradigm, a spatial attention task and a working memory task. fMRI was carried out both before and after administration of dextroamphetamine (25 mg). Changes in the number of activated pixels and changes in the magnitude of the blood-oxygen-level-dependent (BOLD) signal after dextroamphetamine administration were then determined. RESULTS: In keeping with previous findings dextroamphetamine administration decreased regional brain activation in all three tasks. Pretreatment with lithium attenuated changes in the word generation paradigm and the spatial attention task, while pretreatment with valproate attenuated the changes in the working memory task. CONCLUSIONS: These results suggest that both lithium and valproate can significantly attenuate dextroamphetamine-induced changes in brain activity in a task dependent and region specific manner. This is the first human evidence to suggest that both lithium and valproate may have a similar effect on regional brain activation, conceivably via similar effects on PI-cycle activity.     

Synaptic and cellular events: the last frontier?

The use of functional magnetic resonance imaging (fMRI) to follow random or serial sequences of neural activity is explored and illustrated with examples that include auditory hallucinations and a short-term memory paradigm. Despite the availability of ultra-high-speed fMRI sequences, the inherent latency of the haemodynamic response limits the time resolution of fMRI studies. To access finer time-scales, it can be combined with electromagnetic techniques (MEG or EEG). Functional magnetic resonance spectroscopy (MRS) studies, in which infusion of [1-¹³C]glucose enables rates of the tricarboxylic acid cycle to be determined, demonstrates substantial (50%) increases in this flux on visual activation. Not only does this provide a quantitative estimate of the energy cost of brain activation, it also shows that the extra glucose is consumed essentially oxidatively. In the same studies, measurements of the rate of glutamine synthesis, enable the rate of recycling of neurotransmitter glutamate to be estimated.     

Pharmacological and functional magnetic resonance imaging techniques in CNS drug discovery

Functional magnetic resonance imaging (fMRI) has transformed cognitive neuroscience over the past 10 – 15 years, allowing clinical researchers unprecedented access to the functioning of the human brain under many different conditions including motor, sensory and cognitive stimulation. During the past 5 years, increasing interest has also focused on mapping pharmacologically induced changes in human brain activity produced following exposure to psychoactive agents such as amphetamine and cocaine, and is now frequently termed pharmacological MRI (phMRI). Unfortunately, preclinical fMRI and phMRI studies have not kept pace with human research, largely due to numerous technical hurdles inherent in small laboratory animal imaging, as well as the high cost of necessary equipment. However, this is now set to change with significant investment being made across academic and industry laboratories, as researchers attempt to tap into the huge potential of this noninvasive and powerful translational tool. This review introduces the principles and fundamental assumptions behind the technologies, details some important applications of fMRI and phMRI within a CNS research environment, and examines the potential future impact of the technology.     

Cholinergic agonism alters cognitive processing and enhances brain functional connectivity in patients with multiple sclerosis

The aim of this study is to define mechanisms underlying the pharmacological effects of brain cholinesterase inhibition on cognitive function in patients with multiple sclerosis (MS). Both a Stroop task and an N-back task were used to probe the changes in brain activity using functional magnetic resonance imaging (fMRI) in a single (investigator)-blind, crossover treatment design studying 15 patients with multiple sclerosis (12 relapsing remitting, 3 secondary progressive) taking rivastigmine (4.5 mg po bid) and domperidone (10 mg po qd) or domperidone alone. Administration of rivastigmine increased Stroop functional magnetic resonance imaging activation in the right inferior frontal gyrus for the Stroop task (P < 0.05, corrected). Incremental functional magnetic resonance imaging activation with progressively greater N-back task difficulty was enhanced by rivastigmine in prefrontal and parietal cortical regions (P < 0.01, ANOVA). Functional connectivity analysis of the N-back functional magnetic resonance imaging data based on correlations between pair-wise interregional activations showed increased connectivity between left to right prefrontal, anterior cingulate to left prefrontal and right parietal to right prefrontal regions with rivastigmine (P < 0.05, corrected). Although there were no statistically significant changes in the neuropsychological task performance with rivastigmine in this small study, 11 of 15 patients showed improvements, whereas only 4 of 15 patients showed decline in performance (P = 0.07). With regard to the previous data, these findings suggest different patterns of brain response to lower dose acute and higher dose chronic administration of rivastigmine in patients with multiple sclerosis. They showed that rivastigmine enhances the prefrontal function and alters the functional connectivity associated with cognition. We interpret this as evidence for greater efficiency of brain information transfer that should increase confidence in a potentially beneficial clinical therapeutic effect.     

Alcohol intoxication effects on simulated driving: exploring alcohol-dose effects on brain activation using functional MRI.

Driving while intoxicated is a major public health problem. We investigated impaired driving using a simulated driving skill game that presents an 'in-car' view of a road and a readout of speed. We explored brain activation and behavioral alterations from baseline at two blood alcohol concentrations (BACs). Participants received single-blind individualized doses of beverage alcohol designed to produce blood alcohol content (BAC) of 0.04 and 0.08 or placebo. Scanning occurred on a 1.5 Tesla Philips MRI scanner after training to asymptote performance. Analysis was performed using independent component analysis (ICA) to isolate systematically nonoverlapping 'networks' and their time courses. Imaging results revealed seven separate driving-related brain networks with different time courses. Several significant findings were observed for the imaging data. First, dose-dependent functional magnetic resonance imaging (fMRI) changes were revealed in orbitofrontal (OF) and motor (but not cerebellar) regions; visual and medial frontal regions were unaffected. Second, cerebellar regions were significantly associated with driving behavior in a dose-dependent manner. Finally, a global disruptive effect of alcohol on the ICA time courses was observed with highly significant differences in OF and motor regions. Alcohol thus demonstrated some behavioral effects and unique, disruptive, dose-dependent effects on fMRI signal within several brain circuits. The fMRI data also suggest that the deficits observed in alcohol intoxication may be modulated primarily through OF/anterior cingulate, motor and cerebellar regions as opposed to attentional areas in frontoparietal cortex.     

Magnetic resonance imaging and magnetic resonance spectroscopy assessment of brain function in experimental animals and man

This paper introduces the basic principles and techniques of functional magnetic resonance imaging (fMRI) and spectroscopy (MRS). Examples are given of single event human fMRI studies on control subjects, and a graded activation protocol applied to Parkinsonian patients. Possibilities are discussed for using fMRI techniques to study the neural substrate of various pharmacological agents, including drugs of abuse. The application of these pharmacological MRI (phMRI) studies to animal models and the associated technical issues are also addressed. The use of MRS in studying brain status and function is reviewed, with particular emphasis on 13C isotopic labelling studies.     

Treatment with Olanzapine is Associated with Modulation of the Default Mode Network in Patients with Schizophrenia

Earlier studies have shown widespread alterations of functional connectivity of various brain networks in schizophrenia, including the default mode network (DMN). The DMN has also an important role in the performance of cognitive tasks. Furthermore, treatment with second-generation antipsychotic drugs may ameliorate to some degree working memory (WM) deficits and related brain activity. The aim of this study was to evaluate the effects of treatment with olanzapine monotherapy on functional connectivity among brain regions of the DMN during WM. Seventeen patients underwent an 8-week prospective study and completed two functional magnetic resonance imaging (fMRI) scans at 4 and 8 weeks of treatment during the performance of the N-back WM task. To control for potential repetition effects, 19 healthy controls also underwent two fMRI scans at a similar time interval. We used spatial group-independent component analysis (ICA) to analyze fMRI data. Relative to controls, patients with schizophrenia had reduced connectivity strength within the DMN in posterior cingulate, whereas it was greater in precuneus and inferior parietal lobule. Treatment with olanzapine was associated with increases in DMN connectivity with ventromedial prefrontal cortex, but not in posterior regions of DMN. These results suggest that treatment with olanzapine is associated with the modulation of DMN connectivity in schizophrenia. In addition, our findings suggest critical functional differences in the regions of DMN.     

Reactive oxygen species and the central nervous system in salt-sensitive hypertension: possible relationship with obesity-induced hypertension

1. There are multiple and complex mechanisms of salt-induced hypertension; however, central sympathoexcitation plays an important role. In addition, the production of reactive oxygen species (ROS) is increased in salt-sensitive hypertensive humans and animals. Thus, we hypothesized that brain ROS overproduction may increase blood pressure (BP) by central sympathostimulation. 2. Recently, we demonstrated that ROS levels were elevated in the hypothalamus of salt-sensitive hypertensive animals. Moreover, intracerebroventricular anti-oxidants suppressed BP and renal sympathetic nerve activity more in salt-sensitive than non-salt-sensitive hypertensive rats. Thus, brain ROS overproduction increased BP through central sympathoexcitation in salt-sensitive hypertension. 3. Salt sensitivity of BP is enhanced in obesity and metabolic syndrome. Interestingly, it is also suggested that, in obesity-induced hypertension models, increases in BP are caused by brain ROS-induced central sympathoexcitation. 4. Recent studies suggest that increased ROS production in the brain and central sympathoexcitation may share a common pathway that increases BP in both salt- and obesity-induced hypertension.     

Assessment of cognitive brain function in ecstasy users and contributions of other drugs of abuse: results from an FMRI study.

Heavy ecstasy use has been associated with neurocognitive deficits in various behavioral and brain imaging studies. However, this association is not conclusive owing to the unavoidable confounding factor of polysubstance use. The present study, as part of the Netherlands XTC Toxicity study, investigated specific effects of ecstasy on working memory, attention, and associative memory, using functional magnetic resonance imaging (fMRI). A large sample (n=71) was carefully composed based on variation in the amount and type of drugs that were used. The sample included 33 heavy ecstasy users (mean 322 pills lifetime). Neurocognitive brain function in three domains: working memory, attention, and associative memory, was assessed with performance measures and fMRI. Independent effects of the use of ecstasy, amphetamine, cocaine, cannabis, alcohol, tobacco, and of gender and IQ were assessed and separated by means of multiple regression analyses. Use of ecstasy had no effect on working memory and attention, but drug use was associated with reduced associative memory performance. Multiple regression analysis showed that associative memory performance was affected by amphetamine much more than by ecstasy. Both drugs affected associative memory-related brain activity, but the effects were consistently in opposite directions, suggesting that different mechanisms are at play. This could be related to the different neurotransmitter systems these drugs predominantly act upon, that is, serotonin (ecstasy) vs dopamine (amphetamine) systems.     

Pharmacological magnetic resonance imaging: a new application for functional MRI

Various methods, including functional magnetic resonance imaging (fMRI), have recently been developed to allow investigators to study functional activity in the living brain. Such techniques are now being used to investigate regionally specific brain activity associated with the administration of CNS-active drugs. fMRI in particular is increasingly recognized as being a relatively non-invasive way to perform pharmacological investigations in experimental animals, healthy human volunteers, and individuals with CNS disease. This use of fMRI, dubbed 'pharmacological MRI' or 'phMRI', holds the promise of providing relatively straightforward pharmacodynamic assays and can be used to establish brain-penetrability parameters, or dose-ranging information for novel therapeutic compounds.