Abstract: A advances in functional magnetic resonance imaging (fMRI) permit the possibility of helping with dose ranging, as well as potential drug efficacy and side-effect profiles. However there are no current guidelines or standards for fMRI that meet established standards of care. Guidelines must be adopted to be used when patients are exposed to novel drugs, in particular, when immediate access to the patient is limited. When used in initial, MRI mandates certain safety standards because subjects are positioned in the magnet thereby limiting direct observation, communication or immediate access in an emergency; in testing new drugs using fMRI, we suggest that safety guidelines merit discussion and definition. This could lead to the adoption of standards. Some of these issues are unique to the application of the technology in early-phase trials.
Abstract: The cerebellum is classically considered to be a brain region involved in motor processing, but it has also been implicated in non-motor, and even cognitive, functions. Though previous research suggests that the cerebellum responds to noxious stimuli, its specific role during pain is unclear. Pain is a multidimensional experience that encompasses sensory discriminative, affective motivational, and cognitive evaluative components. Cerebellar involvement during the processing of pain could thus potentially reflect a number of different functional processes. This review will summarize the animal and human research to date that indicates that (1) primary afferents conduct nociceptive (noxious) input to the cerebellum, (2) electrical and pharmacological stimulation of the cerebellum can modulate nociceptive processing, and (3) cerebellar activity occurs during the presence of acute and chronic pain. Possible functional roles for the cerebellum relating to pain will be considered, including perspectives relating to emotion, cognition, and motor control in response to pain.
Abstract: PURPOSE: To determine a simple yet robust method to generate parsimonious design matrices that accurately estimate the "pharmacological MRI" (phMRI) response amplitude in the presence of both confounding signals and variability in temporal profile. Variability in the temporal response profile of phMRI time series data is often observed. If not properly accounted for, this variation can result in inaccurate and unevenly biased signal amplitude estimates when modeled within a general linear model (GLM) framework. MATERIALS AND METHODS: The approach uses a low-rank singular value decomposition (SVD) approximation to a set of vectors capturing anticipated variations of no interest around the signal model to generate additional regressors for the design matrix. The method is demonstrated for both plateau and bolus type phMRI response profiles in the presence of variation in signal onset and/or shape, and applied to an in vivo blood oxygenation level-dependent (BOLD) phMRI study of buprenorphine in healthy human subjects. RESULTS: In general, 2-3 additional regressors, capturing >75% of the anticipated variance, resulted in robust and unbiased signal amplitude estimates in the presence of substantial variability. CONCLUSION: This method provides a simple and flexible means to provide robust phMRI amplitude estimates within a GLM framework.
Abstract: A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n=10); from a larger study on prescription opioid dependent patients (n=133)] and matched healthy individuals (n=10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function.
Abstract: During migraine attacks, alterations in sensation accompanying headache may manifest as allodynia and enhanced sensitivity to light, sound, and odors. Our objective was to identify physiological changes in cortical regions in migraine patients using painful heat and functional magnetic resonance imaging (fMRI) and the structural basis for such changes using diffusion tensor imaging (DTI). In 11 interictal patients, painful heat threshold + 1 degrees C was applied unilaterally to the forehead during fMRI scanning. Significantly greater activation was identified in the medial temporal lobe in patients relative to healthy subjects, specifically in the anterior temporal pole (TP). In patients, TP showed significantly increased functional connectivity in several brain regions relative to controls, suggesting that TP hyperexcitability may contribute to functional abnormalities in migraine. In 9 healthy subjects, DTI identified white matter connectivity between TP and pulvinar nucleus, which has been related to migraine. In 8 patients, fMRI activation in TP with painful heat was exacerbated during migraine, suggesting that repeated migraines may sensitize TP. This article investigates a nonclassical role of TP in migraineurs. Observed temporal lobe abnormalities may provide a basis for many of the perceptual changes in migraineurs and may serve as a potential interictal biomarker for drug efficacy.
Abstract: Anesthesia is a state of drug-induced unconsciousness with suppression of sensory perception, and consists of both hypnotic and analgesic components. The anesthesiologist monitors the clinical response to noxious stimuli and adjusts drug dosage(s) to achieve an adequate depth of anesthesia, with the aim of reducing operative stress. Acute stress in the perioperative period has four major contributors: anxiety, pain, the surgical stress response, and the potential neurotoxicity of anesthetic agents. Any or all of these may act deleteriously on multiple systems in the brain and have known significant effects on brain regions such as the hippocampus and the hypothalamic-pituitary-adrenal axis. Perioperative stress on the nervous system and the resultant central nervous system (CNS) changes are likely to be causative for altered behaviors that are seen postoperatively, including chronic pain, posttraumatic stress disorder, and learning difficulties. Improving the ability of the anesthesiologist to control all four components of acute perioperative stress could potentially reduce the negative impact of surgery on the brain. Currently, there is no objective measurement for any of these stressors. The development and application of objective measures for perioperative stressors is the first step towards controlling these risk factors and eliminating or reducing their serious postoperative consequences. In this paper we review known and likely effects of perioperative stressors on brain systems and how they may play a significant role in altered postoperative behaviors. We discuss the role of current (and developing) measures of brain function and their potential for monitoring perioperative stress, with an emphasis on functional neuroimaging.
Abstract: OBJECTIVE: Focal somatic pain can evolve into widespread hypersensitivity to nonpainful and painful skin stimuli (allodynia and hyperalgesia, respectively). We hypothesized that transformation of headache into whole-body allodynia/hyperalgesia during a migraine attack is mediated by sensitization of thalamic neurons that process converging sensory impulses from the cranial meninges and extracephalic skin. METHODS: Extracephalic allodynia was assessed using single unit recording of thalamic trigeminovascular neurons in rats and contrast analysis of blood oxygenation level-dependent (BOLD) signals registered in functional magnetic resonance imaging (fMRI) scans of patients exhibiting extracephalic allodynia. RESULTS: Sensory neurons in the rat posterior thalamus that were activated and sensitized by chemical stimulation of the cranial dura exhibited long-lasting hyperexcitability to innocuous (brush, pressure) and noxious (pinch, heat) stimulation of the paws. Innocuous, extracephalic skin stimuli that did not produce neuronal firing at baseline (eg, brush) became as effective as noxious stimuli (eg, pinch) in eliciting large bouts of neuronal firing after sensitization was established. In migraine patients, fMRI assessment of BOLD signals showed that brush and heat stimulation at the skin of the dorsum of the hand produced larger BOLD responses in the posterior thalamus of subjects undergoing a migraine attack with extracephalic allodynia than the corresponding responses registered when the same patients were free of migraine and allodynia. INTERPRETATION: We propose that the spreading of multimodal allodynia and hyperalgesia beyond the locus of migraine headache is mediated by sensitized thalamic neurons that process nociceptive information from the cranial meninges together with sensory information from the skin of the scalp, face, body, and limbs.
Abstract: The use of MRI-based imaging in drug development has received increased interest recently because of the difficulties associated with the development of CNS pharmacotherapies. While not yet routine, there have been significant advances in imaging that allow this technology to be used for evaluating disease state and drug effects. For disease states, both single and longitudinal studies of non-invasive measures may be obtained to provide a read-out of disease processes and, potentially, to predict the disease state and its evolution. In addition, imaging has enabled the development of improved preclinical disease models based on changes in brain circuitry. Pharmacological MRI, the imaging-based evaluation of drug effects, includes measures of direct effects on the brain, as well as the effects of chronic dosing on brain changes and neurochemical changes associated with these brain effects using magnetic resonance spectroscopy. Thus, imaging may become an integrated process in drug development, during both the preclinical and clinical stages. However, validation, the implementation of good clinical practices and regulatory acceptance are hurdles that remain to be overcome.
Abstract: Imaging pain pathways in rats offers a tool to investigate CNS systems in acute and chronic rodent models of pain, neural plasticity associated with the latter, and the opportunity to evaluate pharmacological effects of analgesics on these systems. Furthermore, the evaluation of CNS circuits (e.g., sensory, emotional, endogenous analgesic) offers the potential for defining the complexity of circuit-based behaviors that are difficult to evaluate in current preclinical behavioral models of pain. In these studies, we performed functional MRI in trained, acclimated, awake rats to define neural systems activated by noxious thermal stimuli. Analysis revealed activation in response to a 48°C stimuli in cortical, subcortical and brainstem areas, known to be substrates of the pain pathways. Our results demonstrate the ability to characterize CNS patterns of activation in response to pain in rodents while avoiding the potential complicating effects of anesthesia.
