Doctor of Philosophy, University of Vermont, Neuroscience (2017)
Bachelor of Science, Virginia Tech, Biological Sciences (2007)
David Spiegel, Postdoctoral Faculty Sponsor
Brain network alterations in the inflammatory soup animal model of migraine
2017; 1660: 36-46
Advances in our understanding of the human pain experience have shifted much of the focus of pain research from the periphery to the brain. Current hypotheses suggest that the progression of migraine depends on abnormal functioning of neurons in multiple brain regions. Accordingly, we sought to capture functional brain changes induced by the application of an inflammatory cocktail known as inflammatory soup (IS), to the dura mater across multiple brain networks. Specifically, we aimed to determine whether IS alters additional neural networks indirectly related to the primary nociceptive pathways via the spinal cord to the thalamus and cortex. IS comprises an acidic combination of bradykinin, serotonin, histamine and prostaglandin PGE2 and was introduced to basic pain research as a tool to activate and sensitize peripheral nociceptors when studying pathological pain conditions associated with allodynia and hyperalgesia. Using this model of intracranial pain, we found that dural application of IS in awake, fully conscious, rats enhanced thalamic, hypothalamic, hippocampal and somatosensory cortex responses to mechanical stimulation of the face (compared to sham synthetic interstitial fluid administration). Furthermore, resting state MRI data revealed altered functional connectivity in a number of networks previously identified in clinical chronic pain populations. These included the default mode, sensorimotor, interoceptive (Salience) and autonomic networks. The findings suggest that activation and sensitization of meningeal nociceptors by IS can enhance the extent to which the brain processes nociceptive signaling, define new level of modulation of affective and cognitive responses to pain; set new tone for hypothalamic regulation of autonomic outflow to the cranium; and change cerebellar functions.
View details for DOI 10.1016/j.brainres.2017.02.001
View details for Web of Science ID 000398006100005
View details for PubMedID 28167076
Effect of Stretching on Thoracolumbar Fascia Injury and Movement Restriction in a Porcine Model.
American journal of physical medicine & rehabilitation
Stretching of fascia is an important component of manual and movement therapies. We previously showed that in pigs, a unilateral thoracolumbar fascia injury combined with movement restriction (hobble) produced contralateral loss of fascia mobility (shear strain during passive trunk flexion measured with ultrasound) similar to findings in human subjects with chronic low back pain. We now tested whether such abnormalities could be reversed by removing the hobble with or without daily stretching for 1 mo.Thirty pigs were randomized to control, injury, or injury + hobble for 8 wks. The hobble restricted hip extension ipsilateral to the injury. At week 8, the injury + hobble group was subdivided into continued hobble, removed hobble, and removed hobble + stretching (passively extending the hip for 10 min daily).Removing hobbles restored normal gait speed but did not restore fascia mobility. Daily passive stretching was not superior to removing hobbles, as there was no significant improvement in fascia mobility with either treatment group (removed hobble or stretching).Reduced fascia mobility in response to injury and movement restriction worsens over time and persists even when movement is restored. Reversing fascia abnormalities may require either longer than 1 mo or a different treatment "dose" or modality.
View details for DOI 10.1097/PHM.0000000000000824
View details for PubMedID 28901961
- The Vicious Cycle of Chronic Pain in Aging Requires Multidisciplinary Non-pharmacological Approach to Treatment Current Behavioral Neuroscience Reports 2017; 4 (3): 176–187
Ultrasound Evaluation of the Combined Effects of Thoracolumbar Fascia Injury and Movement Restriction in a Porcine Model
2016; 11 (1)
The persistence of back pain following acute back "sprains" is a serious public health problem with poorly understood pathophysiology. The recent finding that human subjects with chronic low back pain (LBP) have increased thickness and decreased mobility of the thoracolumbar fascia measured with ultrasound suggest that the fasciae of the back may be involved in LBP pathophysiology. This study used a porcine model to test the hypothesis that similar ultrasound findings can be produced experimentally in a porcine model by combining a local injury of fascia with movement restriction using a "hobble" device linking one foot to a chest harness for 8 weeks. Ultrasound measurements of thoracolumbar fascia thickness and shear plane mobility (shear strain) during passive hip flexion were made at the 8 week time point on the non-intervention side (injury and/or hobble). Injury alone caused both an increase in fascia thickness (p = .007) and a decrease in fascia shear strain on the non-injured side (p = .027). Movement restriction alone did not change fascia thickness but did decrease shear strain on the non-hobble side (p = .024). The combination of injury plus movement restriction had additive effects on reducing fascia mobility with a 52% reduction in shear strain compared with controls and a 28% reduction compared to movement restriction alone. These results suggest that a back injury involving fascia, even when healed, can affect the relative mobility of fascia layers away from the injured area, especially when movement is also restricted.
View details for DOI 10.1371/journal.pone.0147393
View details for Web of Science ID 000369528400023
View details for PubMedID 26820883
View details for PubMedCentralID PMC4731465
Triptans disrupt brain networks and promote stress-induced CSD-like responses in cortical and subcortical areas
JOURNAL OF NEUROPHYSIOLOGY
2016; 115 (1): 208-217
A number of drugs, including triptans, promote migraine chronification in susceptible individuals. In rats, a period of triptan administration over 7 days can produce "latent sensitization" (14 days after discontinuation of drug) demonstrated as enhanced sensitivity to presumed migraine triggers such as environmental stress and lowered threshold for electrically induced cortical spreading depression (CSD). Here we have used fMRI to evaluate the early changes in brain networks at day 7 of sumatriptan administration that may induce latent sensitization as well as the potential response to stress. After continuous infusion of sumatriptan, rats were scanned to measure changes in resting state networks and the response to bright light environmental stress. Rats receiving sumatriptan, but not saline infusion, showed significant differences in default mode, autonomic, basal ganglia, salience, and sensorimotor networks. Bright light stress produced CSD-like responses in sumatriptan-treated but not control rats. Our data show the first brain-related changes in a rat model of medication overuse headache and suggest that this approach could be used to evaluate the multiple brain networks involved that may promote this condition.
View details for DOI 10.1152/jn.00632.2015
View details for Web of Science ID 000369061900018
View details for PubMedID 26490291
View details for PubMedCentralID PMC4760506
Diffusion Capillary Phantom vs. Human Data: Outcomes for Reconstruction Methods Depend on Evaluation Medium.
Frontiers in neuroscience
2016; 10: 407-?
Diffusion MRI provides a non-invasive way of estimating structural connectivity in the brain. Many studies have used diffusion phantoms as benchmarks to assess the performance of different tractography reconstruction algorithms and assumed that the results can be applied to in vivo studies. Here we examined whether quality metrics derived from a common, publically available, diffusion phantom can reliably predict tractography performance in human white matter tissue.We compared estimates of fiber length and fiber crossing among a simple tensor model (diffusion tensor imaging), a more complicated model (ball-and-sticks) and model-free (diffusion spectrum imaging, generalized q-sampling imaging) reconstruction methods using a capillary phantom and in vivo human data (N = 14).Our analysis showed that evaluation outcomes differ depending on whether they were obtained from phantom or human data. Specifically, the diffusion phantom favored a more complicated model over a simple tensor model or model-free methods for resolving crossing fibers. On the other hand, the human studies showed the opposite pattern of results, with the model-free methods being more advantageous than model-based methods or simple tensor models. This performance difference was consistent across several metrics, including estimating fiber length and resolving fiber crossings in established white matter pathways.These findings indicate that the construction of current capillary diffusion phantoms tends to favor complicated reconstruction models over a simple tensor model or model-free methods, whereas the in vivo data tends to produce opposite results. This brings into question the previous phantom-based evaluation approaches and suggests that a more realistic phantom or simulation is necessary to accurately predict the relative performance of different tractography reconstruction methods.
View details for DOI 10.3389/fnins.2016.00407
View details for PubMedID 27656122
View details for PubMedCentralID PMC5013034
Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
2013; 345 (1): 41-51
Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although phMRI has been frequently used in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work in which the functional response to 0.1 and 0.2 mg/70 kg i.v. buprenorphine (partial µ-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg i.v. buprenorphine in conscious, naive rats to establish the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg i.v. buprenorphine yielded dose-dependent activation in a brain network composed of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray, and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the usefulness of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development.
View details for DOI 10.1124/jpet.112.201145
View details for Web of Science ID 000316367000006
View details for PubMedID 23370795
Pain Facilitation Brain Regions Activated by Nalbuphine Are Revealed by Pharmacological fMRI
2013; 8 (1)
Nalbuphine, an agonist-antagonist kappa-opioid, produces brief analgesia followed by enhanced pain/hyperalgesia in male postsurgical patients. However, it produces profound analgesia without pain enhancement when co-administration with low dose naloxone. To examine the effect of nalbuphine or nalbuphine plus naloxone on activity in brain regions that may explain these differences, we employed pharmacological magnetic resonance imaging (phMRI) in a double blind cross-over study with 13 healthy male volunteers. In separate imaging sessions subjects were administered nalbuphine (5 mg/70 kg) preceded by either saline (Sal-Nalb) or naloxone 0.4 mg (Nalox-Nalb). Blood oxygen level-dependent (BOLD) activation maps followed by contrast and connectivity analyses revealed marked differences. Sal-Nalb produced significantly increased activity in 60 brain regions and decreased activity in 9; in contrast, Nalox-Nalb activated only 14 regions and deactivated only 3. Nalbuphine, like morphine in a previous study, attenuated activity in the inferior orbital cortex, and, like noxious stimulation, increased activity in temporal cortex, insula, pulvinar, caudate, and pons. Co-administration/pretreatment of naloxone selectively blocked activity in pulvinar, pons and posterior insula. Nalbuphine induced functional connectivity between caudate and regions in the frontal, occipital, temporal, insular, middle cingulate cortices, and putamen; naloxone co-admistration reduced all connectivity to non-significant levels, and, like phMRI measures of morphine, increased activation in other areas (e.g., putamen). Naloxone pretreatment to nalbuphine produced changes in brain activity possess characteristics of both analgesia and algesia; naloxone selectively blocks activity in areas associated with algesia. Given these findings, we suggest that nalbuphine interacts with a pain salience system, which can modulate perceived pain intensity.
View details for DOI 10.1371/journal.pone.0050169
View details for Web of Science ID 000313429800004
View details for PubMedID 23341872
View details for PubMedCentralID PMC3540048
Modulation of CNS pain circuitry by intravenous and sublingual doses of buprenorphine
2012; 59 (4): 3762-3773
Buprenorphine (BUP) is a partial agonist at μ-, δ- and ORL1 (opioid receptor-like)/nociceptin receptors and antagonist at the κ-opioid receptor site. BUP is known to have both analgesic as well as antihyperalgesic effects via its central activity, and is used in the treatment of moderate to severe chronic pain conditions. Recently, it was shown that intravenous (IV) administration of 0.2mg/70 kg BUP modulates the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) response to acute noxious stimuli in healthy human subjects. The present study extends these observations by investigating the effects of BUP dose and route of administration on central nervous system (CNS) pain circuitry. Specifically, the modulation of evoked pain BOLD responses and resting state functional connectivity was measured following IV (0.1 and 0.2mg/70 kg) and sublingual (SL) (2mg) BUP administration in healthy human subjects. While 0.1mg/70 kg IV BUP is sub-analgesic, both 0.2mg/70 kg IV BUP and 2.0mg SL BUP are analgesic doses of the drug. Evoked BOLD responses were clearly modulated in a dose-dependent manner. The analgesic doses of BUP by both routes of administration yielded a potentiation in limbic/mesolimbic circuitry and attenuation in sensorimotor/sensory-discriminative circuitry. In addition, robust decreases in functional connectivity between the putamen and the sensorimotor/sensory-discriminative structures were observed at the two analgesic doses subsequent to measuring the maximum plasma BUP concentrations (C(max)). The decreases in functional connectivity within the sensorimotor/sensory-discriminative circuitry were also observed to be dose-dependent in the IV administration cohorts. These reproducible and consistent functional CNS measures at clinically effective doses of BUP demonstrate the potential of evoked pain fMRI and resting-state functional connectivity as objective tools that can inform the process of dose selection. Such methods may be useful during early clinical phase evaluation of potential analgesics in drug development.
View details for DOI 10.1016/j.neuroimage.2011.11.034
View details for Web of Science ID 000301090100070
View details for PubMedID 22119647
Imaging Drugs with and without Clinical Analgesic Efficacy
2011; 36 (13): 2659-2673
The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with μ-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK(1) receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.
View details for DOI 10.1038/npp.2011.156
View details for Web of Science ID 000296863600008
View details for PubMedID 21849979
View details for PubMedCentralID PMC3230490
Robust Reproducible Resting State Networks in the Awake Rodent Brain
2011; 6 (10)
Resting state networks (RSNs) have been studied extensively with functional MRI in humans in health and disease to reflect brain function in the un-stimulated state as well as reveal how the brain is altered with disease. Rodent models of disease have been used comprehensively to understand the biology of the disease as well as in the development of new therapies. RSN reported studies in rodents, however, are few, and most studies are performed with anesthetized rodents that might alter networks and differ from their non-anesthetized state. Acquiring RSN data in the awake rodent avoids the issues of anesthesia effects on brain function. Using high field fMRI we determined RSNs in awake rats using an independent component analysis (ICA) approach, however, ICA analysis can produce a large number of components, some with biological relevance (networks). We further have applied a novel method to determine networks that are robust and reproducible among all the components found with ICA. This analysis indicates that 7 networks are robust and reproducible in the rat and their putative role is discussed.
View details for DOI 10.1371/journal.pone.0025701
View details for Web of Science ID 000296186900016
View details for PubMedID 22028788
View details for PubMedCentralID PMC3196498
CNS activation maps in awake rats exposed to thermal stimuli to the dorsum of the hindpaw
2011; 54 (2): 1355-1366
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.
View details for DOI 10.1016/j.neuroimage.2010.08.056
View details for Web of Science ID 000285486000060
View details for PubMedID 20817102
Improved characterization of BOLD responses for evoked sensory stimuli
2010; 49 (3): 2275-2286
Pain and somatosensory processing involves an interaction of multiple neuronal networks. One result of these complex interactions is the presence of differential responses across brain regions that may be incompletely modeled by a straightforward application of standard general linear model (GLM) approaches based solely on the applied stimulus. We examined temporal blood oxygenation-level dependent (BOLD) signatures elicited by two stimulation paradigms (brush and heat) providing innocuous and noxious stimuli. Data were acquired from 32 healthy male subjects (2 independent cohorts). Regional time courses and model-free analyses of the first cohort revealed distinct temporal features of the BOLD responses elicited during noxious versus innocuous stimulation. Specifically, a biphasic (dual peak) BOLD signal was observed in response to heat but much less so in response to brush stimuli. This signal was characterized by a stimulus-locked response along with a second peak delayed by approximately 12.5 s. A cross-validation error analysis determined a modified design matrix comprising two explanatory variables (EVs) as a parsimonious means to model the biphasic responses within a GLM framework. One EV was directly derived from the stimulation paradigm (EV1), while the second EV (EV2) was EV1 shifted by 12.5 s. The 2EV GLM analysis enabled a more detailed characterization of the elicited BOLD responses, particularly during pain processing. This was confirmed by application of the model to a second, independent cohort[AU1]. Furthermore, the delayed component of the biphasic response was strongly associated with the noxious heat stimuli, suggesting that this may represent a sensitive fMRI link of pain processing.
View details for DOI 10.1016/j.neuroimage.2009.10.053
View details for Web of Science ID 000273626400033
View details for PubMedID 19854280