CNS animal fMRI in pain and analgesia

Abstract

Animal imaging of brain systems offers exciting opportunities to better understand the neurobiology of pain and analgesia. Overall functional studies have lagged behind human studies as a result of technical issues including the use of anesthesia. Now that many of these issues have been overcome including the possibility of imaging awake animals, there are new opportunities to study whole brain systems neurobiology of acute and chronic pain as well as analgesic effects on brain systems de novo (using pharmacological MRI) or testing in animal models of pain. Understanding brain networks in these areas may provide new insights into translational science, and use neural networks as a "language of translation" between preclinical to clinical models. In this review we evaluate the role of functional and anatomical imaging in furthering our understanding in pain and analgesia.

Figure 1. Research Reports on Preclinical Functional Imaging of Pain

Numbers of papers published in the field of “functional magnetic resonance imaging and pain and rats” from before 2000 and through each year to 2009. Search Source PubMed (www.ncbi.nlm.nih.gov/pubmed/).

Figure 2. fMRI Measures of Acute Pain in the Rat Brain

Common activated structures across evoked painful stimuli studies: Pseudo-colors represent percentage of 15 studies that a particular brain area has been to activate in response to an evoked painful stimulus. Cortical structures (sensory, motor, cingulate) tend to be most commonly activated that subcortical structures. See Table 4 for more details.

Figure 3. Examples of Activations in clinical models of pain

A: Visceral Pain: Activation in the thalamus in response to abdominal stimulation in a model of visceral pain ((Westlund et al., 2009); with permission, Neuroimage). Note the increase in the lateral and dorsal thalamus suggesting increased activation in lateral and medial pain pathways. B: Neuropathic Pain: Activation in response to trunk stimulation in a rat model of spinal cord injury. Panel A shows activation in response to the stimuli in SI (arrow) in normal animals that is increased in the injured animal ((Endo et al., 2008a); with Permission, IASP Press).

Figure 4. phMRI showing Activation Maps

A: Remifentanil. The figure shows positive (red-yellow) and negative (blue-green) changes in CBV following remifentanil infusion (10µg/kg). Activation patterns are noted in piriform cortex (white rostral slices), ventral tegmental areas (yellow), hippocampus (green rostral areas), raphe (red), reticular formation (green caudal areas). From ((Liu et al., 2007); with permission, Neuroimage). B: Gabapentin. The figure shows BOLD signal activation following 100mg/kg infusion of gabapentin vs. saline resulting in activation in a number of regions including the thalamus, PAG, hippocampus and tegmental area (From (Governo et al., 2008); permission, British Journal of Pharmacology, with minor modifications). Numbers indicate distance from Bregma.

Figure 5. Human – Rat Correlations using fMRI (Box)

A: Functional Correlations (from (Borsook et al., 2007); with permission, Drug Discovery Research). The figure shows the thermal response of rats and humans to a 46°C stimulus applied to the dorsum of the foot. Note that the activation patterns in the regions of interest (primary somatosensory cortex (SI), thalamus (Th), insula (I), anterior cingulate cortex (aCG) and amygdala (A)) is similar in each species. Furthermore, the signal sign (i.e., increase or decrease in BOLD signal) is similar in both species). B: Morphological Correlations: B1: The Figure shows cortical gray matter volume loss (gray matter density) in the dorsolateral prefrontal cortex (DLPF) in patients with chronic back pain (From (Apkarian et al., 2004); with permission, Journal of Neuroscience). B2: Data from a rat neuropathic pain model (SNI) showing cortical volume loss in the prefrontal cortex (From (Seminowicz et al., 2009); with permission, Neuroimage). C: Analgesic Correlations (from (Borsook et al., 2006); with permission, Drug Discovery Research). Effects of Drugs on Thermal Stressor in Humans. C1: Sample axial slices depicting activation maps for two drugs (imipramine and clonazepam) and placebo. Visual inspections indicate that there is an overall decrease in activation for imipramine vs. placebo and an overall increase in activation for clonazepam vs. placebo. C2: Voxel count for 5 drugs vs. placebo for whole brain (WHB) activation. Note that for imipramine (I) and gabapentin (G) more voxels are activated in drug vs. placebo while for clonazepam (C), rofecoxib (R) and ketorolac (K) more voxels are activated in the drug vs. placebo. Topiramate (T) has an intermediate or mixed effect. C3: Voxel count for pathway activation (PB). Note a similar pattern is present when compared with whole brain activation. Effects of Drugs on Thermal Stressor in and Rats. C4: Sample axial slices depicting activation maps for two drugs (imipramine and clonazepam) and placebo. Visual inspection indicates that there is an overall decrease in activation for imipramine vs. placebo and an overall increase in activation for clonazepam (C) vs. placebo. C5: Voxel count for 4 drugs vs. placebo for rat whole brain (RWHB) activation. Note that for imipramine (I) more voxels are activated in placebo vs. drug while for clonazepam (C), rofecoxib (R) and ketorolac (K) more voxels are activated in the drug vs. placebo. C6: Voxel count for pathway (RPB) activation in rats, showing a similar pattern to that for RWHB. Key: Red bar = voxels activated in drug > placebo; blue bar = drugs < placebo.

Figure 6. Differentiating Drugs

fMRI images through the rat brain following infusion of a tricyclic antidepressant imipramine 20mg/kg (Drug A) opioid morphine 5mg/kg (Drug B) and showing different activation patterns. The experiments were conducted in trained awake rats. (Borsook et al., unpublished data). Key: ACC = anterior cingulated cortex; H = hypothalamus; Hi = Hippocampus; S = septal region; PAG = periaqueductal gray; SN = substantia nigra; DB = Diagonal band of Broca;

Figure 7. Resting State Networks in the Rat

A: Anesthetized Rat. Horizontal images (except for lower right showing hypothalamus) through the rat brain showing differences in activation patterns in different brain regions to 1% Isoflurane (left columns) and ketamine 50mg/kg/h i.p./xylazine 6mg/kg/h i.p. (right columns) (From (Hutchison et al., 2010) ;with permission, Journal of Neurophysiology, with modification). B: Conscious Rat. Funcitonal connectivity map using the thalamus as a seed region. A number of regions connected to the thalamus including the hippocampus, auditory, motor somatosensory, retrosplenial cingulate, prefrontal regions and the caudate putaminal regions (From (Zhang et al., 2010); with permission, Journal Neurosci Methods, with modification).