Background: 'O (Chronic) Pain Miserum'
Advancing our Understanding of CNS Mechanisms in Acute and Chronic Pain through fMRI
STUDY FOCUS | REFERENCE | MAJOR FINDINGS | COMMENT |
---|---|---|---|
Experimental Allodynia
| |||
Capsaicin induced secondary hyperalgesia | Baron et al., 1999 [81] | 9 Subjects. Capsaicin injection induced secondary mechanical hyperalgesia. Painful mechanical stimulation produced activation in prefrontal cortex >> than in nonpainful mechanical stimulation | First fMRI study of capsaicin induced hypersensitivity. Activation in prefrontal cortex = attention and cogniitvie changes (e.g., planning). |
Brainstem activation by capsaicin | Zambreanu et al., 2005 [82] | Heat-capsaicin model used. Punctate mechanical stimuli applied to region of secondary hyperalgesia. Stimuli in hyperalgesic vs. control region showed activation in contralateral brainstem, cerebellum, bilateral thalamus, contralateral SI and SII, middle frontal gyrus, parietal association cortex and brainstem (cuneiformis, superior colliculi, PAG. | First evaluation of contribution of brainstem in central sensitization. |
Cognitive influences on hyperalgesia | Wiech et al., 2005. [83] | Capsaicin-induced heat hyperalgesia results in frontal and medial prefrontal cortex, insula, and cerebellum. Activity in medial prefrontal cortex and cerebellum modulated by cognitive task. | Study addresses interaction between motivational and cognitive functions and may provide some basis for evaluating similar changes in chronic pain. |
Capsaicin allodynia | Maihofner et al., 2004. [39] | Region of allodynia produced by capsaicin and thermal kindling. Brush to normal skin results in SI, parietal association cortex, SII bilaterally, contralateral insula. Brush to allodynic skin resulted in some overlap to those observed for control in addition to inferior frontal cortex, and ipsilateral insula. | Subtraction (unaffected vs. affected skin) indicates that mechanical allodynia in regions that include SI, parietal association cortex, inferior frontal cortex, and insula. |
STUDY FOCUS | REFERENCE | MAJOR FINDINGS | COMMENT |
---|---|---|---|
Peripheral Nerve
| |||
Trigeminal Ganglion (TG) | Borsook et al., 2003. [63] | Somatotopic activation in the trigeminal ganglion | Measures of the peripheral nervous system may be evaluated using fMRI |
Dorsal Horn
| |||
Trigeminal Nucleus (TN) | DaSilva et al., 2002. [20] | Somatotopic acitivation in the TN | Study reports that pain spinal cord brainstem systems can be defined and somatotopically evaluated. |
Brainstem
| |||
Periaqueductal Gray (PAG) | Becerra et al., 2001 [17] | Both increases (early) and decrease (late) of activation may correlate with ascending and descending (modulatory) components of functioning within this structure. | The PAG is a 'core' structure in understanding how the brain modulates pain, both in placebo and in the effects of analgesics, particularly opioids. |
Right Cuneus | Fulbright et al., 2001 [64] | Cold pressor induced pain produced activation in a number of regions including the frontal lobe and the cuneus. | Measures of affective components of cold pain. |
Brainstem NucleiCuneiformis, parabrachial, PAG, red nucleus | Dunckley et al., 2005 [65] | Activation to somatic and visceral pain. | A big step forward in measures of brainstem measures of pain in humans. Marked similarities in the two processes were observed at a brainstem level. |
Subcortical Gray Regions
| |||
Emotion CircuitryAccumbens, SLEA, Amygdala, Hippocampus, Hypothalamus, Oribitofrontal Cortex | Becerra et al., 2001 [17] | Acute pain activates circuitry that is commonly associated with reward. Emotional circuitry is activated ahead of sensory circuitry | The first demonstration that reward circuitry can be mapped in acute pain. |
Amygdala | Seymour et al., 2005 [21] | Termination of pain (rewarding) activates the amygdala | The significance of understanding the brain systems to natural reward (i.e., pain relief). |
Putamen | Bingel et al., 2004 [66] | 15 Subjects. Laser evoked pain to foot or hand produced contralateral somatotopic organization in putamen | Clear activation in putamen by pain indicative of potential role in emotional or motor processing of pain. |
Accumbens (NAc) | Aharon et al., 2006 [18] | Acute noxious (but not non-noxious) stimuli activate the NAc. Within the structure, different signals may indicate functional processing within the 'core' and 'shell' of the structure. | A number of regions have different functional components (e.g., amygdala, PAG) and the ability to dissect apart these within a set paradigm will contribute further to mechanistic functions of pain processing in humans. |
Cortical Regions
| |||
Anterior Cingulate(aCG) | Becerra et al., 1999 [10], 2001 [17] | One of the first fMRI studies to demonstrate differential aCG activation in the structure. | Differentiation of sensory vs. emotional components of aCG function. |
Hippocampus (Hi) | Ploghaus et al., 1999 [27], 2000 [67], 2001 [28] | Hippocampal activation correlates with anxiety/ | Papers address a specific function of the hippocampus in pain and further show a correlation with insula activity. |
Insula (I) | Brooks et al., 2005. [19] | Somatotopic organization in the insula defined | The insula has been a bit of an enigma. Based on preclinical work, human work seems to support the notion that the insula is receives thermal information from the ventromedial nucleus of the thalamus (VMpo) specific thermal stimuli |
Oribtofrontal Cortex (GOb) | Rolls et al., 2003. [68] | Effects of pleasant and painful touch to hand. Oribitofrontal activation > pleasant or pain vs. neutral. SI less activated by pleasant and pain than neutral touch. Regional differences in aCG to pleasant (rostral aCG) and pain (posterior dorsal). Brainstem (e.g., PAG) activated by all 3 touch stimuli. | Clear dissociation between sensory and emotional systems to 'reward' and aversion. |
Somatosensory Cortex | Bingel et al., 2004 [66] | Painful laser stimuli applied to hand and foot produced somatotopic organization in contralateral and ipsilateral SI cortex. | Laser stimuli can provide stimuli without tactile components. |
fMRI of Chronic Pain
STUDY FOCUS | REFERENCE | MAJOR FINDINGS | COMMENT |
---|---|---|---|
Neuropathic Pain
| |||
Mechanical Allodynia | Peyron et al., 2004. [69] | Activated regions mirror control network activated by brush, cold to the normal side. Regions activated include SI, SII and insula. | Study tackles an issue of ongoing pain and the problems associated with ongoing background pain. |
Back Pain vs. Postherpetic Neuropathy | Apkarian et al., 2004. [34] | A potentially huge step forward in the use of fMRI to differentiate chronic pain subtypes. | |
Trigeminal Neuropathy | Becerra et al., 2005 [33] Becerra et al., 2006 [70] | V2 neuropathy patients evaluated in a repeat study for mechanical (brush) and thermal (cold and heat) stimuli. | Mechanistic changes in CNS function to specific stimuli. |
Chronic Back Pain | Giesecke et al., 2004. [31] | Heterotopic pressure stimulus applied to the thumb activates a number of brain regions. | Generalized increase in pain sensitivity in chronic pain; pain >> in patients than controls for the same pressure stimulus. Equally painful stimuli produced similar brain activations. |
Spinal Cord Injury (SCI) | Nicotra et al., 2005 [71] | Seven patients with SCI evaluated including painful stimuli (shock) in an aversive paradigm. Conditioning stimuli produces enhancement of activity in dorsal anterior cingulated, PAG and superior temporal gyrus to conditioning stimuli and attenuation in subgenual aCG, ventromedial prefrontal and posterior cingulated to threat of shock. | The study is able to dissect apart possible changes in the brains of SCI patients, including central sensitization and alterations in affective components of the brain (subgenual aCG) that may be part of a disturbance of affective and autonomic processing. |
Unpleasant Odor | Villemure et al., 2005 [72] | Single patient with neuropathic pain where pain increased when exposed to experimental odors in thalamus, amygdala, aCG and SI. | This study may suggest subcortical mechanisms of aversion have a common neural circuitry. |
Complex Regional Pain Syndrome
| |||
Pediatric CRPS | Lebel et al., 2005. [73] | Pediatric group with relapsing CRPS of lower extremity. Changes to cold most predominant. | Clinical models within particular groups of diagnosis may be used to determine the etiology of more chronic conditions e.g., adult CRPS. |
Mechanical Allodynia in Adult CRPS | Maihofner et al., 2005 [40] | Twelve Patients. Pin-prick hyperalgesia activates a number of cortical regions (SI, SII, Insula, aCG, frontal cortex). | Study focus is on cortical regions only and indicates significant changes in functioning in affected vs., unaffected. No control group. |
Sympathetically Maintained Pain (SMP) | Apkarian et al., 2001. [74] | Evaluation of stimuli to painful site before and after sympathetic blockade. SMP associated with increased prefrontal, aCG activation and decrease in contralateral thalamus. | Correlates of CNS function shown:ineffective blocks did not change cortical activityplacebo response same as effective block |
Fibromyalgia
| |||
Primary fibromyalgia (FM) | Cook et al., 2004 [75] | Fibromyalgia compared with control group. Fibromyalgia group more sensitive on psychophysical evaluation. Non-painful stimuli produced greater activation in a number of regions including prefrontal, SMA, insula and cingulated cortices. Pain produced greater activation in the contralateral insula in (FM) patients. | Central changes with increased sensitivity/hyperalgesia are clearly manifest behaviorally and on fMRI. Such insights provide a new approach to understanding a heretofore ill- defined disease. |
Catastrophizing | Gracely et al., 2004 [6] | Pressure stimulus applied to the thumb (i.e., heterotopic). SII activation >> in high catasrophizers; contralateral aCG and bilateral lentiform nucleus. This was independent of depression. | Catastrophizing may contribute to the pain state by enhancing the emotional reaction to pain. |
Visceral Pain
| |||
Functional bowel disorder | Kwan et al., 2005 [76] | Healthy (11) vs. Patients (9) underwent painful rectal distention. Activation in the medial thalamus, hippocampus for pain. | On line ratings of pain responses. – clear differences in emotional circuitry of medial thalamus and hippocampus. |
Irritable Bowel Syndrome (IBS) with constipation vs. diarrhea | Wilder-Smith et al., 2004 [77] | Female healthy (10) and IBS (10; 5-constipated and 5-diarrhea) underwent rectal distention and painful heterotopic pain applied to activate DNIC. Significant differences in CNS regions (prefrontal cortex, amygdala, aCG, PAG, Hippocampus) between constipated and diarrhea groups and controls. | Different responses in patient subtypes of IBS suggesting differences in endogenous modulatory systems. |
Irritable Bowel Syndrome (IBS) | Mertz et al., 2000 [78] | Healthy (16) vs. patients with IBS (18), IBS patients have increased activation in aCG. | Increased central sensitivity to the same type of stimulus. |
Visceral and Cutaneous Hypersensitivity in Irritable Bowel Syndrome (IBS) | Verne et al., 2003 [32] | Rectal cutaneous pain produced increased activation in thalamus and SI, I, aCG, pCG and prefrontal cortex. | The brain is adversely affected in chronic pain – both visceral and cutaneous hyperalgesia produced. These findings provide a window on how we may address treatments for these patients. |
Irritable Bowel Syndrome (IBS) | Bonaz et al., 2002. [79] | Rectal pain produced in 11 female subjects with IBS. Activation in insula, amygdala and striatal regions. Greater activation in patients in the insula and frontal regions. | Similar to other studies a more complex alteration in pain processing is present in this group of subjects. Issues of variability in patients are still a concern. |
Chronic Inflammation
| |||
Vulvar vestibulitis | Pukall et al, 2005. [80] | Allodynia measured in patients (14) and controls (14) age and contraceptive matched. | Similar type of changes in patients with IBS, Fibromyalgia. |
fMRI of Human Surrogate Pain Models
fMRI studies of Endogenous Analgesia
STUDY FOCUS | REFERENCE | MAJOR FINDINGS | COMMENT |
---|---|---|---|
Placebo
| |||
Placebo | Wager et al., 2004 [49] | 2 studies report that (1) placebo analgesia decreased activation in thalamus, insula aCG and (2) anticipation increased activation in prefrontal cortex | Placebo analgesia may not only decrease pain but may change the affective response to pain. |
Placebo in Emotional Processing | Petrovic et al., 2005 [84] | Use of pleasant and unpleasant pictures compared with pain. The same modulatory effect is observed in "emotional" placebo and placebo analgesia (anterior cingulated, lateral orbitofrontal cortex) | Placebo is a process in reward processing. |
Placebo analgesia | Bingel et al., 2006 [85] | Nineteen healthy subjects. Placebo analgesia using laser for pain stimulation shows interaction between aCG, amygdala and PAG | Interactions between emotional circuits including the aCG amygdala and affect output processing of endogenous pain control mechanisms. |
Attention
| |||
Attentional modulation | Tracey et al., 2002 [46] | Nine Subjects. Distraction during painful thermal stimulus. Pain ratings significantly lower with distraction with increased activation in the PAG during this condition. | Specific output of modulatory system via a well-known brain region (i.e., PAG) presumably via inputs from higher cortical regions. |
Distraction | Valet et al., 2004 [47] | Stroop task used for distraction during noxious and innocuous heat stimuli. Distraction produced decreases in VAS pain intensity and unpleasantness scores. Distraction increased activation in orbitofrontal cortex, perigenual aCG, PAG and posterior thalamus. | Covariate analysis indicated that the brain may gate information by exerting a top-down effect on PAG and posterior thalamus. |
Cognitive Distraction Task | Bantick et al., 2002 [86] | Stroop task used. Intermittent thermal pain applied. Distraction produced increased activation in affective region of the aCG and in the Gob, but decreased activation in pain sensory regions including the cognitive area of the aCG, insula, and thalamus. | Dissection of the effects of distraction on emotional/affective vs. sensory systems in a distraction paradigm. |
Virtual Reality Distraction | Hoffman et al., 2004. [87] | Virtual reality decreased pain; both psychophysical ratings and brain activity in aCG, SI, SII, insula and thalamus. | Distraction has not been used in fMRI studies of chronic pain. |
Attention to 'location' and 'unpleasantness' | Kulkarni et al., 2005 [88] | Attention to location – activity in SI and inferior parietal cortex. Attention to unpleasantness – activation reported in aCG, orbitofrontal and frontal cortex, amygdala, hypothalamus and | Study focus is on how attention can significantly modulate pain processing. |
Miscellaneous
| |||
Empathy pain activates affective but not sensory pain | Singer et al., 2004. [89] | Empathy evaluated by subject in magnet observing loved one receive similar painful stimulus (empathetic pain). Activation in insular, aCG, brainstem and cerebellum by both direct or empathetic pain. | Activation in affective circuits not sensory – this may be further support for affective circuits being a focus of study in chronic pain. |
Pain and Social Loss | Panksepp, 2003 [90] | Evaluation of social exclusion (rejection). Activation in aCG and ventral prefrontal cortex > with exclusions | Commonality of physical pain response and emotional rejection/hurt? |
Salience of Painful Stimuli | Downar et al., 2003 [91] | Sustained pain and non-painful electrical stimulation. Transient activation during 'on' and 'off' of non-painful stimuli in aCG, inferior frontal, temporoparietal regions to non-painful. Same regions in addition to thalamus and putamen showed sustained response during painful stimulus. | Basal ganglia play a role in sustained salience. |
Expectancy orAnticipation
| |||
Dissociation of pain from its anticipation | Ploghaus et al., 1999 [27] | Expectation of pain produced activation in medial frontal region, insula, and cerebellum. These differed from pain experience. | Emotional/cognitive evaluation of a situation can produce adaptation that can modify the experience. This has enormous implications in the clinical situation e.g., anticipating a procedure. Effects in or on chronic pain are unknown. |
Expectation of Pain | Sawamoto et al., 2000 [92] | Expectation increases response to non-painful stimuli in the aCG and posterior insula. | Pain/unpleasantness and pain relief may be opponent processing using similar circuitry. |
Expectation of Pain Relief | Seymour et al., 2005. [21] | Activation in the amygdala and midbrain by pain are mirrored by opposite aversion signals in the lateral orbitofrontal cortex and aCG. | |
Expected vs. Experience Pain | Koyama et al., 2005. [93] | Pain intensity to expected vs. experienced pain evaluated. With increased level of expected pain, activation increased in aCG, insula, thalamus, and prefrontal cortex. Pain experience produced activation in a number of regions (partial overlap with expectancy related pain). | Expectation can modulate the actual experience. |
Anticipation of pain | Porro et al., 2002 [94] | Expectation of a pain/no pain stimulus to the foot. Activations increased in contralateral SI but decreased in ipsilateral SI, aCG. | Focus on cortical system |
Hypnotically induced (HI) or imagined pain | Derbyshire et al., 2004. [95] | HI pain produced activation in thalamus, aCG, I, prefrontal and parietal cortices. | Pain pathways can be activated without a noxious stimulus. This has implications for understanding CNS processing in chronic pain disorders with no specific etiology. |
Expectancy using a conditioning cue | Keltner et al,. 2006 [45] | Pain intensity expectancy acts via a modulatory network that converges on the nucleus cuneiformis (nCF) | A study defining a specific modulatory pathway on this brainstem nucleus. |
Paradoxical Sensations
| |||
Paradoxical heat | Davis et al., 2004. [48] | When subjects perceived a painful stimulus even though the stimulus was cool or neutral, activation in the right insular cortex was observed. | Sensory inputs in the normal healthy condition can "confuse" the brain. Such insights will be helpful in understanding pain processing in chronic conditions, particularly neuropathic pain. |
Prickle sensation | Davis et al., 2002. [12] | Prickle sensation using cold, produced activations present in pain, motor and sensory areas. aCG, SII, prefrontal cortex, caudate, dorsomedial thalamus, prefrontal cortex. | Definition of the utility of percept-related fMRI – i.e., importance of on-line measures of psychophysical data. |
Non-dermatomal sensory deficits. | Mailis-Gagnon et al., 2003 [96] | Noxious and non-noxious stimuli were not perceived in these dermatomes (Perceived stimuli activated posterior region of the aCG, thalamus); but produced decreased signal changes in a number of cortical regions (SI, SII, parietal cortex, prefrontal cortex and rostral aCG). | Four Patients tested to evaluate nondermatomal neurosensory deficits. Another insight into evaluating complex patient groups with altered pain processing. fMRI however does provide data in support of a testable neurobiological hypothesis instead of generic labeling of such patients. |
Acupuncture
| |||
Electroacupuncture vs. manual acupuncture | Napadow et al., 2005 [97] | For regional responses electroacupuncture>manual>placebo. Acupuncture induced increased activations in insula and decreased activations in amygdala, hippocampus and cingulated (subgenual and retrospelenial), ventromedial prefrontal cortex. No activations were seen for tactile control stimulations. | Difficult studies because good controls are so difficult. Process of activation of limbic and paralimbic structures may nevertheless be highly important in the therapeutic effect in clinical conditions. |
Activation of PAG | Liu et al., 2004 [98] | Mechanical stimulation produced activation in PAG after 20+ min of stimulation. | Activation of endogenous analgesic systems may be part of underlying effects of acupuncture. |
Pain Control
| |||
Controllability | Salomons et al, 2004 [99] | Control attenuated activation in anterior cingulated and insula. | Cognitive and affective control of pain has enormous implications in clinical aspects of potential painful procedures. |
Immediate Control of Brain Activation and Pain | deCharms et al., 2005. [100] | Real time fMRI (rtfMRI) to train subjects to control activation in rACC. Subjects (control and chronic pain) could change activation in ACC with corresponding change in perception to noxious stimuli | First use of rtfMRI in pain. |
fMRI Studies of Analgesics
STUDY FOCUS | REFERENCE | MAJOR FINDINGS | COMMENT |
---|---|---|---|
Opioids
| |||
Remifentanil(short acting μ opioid) | Wise et al., 2004. [101] | Activation measured in insula to noxious stimulus in subjects receiving Rx. | Study evaluates time course and half life of action of Rx in brain region. |
Remifentanil | Wise et al., 2002 [102] | Activation in brain regions to noxious heat stimulus in patients receiving Rx vs. saline. Rx produced decrease in level of pain activation in insula cortex. | First study to Evaluate CNS effects on stimulus; this allowed for extraction of regions most affected by the Rx. |
NaloxoneOpioid (μ antagonist) | Borras et al., 2004. [59] | 10 subjects. Direct drug effects indicated increased in aCG, prefrontal cortex, hippocampus and entorrhinal cortex. Post infusion painful heat produced increase in activation (correlated with psychophysical effects). | First study on opioids to address direct CNS effects. Naloxone is a drug that has no cognitive effects in normal healthy volunteers. |
Morphine (μ agonist) | Becerra 2006. [58] | Low dose morphine produces changes in reward (SLEA, NAc, GOb) endogenous analgesia (PAG), and hypnotic circuits. | fMRI of the effects of morphine on CNS circuits – indicating the use of this approach to define specific circuitry activated by a drug. |
Antiseizure meds
| |||
Gabapentin | Ianetti et al., 2005 [41] | Healthy volunteers. In a capsaicin model, single dose gabapentin has an antinociceptive effect but a stronger antihyperalgesic effect: the study indicates that the drug is more effective in the sensitized state. | An excellent example of the application of fMRI to drug evaluation in dissecting the value of a model with potential clinical relevance. |
Anti-inflammatory
| |||
Cyclogoxygenase-2 inhibitor (Cox 2) | Baliki et al., 2005 [61] | Patient with psoriatic arthritis. Single subject evaluation. Activation induced by palpating joints included thalamus, insula, SI, SII, aCG. Rx produced decrease at 1 h. | An example of specific application on evaluating efficacy of Rx. No drug site of action could be detected in this study. |
Antidepressant
| |||
Amitriptyline | Morgan et al., 2005 [62] | Evaluation of rectal pain in patients with irritable bowel syndrome. Rx produced a decrease in activation in aCG, parietal association cortex. | Another example of how the focus on efficacy (CNS) of drugs may be evaluated. |