Table 4 Examples of Contributions of fMRI on Endogenous Mechanisms of Pain or Analgesia

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.