In this sham-controlled trial of the effects of fast left dorsolateral prefrontal rTMS on perceived pain controllability, rTMS appeared to acutely interrupt the analgesic benefit of participants’ perception of control. Specifically, left dorsolateral prefrontal rTMS suppressed the benefits of perceived control on the emotional dimension (pain unpleasantness ratings) of the pain experience, but not the sensory/discriminatory dimension (intensity ratings). This effect was seen when fast rTMS was delivered during the brief period of time that perceived pain-controllability likely exerts it analgesic effect. This suggests that, at least acutely, rTMS might have suppressed the perceived-controllability effect. It is not clear whether this was due to direct manipulation of perceived control circuits in the dorsolateral prefrontal cortex that might exist but have not been well-established, or whether stimulation of the dorsolateral prefrontal cortex has downstream effects on anterolateral and medial prefrontal pathways which appear to be better established areas with respect to perceived control.
In 1967 Seligman and Maier developed the now classic learned helplessness (LH) model in dogs, which is an animal model that bears resemblance to depression, repeated stress, or chronic pain. [38
] The conclusions from this work – that people do better when they are given more control, or at least perceive that they have control – have revolutionized approaches to teaching, treating patients, or even training soldiers. In a more recent LH paradigm, normal healthy rats are yoked or paired, and subjected to intermittent stressors, typically a painful tail shock. One animal is provided a wheel in its cage that, when turned, terminates each of the shocks. For the other yoked animal turning the wheel has no consequence and the duration of each of the shocks is yoked to that determined by its partner whose behavior terminates each of the shocks. Both animals receive the identical amount of shock, but only the yoked animal that does not have control over the shocks develops behaviors that resemble the “depression” (and social isolation) often seen in individuals with chronic pain. [36
] The animal that has ‘the sense of control’ does not develop these behaviors. Recently Maier and colleagues have completed a series of studies that fairly convincingly demonstrate that this ‘sense of control’ is actually a signal from the ventral-medial prefrontal cortex (vmPFC) to the dorsal raphe nucleus (DRN). [1
] Thus, one can temporarily inactivate the prefrontal cortex in the animal that has behavioral control,, and even though they learn to abort the shocks, they still go on to develop behaviors typical of rats that do not have control. Interestingly, if the investigator does not
allow behavioral control, but instead pharmacologically activates the vmPFC during uncontrollable shock, the animal does not develop ‘depression’. [17
] They speculate that ‘..pharmacological activation of the vmPFC appeared to give rats the ‘illusion of control.’
] Growing evidence regarding the psychosocial concomitants of chronic pain suggests that patients with chronic pain resemble, in some ways, the previously yoked rat in the learned helplessness model, where repeated inescapable life stress (pain) leads to a feeling of ‘loss of control’ and despair. [22
In the present study, real TMS was associated with a directional outcome suggestive of analgesia, but this effect was not statistically significant. Previous dorsolateral prefrontal rTMS and pain studies have found analgesic effects, but most have focused on changes in pain perception pre- to post- rTMS and not what happens while rTMS is being delivered[11
]. The present design permits examination of the shorter-term mechanisms that might contribute to the pre- to post-rTMS analgesic effects. It may be that fast stimulation of the left dorsolateral prefrontal cortex acutely and temporarily interrupts circuit activity involved with classic cognitively-mediated analgesic effects (e.g., perceived controllability, expectation placebo analgesia), and that subsequently, this circuitry becomes hyper-excitable as some type of over-correction for the temporary lesion occurs. This hypothetical process might produce the temporary analgesic rTMS effect that is observed when examining changes in pain perception pre- (before simulation) to post- (during the hyper-excitability/over-correction period) stimulation.
With respect to mood and chronic pain, chronic repetitive stimulation of the dorsolateral prefrontal cortex likely initiates a cascade of events in the prefrontal cortex and in connected limbic regions. [24
] Interleaved TMS/fMRI and TMS/PET studies provide evidence to support this hypothesis. Prefrontal TMS sends information to important mood and pain regulating regions including the cingulate gyrus, orbitofrontal cortex, insula and hippocampus, and there is PET evidence that prefrontal TMS causes dopamine release in the caudate nucleus (and reciprocal activity with the anterior cingulate gyrus). [49
] Daily dorsolateral prefrontal rTMS for several weeks has antidepressant effects and the FDA has recently approved it as a standard treatment for depression. Further, repeated dorsolateral prefrontal rTMS treatments appear to have net analgesic effects (pre- to post- stimulation), but this is the first study to date suggesting that the immediate effects may involve interference with perceived-control-circuit activity, and that the longer-term effects (anti-depressant and/or analgesic) may be due to a homeostatic brain mechanism (i.e., increased activity to correct for a temporary lesion).
Thoughts, expectations and beliefs affect perception and influence behavior, and the research base addressing the neural circuitry mediating expectation-related analgesia is growing. The placebo response is likely a learning phenomenon [8
] that involves both subcortical and cortical mechanisms [27
]. Placebo analgesia is reportedly dependent on reward-related dopaminergic activity [46
], may share a common neural network with opioid analgesia [42
], and may reduce neural transmission within common pain pathways [51
]. Nonetheless, a growing body of evidence [8
] suggests that the prefrontal cortex is involved with what has been classically termed “placebo” analgesia, as the prefrontal cortex has repeatedly been shown to be involved in cognitive, attention, and expectation-related analgesia [22
The present study suggests that the decreases in the experience of the affective dimension of pain that are typically seen in response to the perception of control over noxious stimuli are modulated by the prefrontal cortex, and that concurrent prefrontal TMS can ‘knock out’ this behavior likely by interacting with this circuit. Krummenacher et al[28
] found that expectation-related analgesia could similarly be knocked-out with 1Hz rTMS over both the left and right dorsolateral prefrontal cortex, however, the present study only examined the immediate effects of “excitatory” rTMS over the left dorsolateral prefrontal cortex (a common treatment strategy for depression and some types of pain). More work is needed to establish the time course of prefrontal cortical activation and deactivation patterns in response to high-frequency rTMS (both during stimulation and after) in order to better establish neurocognitive mechanisms of action of prefrontal rTMS for chronic pain.
Despite evidence that prefrontal TMS can have analgesic effects, fast left prefrontal TMS appears to acutely suppress analgesia associated with perceived-control. This effect may be limited to the emotional dimension of pain experience.