Qu. What do a rat, a fur coat, and a Santa mask have in common?
Ans. Ethically dodgy science!
‘Little Albert’ was the victim of early 20th century psychology experimentation. At nine months of age he was given a white rat, and then frightened by a loud noise whenever he reached for it. Naturally, he came to fear white rats. Surprisingly, he also came to fear things that shared characteristics with the rat such as other animals, a fur coat and a person with Santa Claus beard. This spread of fear is common among individuals with anxiety disorders – phobias, post-traumatic stress and the like.
One explanation of this is that there is a problem in the brain’s ability to tell the difference between cues truly associated with danger (the rat), and cues simply sharing some of the characteristics of that cue (Santa beard and coat). The result is the inappropriate breaking of the proverbial ‘in case of emergency’ glass, activating physiological alarm systems – inappropriately.
So, how does the brain tell such cues apart? The authors of a recent article (published in Nature Neuroscience) think that it relates to whether your brain’s secretary has a meticulous, well-labelled filing system with many subfolders. This kind of filing system is established by a process called ‘pattern separation’ – the process by which (even) similar cues (and their meaning) are transformed into discrete, non-overlapping neural representations or memory files. If the representations of cues that share characteristics are not filed in discrete folders, then activation of one folder (i.e. the fur coat) may also inappropriately activate another (i.e. the rat).
The authors go on to suggest that brain areas (the hippocampus) and neurophysiological processes (neurogenesis) have been shown to be fundamental in the process of pattern separation. They suggest that stimulating neurogenesis in the hippocampus might enhance pattern separation and ameliorate anxiety (or, at least, relevant phenotypes of the disorder)1.
Seems like a hypothesis worth paying attention to!
Could this theory relate to chronic pain?
Here I see two potential links to chronic pain. The most obvious link relates to subgroups of patients in whom pain-related fear and anxiety are prevalent and are primary drivers of distress and disability[2,3]. Here, impaired pattern separation may help to explain the spread of fear from true danger cues to activities and movements which are not truly dangerous.
Secondly, failure of pattern separation may provide a mechanism by which non-nociceptive cues might come to activate pain responses. That is, if representations of non-noxious cues are filed in a way that overlaps with representations of painful noxious events, these non-noxious cues might come to cause pain. One example of this might be dysynchiria, shown to occur in some patients with Complex Regional Pain Syndrome. Dysynchiria is a phenomenon where visual input (looking at the reflection of the non-affected hand placed to look like the affected hand) elicits a painful response. Perhaps an overlapping visual and noxious (hand-related) filing has enabled visual input to activate pain representations. Certainly an idea worth pursuing….
In the meantime, I hope my external filing system is not a reflection of my internal one!!
New research from the ‘7th World Congress on Behavioural and Cognitive Therapies’Cognitive and behavioural therapy (CBT) is the most widely researched and used approach in psychology. A recent review of 108 meta-analyses showed that, when compared to other treatments (for psychological problems), CBT generally proves to be equally or more effective regardless of the condition – though it’s best with anxiety disorders. Where chronic pain is concerned, benefits are in the small to medium range with the greatest effects on disability and distress. Surprisingly, despite the magnitude of the pain problem and the large scale of this congress, the word ‘chronic pain’ would have barely been uttered if not for the small group of outstanding scientists depicted above.
Petra Karsdorp, Stéphanie Volders, Ann Meulders, Judy Veldhuijzen
In their packed out session, Dr Ann Meulders (second from right) led the discussion on fear, motivational goals and attention as mediators of pain, disability and suffering. Underpinning these presentations were the theoretical assumptions of the fear-avoidance model (FAM) – with each presentation confirming that those closest to the model are also the most aware of its insufficiencies and the most intent on testing its assumptions and extending its boundaries (for a blog about the FAM see Neil O’Connell‘s or Lorimer Moseley‘s blog post).
Dr Ann Meulders opened by pointing out that the FAM relies on the idea that after an injury, movements associated with pain, become initiators of conditioned fear responses (see blog post on classical conditioning and pain). As the FAM then stipulates, these fear responses (under certain conditions) drive hypervigilance and avoidance behaviour resulting in disuse, disability and distress (you know the cycle!). The conundrum here is that if movement (the conditioned initiator of fear) is avoided, then there should be no conditioned fear responses – leaving the relationship between fear and avoidance unexplained. Ann used a neat experimental design where particular movements of a joystick are paired with a painful shock (to induce movement-related fear), to show that after this pairing, increases in fear were present on the intention to move (as measured via a fear modulated reflex – ‘the startle response’). Thus the thought of/intention to move might be a covert initiator of pain-related fear and provide the link between fear and avoidance. Conundrum solved!?
Dr Petra Karsdorp (far left) followed this by pointing out that pain-related fear has only a small to moderate relationship with the development of pain-related disability, leaving the cause of avoidance largely unexplained. She proposed that another factor might be one’s ability to resist/inhibit automatic withdrawal responses in favour of other goals. To test this theory, Petra measured subject’s ability to inhibit automatic responses using a test called the ‘stop signal test’ (which you can read about in her paper). She then asked subjects to hold their hand in icy water and promised cash for persisting. Here the automatic pain-related withdrawal response was competing with the motivational goal of earning money. She then tested whether subjects ability to inhibit automatic responses (stop signal test score), predicted withdrawal of a hand from icy water. Whilst pain-related fear did not relate to quicker withdrawal, low score on the response inhibition task did. This raises the possibility that during a painful event, one’s capacity to inhibit automatic withdrawal responses, might contribute to the avoidance-related cycle. Early management might therefore benefit from enhancing focus on motivational goals and improving automatic response inhibition.
Dr Judy Veldhuijzen (far right) discussed the prioritisation of pain-related information (attentional bias) and associated clinical phenomena such as hyper-vigilance and impaired cognitive performance. Whereas the FAM proposes that pain-related fear drives this shifting of attention, meta-analyses have shown this not to be the case . Judy then proposed that if these attentional biases are not related to fear, then fear-based treatments are unlikely to assist this component of the problem. Rather, targeting attentional processes directly might better treat hyper-vigilance toward pain-related cues. She offered ideas here including an approach called ‘attentional bias modification’ to address implicit attentional biases, and altering cognitions to address more explicit biases.
Finally Dr Stéphanie Volders (second from left) discussed her research investigating why pain-related fear (and associated problems) might return after its successful treatment using exposure therapy (the model treatment for pain-related fear). Specifically she examined whether the things people do to feel safe in the short term (known as ‘safety behaviours), such as wear a back brace, might actually prevent successfully treatment. Using a laboratory study of healthy subjects, Stéphanie induced fear of movement by pairing a joystick movement with a painful shock . She then split the subjects into two groups. In one group subjects performed the same task without the painful shock (an analogy to exposure therapy which reduces fear by disconfirming the relationship between movement and harm) while those in the other group performed the same procedure except that participants were given the opportunity to press a button they were told would enable them to avert the shock (but which actually did nothing). In both conditions self-report data confirmed that fear of movement had been successfully extinguished. This phase was then repeated with neither group having the button. In the group that previously had the button, the fear of movement returned. Here it seems that even though the button did nothing, subjects attributed their safety to it. This she proposed was a clinical parallel for patients who might improve greatly in the short term, but attribute safety to the presence of the therapist, the walking stick, or the back brace and thus fail to make persistent gains in pain-related fear.
It seems that even 30 years on since it was proposed, and with all of its inadequacies, the FAM continues to be a catalyst for ideas for those who would look past its superficial exterior. Perhaps with important contributions such as these it is time for a new model.
When pain is predictably provoked by mechanical stress, and eased by its alleviation, we quickly implicate a mechanical, or at least peripheral, nociceptive mechanism, and apply diagnoses like mechanical low-back pain that justify our favoured peripherally directed interventions. While the logic is attractive, what if central processes could mediate this presentation? Centrally mediated pain masquerading as peripheral.
We recently investigated the idea of centrally-mediated mechanical symptoms (Harvie et. al 2015 PDF). The study involved twenty-four people with the type of persistent neck pain problems seen in everyday practice, and all with pain on rotation. They performed head rotation to their first onset of pain (P1), in three virtual-reality conditions where the amount of rotation that they saw did not match reality. Instead, the viewed rotation was more or less than was actually occurring, creating an illusion of movement that was different to actual movement. Remarkably, pain with movement depended not only on how far people actually moved, but how far it appeared they had moved (see figure and explanation in caption below).
Mean (circle) and 95% confidence interval (error bars) for the range of motion to first onset of pain presented as a proportion of the mean range of rotation for the neutral condition. When the visual feedback suggested less movement, the first onset of pain (P1) was delayed by 6%, when the visual feedback suggested more movement, P1 7% sooner.
That pain with movement can be reliably modulated by the (visual) suggestion of more or less movement (i.e. by a non-mechanical input) is significant, and prompts us to reconsider the mechanical presentation.
In the past, perceptions such as pain were simply considered a read-out of incoming information. However, it has become clear that we could not make sense of the world if sensory information was not first filtered and arranged by our subconscious. In the case of visual perception, for example, the infinite array of colours, edges and shapes are arranged by our subconscious into the meaningful objects that we see and understand. Certain rules seem to govern this process — such as the way objects are arranged according to continuity of lines, colour and motion. The rules that govern the construction of pain, while only recently receiving attention, appear to involve the brains analysis of information relating to bodily danger. Nociception is the most obvious signal of danger to the body — but not the only one. Specific movements for example, might also become signals of bodily danger because of their meaning derived from association with injury. This would explain how (visual) signals of movement may have come to be a contributor to pain in these people with neck pain.
While ample research supports the idea that signals of threat influence pain, this study suggests specifically that information about the body in space (whether visual, proprioceptive or vestibular) that has been associated with an injury, might be relevant signals of threat. Indeed their influence may even result in a clinical pattern that appears mechanical, but is in fact centrally driven.
The treatment of threatening pain-associations is an ongoing field of study. In the meantime I think that there are a few things we can do to better align clinical practice with the threat-based understanding of pain that this finding aligns with. Firstly, we can expand our minds and clinical assessments to identify both nociceptive and non-nociceptive sources of threat (guaranteed we wont treat something we don’t assess!). Secondly, we can leverage our skills in education and behaviour therapy to encourage thoughts and actions that counter threat.
Some for some ideas about countering threat/threatening associations in the clinic:
Primary nociceptor activity is clearly not the only mechanism that can increase central sensitivity and pain. For example, certain cognitive and emotional states can also enhance pain and act centrally.
A recent proposal has suggested that associative learning mechanisms such as classical conditioning, may also contribute to the clinical features of sensitisation (hyperalgesia and allodynia) and the development of chronic pain (Moseley and Vlaeyen, 2015). The theory proposes that after repeated pairing of a non-nociceptive stimulus and a nociceptive stimulus, the non-nociceptive stimulus might come to elicit responses that are intrinsically associated with nociception—think of the bell causing salivation in Pavlov’s dogs.
That is, by association with nociception, non-nociceptive stimuli might acquire nociception-like properties.
A number of studies have investigated the nociception-like effects of pain-associated stimuli. For example, some studies have shown that after a visual stimulus is repeatedly paired with a noxious stimulus, the visual stimulus starts to activate the brain in nociception-like ways, and can enhance the pain evoked by other stimuli (Atlas et al., 2010; Diesch and Flor 2007; Jensen et al., 2014; Keltner et al., 2006; Jensen et al., 2012). Thus, pain-associated visual cues can cause temporary (centrally) sensitised states. Quite profound, I think. However, given that people rarely report pain in response to visual cues (dysynchiria being one exception), instead more often in response to touch and movement, we tested whether tactile cues would have the same effect (SJP paper here).
To test this we made a device that could deliver touch at different locations using small vibrating motors attached to the skin—the same ones that make your mobile phone vibrate. We paired touch at one location with a painful electrical stimulus, and touch at another location with a non-painful electrical stimulus. In the following test phase a painful electrical stimulus was perceived as more intense when paired with the pain-associated touch.
Notably, the effect of the pain-associated tactile cues was smaller than that shown for visual cues in the studies I mentioned previously. We are still trying to understand why this might be. It could be that an equally influential association may take more than the time of a short experiment to develop within the tactile system, which tends to be less dominant than the visual system.
Interestingly, the effect that we did see didn’t seem to depend on the expectation of pain that might be elicited by the tactile cue. That is, when we delivered the pain-associated tactile cue at virtually the same time as the noxious stimulus (such that there was no time to expect the stimulus) the effect remained the same—suggesting that the effect is not dependent on conscious processes.
This kind of associative central sensitisation might explain other findings, such as why visual signals of exaggerated movement can contribute to pain in people with persistent pain (Harvie et al. 2015), or why the colour red might increase sensitivity (Moseley & Arntz 2007)—because these signals might have a prior association with danger.
Perhaps in the future we will be treating pain by extinguishing associations between touch or movement and pain, or by associating touch or movement with less threatening experiences and information. Perhaps some are already pioneering this approach.
The nociceptive system has evolved a range of intriguing characteristics. Spatial summation is one such characteristic, whereby increasing the area of a stimulus, or the distance between multiple stimuli, results in more intense pain—not only a greater area of pain. This befits pains’ protective function, because larger/multi-site injuries are likely to be more dangerous.
Defining terms. The effects of increased stimulus area, and inter-stimulus distance, have been labelled area- and distance-based summation respectively. In the lab, area-based spatial summation can be examined by contrasting the pain evoked by different sized noxious stimulations. Distance-based spatial summation can be examined by contrasting the pain evoked by pairs of noxious stimuli at increasing separations, relative to a pair adjacent. So far, studies show summation at separations up to at least 20cm.
One of the many questions that get me up in the morning is: Why is chronic spinal pain so prevalent compared to, say, chronic hand pain? It seems to me that pathological tissue models have so far failed to fully explain this discrepancy. One idea is that anatomical differences in the characteristics of the nociceptive system, such as the degree to which inputs summate, might help explain the vulnerability of one region over another. In a recent study we hypothesised that the effectiveness of the spatial summation effect would be greater at the spine than it is at the arm. We tested this hypothesis by asking participants to rate the intensity of pain evoked by various stimulus configurations at different body sites (for the precise methodology see free full text here).
Contrary to our hypothesis, all sites demonstrated the same magnitude of area- and distance-based spatial summation. Nonetheless, spatial summation is still likely to be a more relevant mechanism at some sites than others. For example, there is increased chance of spatial summation events in the spinal region, because there is significantly more tissue within relevant proximity compared to, say, a distal inter-phalangeal joint. In pure speculation: One could see a scenario where co-existing somatic and or/visceral conditions, particularly around the lumbar-pelvic region, might summate in such a way that the sum of (ordinarily more manageable) parts, results in a far more painful whole.
Dr Daniel Harvie is an NHMRC Early Career Research Fellow based at The Hopkins Centre in the Menzies Health Institute QLD at Griffith University. His main focus is the investigation of central nervous system contributions to persistent pain, and the development of brain-based treatments for preventing and treating persistent pain, including those that involve sensory re-training, virtual reality, and education.