It is no longer a question of “if” thoughts affect the body but “how”? Cognitive behavioural therapeutic approaches to long term conditions have long demonstrated some of the indirect pathways between thoughts and symptom experience. Namely via the emotions that thoughts elicit and the behavioural responses to thoughts and symptom experience itself. But what about that direct link between thoughts a physiology that seems altogether more magical?
The previous blog posts have looked at the nocebo and placebo effect. These terms refer to the phenomenon whereby expectations of physical effects of an intervention can result in these physical effects without any active substance provided. Research in these areas show us what the mechanistic pathways between thoughts and physical changes in the body resulting in sensory experiences might be.
Perhaps unsurprisingly this is a complex area with no definitive answers. The conclusion thus far from research seems to be that there is no one set pathway, but instead multiple potential pathways. These pathways may interact with each other and be differentially affected by other influences including the situation, environment and individual differences such as age, sex, beliefs, prior experiences, etc. Findings highlight that there is no “one size fits all” when it comes to understanding how thoughts affect physical experiences. That being said, there are some really compelling neuroscientific studies that have generated some fundamental insights into what some of these mechanistic pathways look like.
It can be helpful to think of the process as a journey. This journey starts with a stimulus being presented to an individual. This could be the offering of a medication, or, if we broaden this out to thoughts in general, it could be a situation (leaving the house when knowing symptoms can be unpredictable) or an internal consideration (today seems like it will be a good/bad day). From here, individuals will create an expectation of what the likely outcome is. This is the bit that perhaps there is most ambiguity around precise processes. How does this manifest physiologically? What can be safely asserted is that the creation of expectation is associated with activation in the prefrontal cortex (PFC). The PFC is located at the top and front of the brain and is associated with intentional thought and attentional direction and control (amongst other things). The PFC is therefore considered part of the “cognitive brain” i.e. thinking brain.
Studies have indicated that an additional area of the brain is involved in the forming of expectation in the context of physical outcomes. This is the anterior cingulate cortex, specifically the rostral anterior cingulate cortex (rACC). Studies have demonstrated increased cerebral blood flow to this part of the brain when individuals form an expectation in placebo studies. Furthermore, higher activation in this area of the brain is associated with placebo responders versus non-placebo responders.
The rACC is in a unique position in the brain as it has connections to both the cognitive PFC and the “emotional” limbic system within the brain, which is located in the middle of the brain (to describe the positioning crudely). It stands to reason that the rACC then plays a role in coordinating interactions between the cognitive part of the brain and the parts of the brain that are involved in emotion and pain processing. The rACC has a role in emotional expression, attention allocation and mood regulation.
Activation in the rACC informs activity in another mid brain area of the brain called the periaqueductal gray (PAG). This part of the brain has a critical role in autonomic function (think fight/flight activation in the autonomic nervous system) and behavioural responses to threatening stimuli. The gate control theory of pain places emphasis on this area of the brain in having a downregulating effect on pain, through exertion of control on spinal pathways. Here it is important to remember that the spine acts as a conduit of messages from the brain to the body via vast nerve networks. Neuroimaging studies show that neural interactions between the cognitive brain (the PFC), the rACC and other brainstem areas and the spinal cord can mediate the placebo effect (i.e. the relationship between expectation and physical experience).
If you’re next question is, “but how does brain activation result in these sensory changes in experience?” let me do my best to explain. There seems to be four main neurobiological pathways that may be at play which can be grouped under three categories of processing. Again, what pathways are activated in response to which context, cannot easily be pinned down due to the impact of many individual differences that may occur. To some degree, I think the specifics are less important if you are simply trying to understand the basics of how thoughts become things. We don’t want to aspire to micromanage specific synaptic firings after all (hello perfectionism, am I right?).
The three processes and their underlying neurobiological pathways are:
Pain regulation pathways through opioid and endocannabinoid signalling
Reward pathways through dopamine signalling
Emotion regulation pathways through serotonergic signalling
It’s important to note that these pathways are perhaps best understood as having the potential to interact with one another, rather as separate highways with barriers round the outside. Rather than a highway system, think more the binding of a book; while each page can be considered separate with its own contribution, the existence of one page impacts on the positioning of another in the binding and what words appear where in the book. Together they create a whole narrative.
Let’s start with the first one.
Activity induced in the PFC, PAG and rACC due to analgesic (pain relief) expectations has implicated the role of opioid receptions in the down regulation of pain. Opioid receptors are a particular type of receptors that are embedded on the outer layer of nerve cells (neurons). Particular drugs, opioids, attach to these receptors and this triggers chemical changes within the nerve cells and between them that can lead to the experience of pain relief and pleasure. Opioid receptors therefore play a crucial role in pain signalling withing the central and peripheral nervous systems and the immunological response.
Neuorimaging studies show that opioid receptors on the pain signalling pathways in the brain are activated in response to expectations of analgesia and this activation is the same as if individuals had been given an opioid substance. Interestingly, as well as impacting on pain pathways, opioid systems have also be shown to impact on respiratory responses reducing heart rate.
Another group of neurotransmitters that have a role in pain regulation are implicated in the placebo response. These are endocannabinoids. These bind to specific cannabinoid receptors with differing effects including the regulation of physiological experiences (appetite, pain) and emotional experiences (mood, exercise-induced euphoria). There are specific cannabinoid receptors that are expressed in the central and peripheral nervous systems. Studies demonstrate that increased endocannabinoid levels in the brain are associated with a greater placebo response (i.e. reduced pain experience due to expectation) and improved mood.
It is not yet clear whether these opioid and endocannabinoid pathways have a downregulating effect on pain (i.e. from the brain down to the peripheral site of pain) directly or whether this effect is associated with reward circuitry in the brain. It is postulated that positive expectations may increase positive emotions and activate “reward” systems or decrease negative emotions such as anxiety and therefore interact with emotion regulation pathways.
The signalling of opioid receptors in pain pathways is associated with the activation of reward pathways, as dopamine is released in brain circuitry associated with the experience of pleasure. In fact, studies demonstrate that higher placebo effect correlates with higher level of dopamine activation.
Individual neurons involved in dopamine signalling pathways have axons (extensions from neuron cell body that conduct electrical impulses from one neuron to another) that span the entire length of the pathway. Dopamine neurotransmission has an impact on the regulation of many functions. These including motivation, learning and the release of stress hormones. Reduced dopaminergic activity is related to high pain sensitivity. This has been demonstrated in a range of populations including those with irritable bowel syndrome.
Different factors moderate the effect of expectation (placebo) on dopamine pathways, including the role of genetics. Some people are more or less likely to experience increased dopamine neurotransmission based on genetic expressions.
Emotion regulation pathways
As we have seen some of the changes observed in other pathways are also associated with changes to emotion and mood states. Like dopamine, serotonin is a neurotransmitter that plays a role in positive mood and emotions. While dopamine is predominantly related to rewards and motivation, serotonin is associated with feelings of happiness, calmness and increased focus. Too much or too little serotonin can cause psychological and physical problems. Low levels of serotonin are associated with depression. Serotonin also acts as a hormone. It has many roles including learning, memory formation, regulation of mood, body temperature regulation and sleep.
Some research has implicated serotonin as having a role in the placebo response. Unlike with the other pathways considered so far, researchers hypothesise that serotonergic activity may play a role in the conditioned response to a placebo. That is to say that there is a neurochemical response that may be learned from previous experiences (for example pain relief from taking medication) and that this is triggered when given a placebo. The exact role of serotonin in this conditioned response is not clear but serotonergic pathways have been implicated in the facilitation of this effect. This perhaps is distinct from the dopamine pathway (although could interact) as the conditioned response bypasses conscious cognitive processing. It would make sense that serotonin plays a role in this process given its multi-functionality, specifically overlapping functions of learning, memory, mood and regulation of bodily states. Studies have demonstrated that activation of the serotonergic pathways impact hormonal and immune responses, lowering cortisol and increasing white blood cells in the lymphatic system.
Want a catchy summary of this information to help you make sense of it?
When you have thoughts about something related to your perceived physical experience, this is underpinned by brain activity. If we zoom in and look at the neurobiological processes that underpin this activity, we observe multiple pathways by which thoughts, feelings and sensations interact. This can happen at a conscious level, where you consciously create an expectation about what might occur, or at a subconscious level where previous experiences have been enshrined to a seemingly automated “memory”.
How can I use this information to empower my own health journey and navigate symptom experience?
· Inform yourself about how treatment works and get reputable information about this process that you understand and trust the source of. By understanding the mechanisms you can enhance your expectancy that something will work.
· Pay attention to indicators that things are working as you’d wish, no matter how subtle. Just noting is fine.
· Do things generally to enhance your mood and increase your sense of connection. We’ve seen how pathways between expectation, mood and pain interact. You may not be able to increase your degree of belief but perhaps you can enhance your mood, which may have a knock-on effect.
· Reduce factors that are likely to negatively inform expectations. For example, ongoing google searches and support group scroll holes might make you more aware of the possibility of negative outcomes and scare stories.
· Use imagery to help imagine what it might look like to experience symptom relief or for your body to restore a level of equilibrium. The brain is not good at distinguishing between real and imagined images, so creating an image can shift affective and sensory states.
Cai, L., & He, L. (2019). Placebo effects and the molecular biological components involved. General Psychiatry, 32(5).
Atlas, L. Y. (2021). A social affective neuroscience lens on placebo analgesia. Trends in Cognitive Sciences, 25(11), 992-1005.
Stevens, F. L., Hurley, R. A., & Taber, K. H. (2011). Anterior cingulate cortex: unique role in cognition and emotion. The Journal of neuropsychiatry and clinical neurosciences, 23(2), 121-125.
Wager, T. D., & Atlas, L. Y. (2015). The neuroscience of placebo effects: connecting context, learning and health. Nature Reviews Neuroscience, 16(7), 403-418.
Bishop, F. L., Coghlan, B., Geraghty, A. W., Everitt, H., Little, P., Holmes, M. M., ... & Lewith, G. (2017). What techniques might be used to harness placebo effects in non-malignant pain? A literature review and survey to develop a taxonomy. BMJ open, 7(6), e015516