Exploring Chronic Pain: the Role of the Cortex
Have you ever experienced chronic pain? Find out how the cortex plays a role in its causes and manifestations in this informative article.
Introduction
This is the first in a series, which will explore pain across the three categories which momentum focusses on: global issues, science and music, delving into three specific areas in each category. Pain, and the avoidance of pain is, arguably, the sole motivation behind human action and the causes and manifestations of this experience, in both the artistic and anatomical sense, are vital to understand in attempting to comprehend the world in which we live.
This article will focus on the role of the cortex in the causes and manifestations of chronic pain. Indeed, it is specific - so specific it may seem irrelevant - but more futile still would be to attempt to examine anatomical expressions of pain under a broad lens, as only with precise and specific knowledge can we hope to gain insight. As the Russian playwright Anton Checkhov wrote to his brother; ‘minute particulars are essential. God save us from vague generalisations!’
Pain
Inflammatory pain, the ‘normal’ pain which we are all familiar with, quite happily occurs as a side effect of inflammation, which is a protective response to tissue damage or infection. The typical mechanism progresses as follows:
Diagram 1 - response following noxious stimulation
The ‘various points of termination’ vary depending on the stimulus, but most often, the fibres will synapse at the top of the spinal cord, from where impulses are relayed to specific parts of the brain, including parts of the cortex.
Although unpleasant, inflammatory pain is, more often than not, an angel in disguise - an acute pain appearing briefly as a reassurance that our bodies are taking the necessary responses when faced with danger. More scary is chronic pain, which persists over a long period of time, with significant real world consequences, such as reductions in standards of living and impacts on relationships, as well as mental and physical health.
Current Research on the Cortex and Chronic Pain
Spontaneous pain is pain which occurs without the effect of external stimuli, and is a challenging aspect of pain to deal with, particularly in the case of chronic pain, due to the apparent lack of culprit. In a study published in January by Ding et al., clinically relevant mice were studied using intravital two-photon calcium imaging to deduce that orofacial spontaneous pain activated synchronised neural dynamics within the primary somatosensory cortex (S1), underpinned by decreased activity of local GABAergic interneurones. Let’s break that down. Intravital two-photon calcium imaging is simply a method of analysis which uses a two-photon microscope to visualise fluorescent calcium indicators within cells, in order to measure calcium dynamics. The cerebral cortex is a thin layer of neural tissue, covering the surface of the cerebrum, which plays a key role in processes such as vision and olfaction, and also neurological and psychiatric diseases. The primary somatosensory cortex is part of the cerebral cortex, which is involved in the processing of sensory information that relates to touch, pain, temperature and proprioception. It receives input from sensory receptors, including within the skin, muscles, internal organs and joints. Interestingly, it is organised in a somatotopic manner, which means that distinct regions of the cortex represent different parts of the body. Supposedly, the scientists conducting this study decided to focus on orofacial spontaneous pain because the region projecting the orofacial area in the S1 is the largest of all body area projections. Hence, the study revealed that spontaneous pain caused synchronised activity in the S1 part of the cerebral cortex. This was accompanied by reduced activity of GABAergic interneurones, which are neurones that release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Hypoactivity of these neurones has been associated with epilepsy, schizophrenia, anxiety and developmental disorders. Therefore, by selectively activating GABAergic interneurones, the synchronisation of the S1 networks was reduced. Another mechanism that was discovered is the chemogenetic inhibition of pain-related c-Fos-expressing neurones. The c-Fos protein is a gene which is rapidly synthesised and translated into c-Fos protein following the activation of neurones. Therefore, by inhibiting these neurones, the cascade of gene expression following the activation of neurones relating to pain, is disrupted.
Another unpleasant element of chronic pain is central sensitisation, which is when the central nervous system becomes hypersensitive to pain signals, leading to an enhanced and prolonged pain response. It occurs to neurophysiological changes which occur in the central nervous system, which can contribute to the development of hyperalgesia. Hyperalgesia is a condition where the patient experiences increased sensitivity to pain, and in September 2019, Bai et al. published a paper on the role of the anterior insular cortex (aIC) in the pathogenesis of hyperalgesia in a rat model of CP, induced by trinitrobenzene sulfonic acid treatment. Again, let’s break that down. The anterior insular cortex is an area of the cerebral cortex between the temporal lobe and frontal lobe, involved in functions including sensory processing and emotion. It is interconnected with other brain regions such as the somatosensory cortex and the prefrontal cortex. Damage to the anterior insular cortex has been associated with chronic pain disorders, addiction, mood disorders and schizophrenia. TNBS is a molecule used to trigger an immune response and inflammatory reaction in the intestinal mucosa of animal models, leading to tissue damage and inflammation. The results of the study revealed that TNBS treatment led to anxiety-like behaviour and long-term hyperalgesia. The rats showed an increased expression of c-Fos and enhanced excitatory synaptic transmission within the aIC. This is consistent with the findings of Ding et al., showing that increased levels of c-Fos are associated with the sensation of pain. What Bai et al. identified was the anterior insular cortex as a possible target in treatment options for chronic pain.
A common thread which may have been noted up to this point, is the link between anxiety and chronic pain; reduced activity of GABAergic neurones was associated with increased anxiety, as well as damage to the anterior insular cortex. This link was explored more explicitly by Gao et al., in a paper published in March. The prelimbic cortex is a region of the prefrontal cortex, and is involved in functions including emotional regulation and decision making. Dysfunctions in its activity are associated with depression anxiety and addiction. It was found that during chronic pain, there was increased neuronal activity in the PrL neurones projecting to the basolateral amygdala and neurones projecting to the ventrolateral periaqueductal gray. The basolateral amygdala (BLA) is a part of the amygdala principally involved in receiving sensory information, which is then processed within the amygdala. The amygdala is involved in emotional processing, memory formation and the regulation of responses to fear and stress. The BLA is particularly important in fear conditioning, by associating a certain stimulus with a fearful outcome. It has also been associated with anxiety disorders, PTSD and addictive behaviours. The ventrolateral periaqueductal gray (vIPAG) is a region in the midbrain, surrounding the cerebral aqueduct, a canal running through the brainstem. The periaqueductal grain is involved in the modulation of certain physiological and behavioural responses, whilst the ventrolateral periaqueductal gray is primarily involved in the regulation of behaviours associated with fear, as well as the modulation of pain processing. It was found that through suppressing the circuit between PrL neurones and the BLA, anxiety behaviour were reduced, and through suppression of the circuit between PrL neurones and the ventrolateral periaqueductal gray, hyperalgesia was reduced. Thus, anxiety and pain, although clearly linked through the prelimbic cortex, are involved in different circuits, and whether a more robust neurobiological link exists remains to be seen.
Bibliography:
https://www.jci.org/articles/view/166408
https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-019-0497-5