What Factors Impact Our Perception of Pain?

Post by Lani Cupo 

Do individuals perceive pain differently?

Describing how bad our headache is, how much our broken arm hurts, or what childbirth feels like are complex and nuanced exercises in communication. If you and your sibling both have your wisdom teeth removed, what factors determine whether one of you will be in enough pain to fill a prescription for medication and the other won’t?

Among humans, the perception of pain can vary dramatically among individuals. According to a biopsychosocial model of pain, the perception of painful stimuli are influenced by three main types of factors: biological, psychological, and social factors. This means that there is not necessarily a consistent correspondence between pain and pathology. In other words, the same stimulus — consider a broken bone for example — may correspond with high degrees of distress in some individuals while others barely register the break as painful.

How do sex and gender impact the perception of pain?

Two widely investigated, nuanced factors impacting pain perception and expression are gender identity and biological sex. Scientific studies repeatedly report that in comparison with men, women exhibit more robust perceptual responses to experimentally-induced pain. For example, women report lower thresholds and tolerances to stimuli such as heat and pressure. Nevertheless, recent research suggests that differences in pain perception are fairly subtle, and driven by context. Sex differences are in part explained by the way in which experiments are conducted, as women may be more sensitive to rapid or dynamic changes in noxious stimuli, such as when the stimulus begins or increases in intensity. In contrast, women have been shown to habituate or adapt faster than men when a painful stimulus is consistently applied. Further, it is important to note that women tend to be more perceptive in general than men across many sensory modalities, including temperature, smell, taste, and vision. It can be easy to misconstrue reported sex differences and view them with an archaic lens that portrays women as oversensitive or weak in the face of adversity.

In humans, it can be tricky to separate the impact of biological sex from the impact of sociological factors. Rodent studies can lend insight, where biological sex is considered at the exclusion of gender. Such studies also reveal sex differences in pain perception, but recent research suggests that there is an interaction between sex and background genetic strain in mice and rats, with some strains demonstrating increased sensitivity in females, others demonstrating the opposite, and still others showing no difference.

The causes underlying sex or gender differences in pain perception have yet to be fully investigated, however, there are several proposed mechanisms. One hypothesis states that gender roles may alter the perception of pain; women may feel it is more permissible to express and feel pain. From a biological viewpoint, sex hormones have been shown to alter nociceptive processing. Castration of male rats and androgenization of female rats in the first week of life has also been shown to reverse sex-dependent effects of pain perception, pointing to a role of gonadal hormones on altered perception.

How does age impact the perception of pain?

Another common factor that can alter pain perception is age. As humans age, the threshold for pain increases, meaning it takes a more intense noxious signal to alert an older individual that something is wrong. This increases the risk of injury in older adults. Contrarily, tolerance for pain usually decreases, with older participants withdrawing from painful stimuli sooner than younger participants in experimental settings. This could be in part due to increased perception of pain as unpleasant in older ages. Unpleasantness differs from intensity, with the former representing how bothersome the pain is and the latter representing how severe it is. Most studies in humans, however, neglect to report data on the changing perception of pain unpleasantness.

Aging is associated with degradations to both neurons themselves and connections between brain cells. Changes in brain regions involved in the processing of painful stimuli, such as the prefrontal cortex, primary and secondary somatosensory cortex, hippocampus, anterior cingulate, insula, and thalamus, may in part be responsible for the changes in pain perception over the lifetime.

How do psychosocial factors impact pain perception?

Mood is one of the major psychosocial factors investigated in relation to pain perception. In patients with chronic pain, negative mood, such as transient anxiety and depression, are associated with greater intensity of pain. Of course, more intense pain could also result in lowered mood, however, in studies examining acute pain stimulus in healthy individuals, negative mood has also been linked with greater pain sensitivity. In contrast, positive moods can relieve pain, with pleasant stimuli such as music, pictures, and funny movies reducing pain perception. While not all pain can be mitigated by distraction or a positive mood, the idea that positive affect can help reduce the valence of painful stimuli is very powerful, providing alternative routes of analgesia to individuals experiencing acute or chronic pain in some cases instead of pharmaceutical drugs. Finally, some studies have investigated the impact of brief mindfulness or meditative practices on the perception of acute pain in the lab, finding reductions in pain responses and inspiring further research on the topic.

What does it all mean for me?

While there is a robust body of literature suggesting the role sex, gender, and age have on perceptions of pain, individual differences can, of course, outweigh the impact of demographic variables, meaning some women may have a higher pain threshold than men, or some older individuals may have a higher tolerance than some teenagers. Because pain sensation is so subjective and can be extremely difficult to communicate, it is important to recognize that individual differences can affect how people cope with pain and even what they consider to be painful. The fact that psychological variables, such as mood, can ameliorate pain provides an exciting future avenue that has the potential to help some individuals mitigate the negative impact of both acute and chronic pain.

References

Bushnell et al. Cognitive and emotional control of pain and its disruption in chronic pain. Nature Reviews Neuroscience. (2015). Access the original scientific publication here. 

Diatchenko et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Human Molecular Genetics. (2004). Access the original scientific publication here.

Fillingim. Sex, gender, and pain: Women and men really are different. Current Review of Pain. (2000). Access the original scientific publication here.

Gibson & Farrell. A review of age differences in the neurophysiology of nociception and the perceptual experience of pain. Clinical Journal of Pain. (2004). Access the original scientific publication here.

Hashmi & Davis. Deconstructing Sex Differences in Pain Sensitivity. Journal of Pain. (2013). Access the original scientific publication here.

Mogil et al. Sex differences in thermal nociception and morphine antinociception in rodents depend on genotype. Neuroscience & Biobehavioral Reviews. (2000). Access the original scientific publication here.

Sandhu & Leckie. Orthodontic pain trajectories in adolescents: Between-subject and within-subject variability in pain perception. American Journal of Orthodontics and Dentofacial Orthopedics. (2016). Access the original scientific publication here.

Taenzer et al. Influence of psychological factors on postoperative pain, mood and analgesic requirements. The Journal of Pain. (1986). Access the original scientific publication here. 

Zeidan et al. The effects of brief mindfulness meditation training on experimentally induced pain. The Journal of Pain. (2009). Access the original scientific publication here.

Neurofeedback Facilitation Improves Gait and Balance in Post-Stroke Patients

Post by Amanda McFarlan

What's the science?

Recovery from gait and balance impairments that arise following a stroke usually occurs in the first 12 weeks post-stroke, after which point there is little improvement. Recently, it has been shown that functional near-infrared spectroscopy (fNIRS) mediated neurofeedback, a technique where an individual can learn to use feedback about their brain activity to further regulate their neural activity, may be a promising tool to treat post-stroke patients with impairments. This week in Neurology, Mihara and colleagues used a two-center, double-blind, randomized, controlled study to investigate whether fNIRS-mediated neurofeedback is a feasible method of treatment for recovery of gait and balance in post-stroke patients.

How did they do it?

The authors recruited a total of 54 adult patients who had experienced a subcortical stroke that resulted in hemiplegic gait and balance disturbances that persisted more than 12 weeks after stroke onset. The patients were randomly assigned to be in the treatment group or the control group. To evaluate their motor function, all patients received a clinical assessment which included measures like the 3-meter-Timed Up-and-Go test and the Berg Balance Scale. These assessments occurred at three time points: (1) before the neurofeedback intervention, (2) immediately following the neurofeedback intervention, and (3) two weeks after the neurofeedback intervention. The neurofeedback intervention consisted of six sessions in which patients underwent the facilitation of the supplementary motor area using fNIRS while performing a motor imagery task. In the treatment group, patients received real-time neurofeedback signals that represented the activity of their supplementary motor area while performing the task, while the patients in the control group received pre-recorded signals that did not match their brain activity.

What did they find?

The authors found that following the neurofeedback intervention, the treatment group had a significant improvement on the 3-meter-Timed Up-and-Go assessment compared to the control group. The treatment group also had greater improvement on the Berg Balance Scale assessment compared to the control group. Additionally, when comparing the first and last sessions of the neurofeedback intervention, the treatment group had increased activity in the supplementary motor area and increased connectivity between the supplementary motor area and the ventrolateral premotor area. These enhancements in supplementary motor area activity and connectivity were positively correlated with balance recovery. Importantly, no adverse effects related to the neurofeedback intervention were reported during the study.

What’s the impact?

This study highlights the feasibility and efficacy of a neurofeedback-based intervention that can be used for the recovery of gait and balance disturbances in stroke patients. The authors showed that this intervention, which facilitates the activity of the supplementary motor area using fNIRS-mediated neurofeedback was correlated with balance recovery in post-stroke patients. Together, these findings provide evidence for a promising new treatment that may be useful for the recovery of stroke-related motor impairments.

Mihara et al. Effect of Neurofeedback Facilitation on Post-stroke Gait and Balance Recovery: A Randomized Controlled Trial. Neurology (2021). Access the original scientific publication here.

The Anterior Cingulate Cortex Directs Exploration of Alternative Strategies

Post by Andrew Vo

What's the science?

Life often throws us curve balls. How we successfully deal with such changes and challenges in our complex environments involves continuous evaluation of our ongoing strategy and switching away to alternative approaches when suitable. The anterior cingulate cortex (ACC) has been implicated in this arbitration between ongoing and alternative strategies, but whether this brain region plays an active role in this process or simply tracks related variables remains unclear. This week in Neuron, Tervo and colleagues demonstrated the role of ACC in strategy arbitration using a foraging task and pathway-specific ACC perturbation in a rodent model.

How did they do it?

The authors trained rats on a foraging task that allowed them to dissociate strategy commitment from strategy re-evaluation. Each trial was initiated at a central nose port, from which rats would decide between two options (levers on the left or right) cued by two auditory tones that were each paired with a distinct probability of receiving a sugar reward (e.g. tone for left lever: 50% probability of reward, tone for right lever: 90%). To either accept or reject the presented option, rats would perform lever presses for possible reward or re-initiate the trial from the central nose port, respectively (see figure). The probabilities of reward for each option changed independently over time

To test the role of the ACC in two distinct computations underlying strategy arbitration, the authors used optogenetics to temporarily “silence” ACC activity either (1) during tone presentation when rats encountered and committed to an encountered option, or (2) after feedback delivery when rats re-evaluated the ongoing strategy. Extracellular recordings of ACC allowed them to observe the selective engagement of ACC during the task. In addition to silencing the entire ACC, the authors also selectively targeted two candidate ACC subcircuits—the intra-telencephalic (IT) and pyramidal tract (PT) pathways—to examine their unique contributions to either option commitment or strategy re-evaluation.

What did they find?

After training, rats were found to strongly prefer one presented option over the other, however, they would continue to occasionally pursue the available non-preferred option throughout the task. These latter trials represented transient switches away from the ongoing strategy towards an alternative. Perturbing ACC activity during option commitment (tone presentation) significantly reduced acceptance of the non-preferred option following unrewarded preferred trials. In contrast, ACC perturbation during strategy re-evaluation (feedback delivery) significantly increased acceptance of the non-preferred option. The authors found that patterns of neuronal activity in the ACC associated with acceptance of preferred versus non-preferred options were distinct and decodable, suggesting ACC is actively involved in the decision-making process.

Optogenetic manipulation of the IT pathway (an ACC subcircuit) during strategy re-evaluation (but not option commitment) increased the probability that rats would accept the non-preferred option following unrewarded preferred trials. In contrast, perturbation of the PT pathway (another ACC subcircuit) during option commitment (but not strategy re-evaluation) reduced the likelihood that rats would accept the non-preferred option. Taken together, these findings demonstrate that the two perturbation effects observed with ACC inhibition at separable time points are mediated by dissociable ACC subcircuits.

What's the impact?

In summary, this study demonstrates that ACC plays an active role in strategy switching. Computations involving strategy re-evaluation versus commitment to pursue an alternative option were shown to be anatomically and functionally dissociable. Critically, the authors offer causal evidence of this role by using targeted optogenetic perturbations during distinct time points and within specific ACC pathways.

Tervo et al. The anterior cingulate cortex directs exploration of alternative strategies. Neuron (2021). Access the original scientific publication here.