How Are Chronic Pain and Depression Related?

Post by Laura Maile

What is chronic pain?

Pain is a necessary part of life. It helps us learn what is dangerous and how to avoid things that will cause injury to our bodies. In many instances, however, the acute pain that alarms us to a potential threat to our physical safety can outlast both the source of the harm and our physical recovery from the initial injury. When this happens and the pain lasts more than three months, it is called “chronic.” Chronic pain, which is endured by 100 million people in the US alone, is a burden that causes daily suffering, reduces quality of life, often leads to loss of work, and negatively impacts mental health.  

Normally, when an injury or environmental stimulus causes us pain, something has caused physical damage, like burning a finger on a hot stove or surgery to repair a broken arm. In these situations, nociceptors (a type of neuron), receive signals of that damage in the part of the body that is hurt and relay those messages to the spinal cord and then the brain, where those signals are often interpreted as pain. In many instances of chronic pain, there is no apparent ongoing damage in the parts of the body where pain is felt. Pain, therefore, exists in the brain, not in the body. It is now understood that chronic pain can be a symptom of disease, such as cancer-related pain and chronic headache, or it can be a disease in its own right, which is seen in conditions like fibromyalgia.  

How are pain and mood disorders related?

Chronic pain and mood disorders like depression occur frequently in the same patients and tend to exaggerate the symptoms of one another. Studies indicate that if you have major depressive disorder (MDD), you are three times as likely to develop chronic pain. According to the World Health Organization, if you have persistent pain you are four times as likely to have a mood disorder like anxiety or depression. In addition to their frequent co-occurrence, the severity of symptoms also plays a role. In one study of older adults with chronic pain, both the number of body parts affected and the frequency and severity of pain were associated with a higher incidence of depression. In another study where patients were followed for 12 months, a change in the severity of depression symptoms strongly predicted an increase in the severity of reported pain. Chronic pain, understandably, can lead to feelings of loneliness, despair, and anxiety. Symptoms caused by pain, such as loss of sleep, can exacerbate those feelings, many of which overlap with symptoms of depression. It may therefore seem logical that individuals with chronic pain are more likely to develop mood disorders like depression. Why though, are people with depression more likely to develop chronic pain? 

Neurobiology of chronic pain and depression

Both chronic pain and depression have been studied for decades in humans and animal models. Pain researchers have uncovered a set of brain regions involved in pain processing, often called the pain matrix. These include areas of the medial prefrontal cortex (mPFC), anterior cingulate cortex, the somatosensory region of the parietal cortex, insula, amygdala, thalamus, nucleus accumbens, and areas of the midbrain including the periaqueductal gray. Importantly, these regions do not exclusively process pain but are important for various other functions including emotional regulation, motivation, memory, and cognition. Some regions of the pain matrix, like the mPFC, insula, and amygdala, are more significantly involved with the affective emotional component of pain that causes suffering, rather than other elements like location and intensity. These regions are also important in processing emotion and analyzing the contextual and emotional significance of relevant stimuli to help drive behavior.  When patients with acute pain transition to chronic pain, reorganization occurs in the brain that shifts activity patterns, often increasing the activity in the emotion regulation areas. This may help explain why chronic pain often coincides with mood disorders, which are associated with changes in some of the same brain regions. Additional changes in gray matter volume, neural activity, or connectivity occur in overlapping regions of the brain in both depression and chronic pain. For example, both animals and patients with chronic pain show a decrease in both activity and volume of the mPFC. This is similar to observations made in both depressed patients and animal models of depression. 

What’s the treatment for depression and chronic pain?

While drugs like opioids have had success in treating intense pain associated with surgery or traumatic injury, they are insufficient in the treatment of chronic pain and come with dangerous side effects like addiction that have influenced the ongoing opioid epidemic. While a few drugs can offer some help with ongoing symptoms, many chronic pain patients find little to no relief from current drug options. There is therefore an urgent need for more effective treatments for ongoing pain. Treatments for depression and chronic pain often overlap. Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) are often prescribed, with positive effects, in the treatment of both depression and pain. Ketamine, a drug known to be effective in treating acute post-operative pain, shows promise in treating major depressive disorder, with documented improvement of symptoms in treatment-resistant patients. Though its positive effects on depression symptoms occur more quickly than traditional SSRIs, ketamine administration must be repeated often, and it comes with negative side effects, including the potential for abuse. It also shows limited efficacy in treating chronic pain. In addition to drugs, there are also alternative treatments such as psychotherapy and cognitive behavioral therapy (CBT) that offer assistance for those struggling with mood disorders and chronic pain. Though not a complete replacement for drugs or other treatments, evidence suggests CBT can improve symptoms of ongoing pain in some patients. Similarly, CBT and other forms of psychotherapy can lead to the improvement of symptoms in patients with MDD or anxiety disorders, though some reports indicate these effects may be overestimated in many publications. 

What does the future look like?

Despite the dual nature of these diseases, the neurological basis for the overlap in chronic pain and mood disorders is still unclear. Research is ongoing at both the basic and clinical levels, to better understand the neural biology of both diseases and how they may impact one another, and to develop better treatments that target both diseases. Recent research into psychedelics is quickly changing our understanding of ways major depression, post-traumatic stress disorder, and chronic pain, may be successfully treated.  Clinical trials are ongoing, but evidence suggests that psychedelics such as lysergic acid diethylamide (LSD) and psilocybin may be effective in treating both intractable mood disorders and chronic pain conditions such as migraine. These drugs also may represent future positive alternatives to drugs associated with abuse like opioids. 

Pain and mood disorders, though distinct, overlap in the brain areas affected. These debilitating disorders are a huge cost to human health and wellbeing, making the continued advancement of both basic and clinical research into the neuroscience of these diseases and novel treatment options essential.

References +

Bair MJ et al. Depression and pain comorbidity: a literature review. 2003. JAMA Internal Medicine.

Treede RD et al. Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). 2019. Pain.

Sheng J et al. The link between depression and chronic pain: neural mechanisms in the brain. 2017. Neural Plasticity.

Lépine JP, Briley M. The epidemiology of pain in depression. 2004. Hum Psychopharmacol.

Denkinger MD et al. Multisite pain, pain frequency and pain severity are associated with depression in older adults: results from the ActiFE Ulm study. 2014. Age and Ageing.

Yavi M et al. Ketamine treatment for depression: a review. 2022. Discov Ment Health. Access the original publication here.

Jonkman K et al. Ketamine for pain. 2017. Faculty Rev.

Kooijman NI et al. Are psychedelics the answer to chronic pain: A review of current literature.

Hajihasani A et al. The Influence of Cognitive Behavioral Therapy on Pain, Quality of Life, and Depression in Patients Receiving Physical Therapy for Chronic Low Back Pain: A Systematic Review.

Cuijpers P et al. How effective are cognitive behavior therapies for major depression and anxiety disorders? A meta-analytic update of the evidence. 2016. World Psychiatry.

Sleep Loss Has Long-Lasting Consequences On Memory Processes in the Hippocampus

Post by Trisha Vaidyanathan

The takeaway

It is well-known that sleep loss hurts our memory, but it is not known how sleep loss affects memory processes in the brain. This study found that sleep loss prevents the hippocampus from “reactivating and replaying” memories, impairing the process of memory consolidation.

What's the science?

Many studies have demonstrated that the hippocampus is critical for promoting memory during sleep. When a rat runs through a maze, a specific subset of hippocampal neurons is activated and will then “reactivate” during sleep. Further, the order in which neurons activate in the maze will “replay” in the same order during sleep. This “reactivation” and “replay” process allows the brain to transfer the memory to other brain regions for long-term storage, a process called memory consolidation. Just as sleep promotes memory, it’s known that sleep loss can impair memory. However, it’s not known how sleep loss impacts hippocampal memory processes. This week in Nature, Giri and colleagues demonstrated that sleep loss diminishes the ability of the hippocampus to reactivate and replay memories and that these processes are not fully restored, even after recovery from sleep loss. 

How did they do it?

To study memory processes in the hippocampus, the authors used extracellular electrophysiology to record continuous activity from over 800 neurons in the hippocampus of rats. There were three phases of the experiment: First, the rats were able to sleep or rest naturally. Second, the rats explored a new maze for one hour. Third, the rats were either allowed to sleep naturally for 9 hours, or they were sleep deprived for 5 hours, followed by 4 hours of “recovery sleep”.

The authors first investigated how sleep loss impacted sharp-wave ripples, a type of neuronal oscillation known to drive reactivation and replay, and neuronal firing rates. Next, the authors used the neuronal activity recorded during the maze to study how sleep loss impacted hippocampal reactivations and replay. Reactivation was measured by assessing how links between neurons (using pairwise correlation) observed during the maze were similar to the links between neurons observed during subsequent sleep or sleep deprivation. Replay was measured by examining what proportion of the sharp-wave ripples observed after the maze contained neuronal firing patterns that could be used to accurately decode where the rat moved when it was in the maze.

What did they find?

First, the authors analyzed the neuronal recordings for sharp-wave ripples and found that while the rate of ripples decreased over natural sleep, the rate remained elevated during sleep deprivation. However, the sharp-wave ripples had a higher frequency and smaller amplitude than those in natural sleep. Neuronal firing rate also decreased during natural sleep and remained elevated during sleep deprivation. However, when the rats were allowed recovery sleep after sleep deprivation, the ripples and neuronal firing rate recovered to normal levels. 

Next, the authors examined reactivation events. After exploring the maze, rats that were allowed natural sleep exhibited hours of reactivation, while rats that were sleep-deprived had virtually no reactivation. Surprisingly, unlike the sharp-wave ripple rate, reactivations did not return to normal levels during the recovery sleep that followed sleep deprivation. 

Lastly, the authors tested the effect of sleep loss on replay events. As expected from the literature, a high proportion of sharp-wave ripples contained replay events in rats that were allowed to sleep naturally. Rats that were sleep-deprived, however, had significantly fewer replay events. Strikingly, the replay events continued to decrease even during the recovery sleep period. 

Together, the results from this study demonstrated that even though sharp-wave ripples appear to return to normal after recovery from sleep loss, the critical memory processes of reactivation and replay did not, suggesting long-term consequences of sleep loss on memory.

What's the impact?

Sleep loss is highly prevalent in our society and sleep disorders like insomnia are co-morbid with many other diseases. Many functions of sleep are known to return to normal levels following sufficient recovery sleep, but this study demonstrates why the effect of sleep loss on memory may be long-lasting.  

Access the original scientific publication here

The Impact of Stress and Anxiety on Eating Disorders

Post by Baldomero B. Ramirez Cantu

The takeaway

Stress causes anxiety-prone female mice to prefer a starvation-like state highlighting the potential neural mechanisms linking stress, anxiety and anorexia nervosa.

What's the science?

Eating disorders, such as anorexia nervosa, are severe psychiatric conditions marked by self-imposed starvation. Despite their complex etiology, characterized by a combination of genetic, environmental, and psychological factors, effective treatments remain limited. Experimental models in rodents have provided insights into underlying neural mechanisms but often fail to capture the crucial aspect of volitional starvation seen in patients. In a recent study published in Neuron, Kucukdereli et al., investigated how repeated stress influences the voluntary seeking of a starvation-like state in mice. Their findings offer an insight into the role of stress-induced anxiety in driving behaviors akin to anorexia nervosa.

How did they do it?

To investigate the role of stress in voluntary seeking of a starvation-like state, researchers developed a virtual reality (VR) real-time place preference protocol for head-fixed mice. Male and female mice were then exposed to two distinct virtual corridors paired with either optogenetic stimulation of agouti-related peptide (AgRP) hypothalamic neurons or a neutral outcome.

Optogenetic stimulation was achieved using a transgenic approach, involving the expression of light-activated channelrhodopsin (ChR2) in AgRP neurons, activated via an optic fiber placed above the arcuate nucleus. 

The experimental VR protocol included conditioning sessions where mice were alternately exposed to the stimulation or neutral corridor, followed by real-time place preference sessions where mice were allowed to choose between the two corridors. To test the hypothesis that stress influences AgRP neuron stimulation preference, researchers introduced repeated stressors by delivering unpredictable tail shocks during conditioning sessions.

Anxiety-like behavior was assessed using open-field tests (OFTs) before and after the stress exposure sessions to confirm effective stress induction. A preference index was calculated based on the duration mice dwelled in the stimulation corridor, excluding bouts of locomotion. Additionally, elevated plus maze (EPM) assays were conducted before the experiments to measure baseline anxiety levels, helping to identify any pre-existing stress-related traits in the mice. 

What did they find?

Before stress exposure, male mice generally exhibited a mild aversion to AgRP neuron stimulation, suggesting that the induced starvation-like state was aversive. Female mice showed no consistent preference or aversion to AgRP stimulation, with individual responses varying.

Following repeated stress exposure through unpredictable tail shocks during conditioning sessions, female mice displayed significant changes in behavior. A subset of females developed a strong preference for AgRP stimulation, actively seeking the starvation-like state, while others exhibited increased aversion. In contrast, male mice showed a reduction in aversion to AgRP stimulation but did not develop a preference for it.

Analysis of baseline anxiety levels, measured using the EPM assay, revealed that female mice with higher anxiety scores were more likely to prefer AgRP stimulation after stress exposure. This correlation was not observed in male mice, indicating that predisposition to anxiety significantly influenced the behavioral response to stress in females.

These results demonstrate a pronounced sex difference in how stress affects the seeking of a starvation-like state, with female mice showing more variability based on their anxiety levels. This suggests that individual susceptibility to stress-induced anxiety plays a crucial role in behaviors associated with conditions such as anorexia nervosa.

What's the impact?

This research provides valuable insights into the complex interplay between stress, anxiety, and behaviors resembling those seen in anorexia nervosa. These findings may inform future studies on the neurobiological mechanisms underlying eating disorders and potentially guide the development of targeted pharmacological and behavioral interventions that consider stress management and anxiety reduction strategies

Access the original scientific publication here.