Michael Trujillo, PhD

Vice President of Clinical Affairs, Karuna Labs, Inc.

Figure 1: A schematic of the central nociceptive (pain) pathway. In acute pain, excitability is temporarily increased in response to painful stimuli such as

Central Sensitization Pain Mechanism

Acute Pain

Acute pain is the sensation triggered by injury or potentially harmful stimulation. While pain is triggered in a body part such as the skin, limbs, joints, or muscles, the perception of pain is an output of the central nervous system (spinal cord and brain). Pain is a critical sensation meant to protect organisms from potential danger. Pain typically induces avoidance of harmful stimuli and tendencies to protect the affected body part while it heals. Under normal conditions, specialized nerve cells in the body called nociceptors send information to the spinal cord when a possible threat of damaging stimuli is detected. The spinal cord relays the information to the brain where specialized networks process the information and pain is perceived (Figure 1). Acute pain is typically temporary and fleeting.

Chronic Pain

Figure 2: A schematic example for hyperalgesia and allodynia in chronic pain. Maladaptive neuroplasticity in the central nervous system reduces pain threshold. Central sensitization (allodynia) shifts pain threshold so that the central pain pathway is activated to stimuli which do not normally provoke pain

Chronic pain is the persistent perception of pain where pain-related circuits in the central nervous remain active for weeks, months, or even years. Chronic pain is a major healthcare burden worldwide with upwards of 11% of the US population suffering from pain lasting at least 6 months (1,2). Chronic pain is associated with depression, anxiety, sleep disturbances, and impairment in decision making tasks (3). While the origin of chronic pain may be initially induced by an injury or infection, chronic persistent pain can continue in the absence of current or past injury or without evidence of damage in the body. Several mechanisms have been proposed to explain the phenomenon of chronic persistent pain including Peripheral Nociceptive (inflammation or mechanical damage in tissue), Neuropathic (damage or entrapment of peripheral nerves), and Central (disturbances in pain processing) (4).

Chronic pain by definition is difficult to treat. Novel approaches have been developed that have promising potential to treat chronic pain that has a Central mechanism. Central pain mechanism can be at least partially attributed to maladaptive neuroplasticity. Neuroplasticity refers to the brain’s ability to adapt the way it processes information based on the demands imposed upon it. The brain is plastic, meaning that it is malleable and can reorganize neural connections throughout life. Maladaptive neuroplasticity are changes to the organization and processing in the brain that have negative consequences. An example of maladaptive neuroplasticity in chronic pain is central sensitization.

Central Sensitization

Central Sensitization results from neuroplastic changes in the spinal cord and brain related to the perception of pain. Sensitized patients are more sensitive to painful stimuli (hyperalgesia) and experience pain with things that are not normally painful (allodynia). In hyperalgesia, there is an enhancement in the excitability of pain circuits in the central nervous system that make neurons in the circuit easier to excite and less susceptible to inhibition. The balance between excitation and inhibition is disrupted and consequently, the circuit is easier to turn on and arouse, leading to a shift in the perception of pain (Figure 2). The shift in pain perception is the result of hyperexcitability of pain-related circuits in the spinal cord and brain that make them more active than they should be in response to pain (5). The increased activity results in the experience of pain as more severe. Hyperalgesia also leads to prolonged aftereffects of painful stimuli and an expansion of receptive fields around a painful region. The expansion of the receptive fields around a painful region results in the triggering of pain circuits in response to touch on non-injured tissue. Due to hyperalgesia and allodynia, patients with central sensitization have a shift of pain perception so that painful events are perceived as more intense than they should and stimuli that should not normally induce pain is perceived as painful. To the patient who has central sensitization, the pain they experience, despite being a product of maladaptive neuroplasticity of the brain, is very real.

Harnessing Positive Neuroplasticity to Treat Central Sensitization

The good news about central sensitization is that it is a consequence of the brain’s ability to adapt processing and organization based on the demands imposed upon it. That means that patients who are inflicted with central sensitization may be able to re-normalize pain-related neural circuitry by engaging in activities that promote positive neuroplasticity, thereby overriding the maladaptive neuroplasticity that has occurred due to chronic pain. Positive neuroplasticity refers to changes in the processing and organization of the central nervous system that have a beneficial impact on perception or behavior.

Karuna labs creates immersive virtual reality tools (Virtual Embodiment Therapy ™ (VET™)) to treat chronic pain. VET™ promotes the renormalizing of the neural circuits associated with chronic pain. Based on the principles of graded motor imagery, VET™ bypasses the attentional mechanisms of pain so that chronic pain patients develop proper neural associations between movement and pain. Graded motor imagery in VET™ utilizes three stages of GMI, which allows the patient to engage a virtual avatar in laterality exercises, movements which they currently avoid because of pain restriction, movement planning/execution, and development of visual/motor memory. Due to the novelty of applying GMI to nonlateralized body parts in VR, VET™ affords new opportunities for the treatment of chronic pain by re-organizing the brain to perceive pain differently.


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