Understanding pain with the neuromatrix theory: How the brain shapes your experience

When Lt. Col. Henry Beecher tended wounded soldiers not long after World War II, he noticed that many had varying degrees of pain despite having similar wounds. In his study published in Annals of Surgery in 1946, Beecher wrote that there is “a common belief that wounds are inevitably associated with pain” and that the more extensive the wound, the worse the pain.

Among 215 patients with penetrating head wounds (7%), penetrating torso wounds (12%), extensive soft-tissue injuries (16%), compound long bone fractures (24%), and penetrating abdominal wounds (48%), nearly 25% of the soldiers had severe pain.

Beecher wrote that 75% of the badly wounded men “have so little pain that they do not want pain relief medication,” even when they have received  no morphine hours after they were wounded.

Beecher was among some researchers in the mid-20th century who questioned the status quo on how pain works. At that time, the prevalent theory of pain was the specificity theory, which states that there is a specific afferent nerve fiber and receptor that responds to external stimuli, such as heat, cold, and tissue damage. 

By the 1950s, some researchers expanded the specificity theory to explain why some people experienced pain in the absence of obvious injury or disease; or they have no pain despite having severe wounds. In 1965, the gate control theory was proposed by Dr. Ronald Melzack and Dr. Patrick Hall that described pain as not a fixed response to injury, but a dynamic process involving the peripheral and central nervous systems.

Based on previous pain theories, the gate control theory suggests that the spinal cord has a neurological “gate” that either blocks or reduces nociceptive signals to pass to the brain from the skin or internal organs. These signals are blocked at the first synaptic level in the spinal cord that connects nociceptors in the skin to nerves that send signals to the brain.

 

Also, the gate can be closed by stimulating afferent nerves by touching at or near the site that is causing the pain. This explains why rubbing an injured area or getting a massage could reduce the pain intensity.

In the 1980s, the gate control theory was expanded to encompass emotional and cognitive factors that affect the pain experience. Melzack called it the neuromatrix theory.

From gate control to the neuromatrix

The gate control theory explains how we feel pain from a semi-linear manner where nociceptive signals from the skin or internal organs travel to the spinal cord. How these signals are interpreted depends on:

• The intensity of the signal
• The person’s previous experience of pain
• Sensory information from the person’s environment
• How the brain modulates all this information.

At the end, these signals are “gated” shut or opened at the first synaptic level of the spinal cord.

The neuromatrix theory expands the gate control with more focus on the brain and how it transmits information down to the spinal cord in a process called descending modulation. This came from studies of phantom limb pain and similar sensations where amputees could “feel” their missing limb or body part despite having no peripheral input.

For example, in a 1962 study of Finnish War veterans, some amputees reported crushing or piercing pain in their missing hand or foot. Meanwhile, Melzack reported patients with surgically removed breast or penis could still feel their missing part. 

In the 1980s, Melzack hypothesized that each person’s pain experience comes from a “neurosignature,” which are distinctive, repeating patterns of neural activity shaped by genetics and life experiences. He compared it to having a “brain fingerprint” where each person’s neurosignature is unique. Therefore, if two people were to have the same nociceptive input, they may have different responses. 

How the neuromatrix theory developed

In 1999, Melzack wrote in Pain that Dutch neuroscientist Willem Noordenbos proposed that large nerve fibers can inhibit signals from smaller nociceptive fibers in the spinal cord. He showed this interaction happening in the substantia gelatinosa of the dorsal horn, but Noordenbos didn’t explain how the inhibition worked. His model stopped at the brain’s thalamus, a relay station in the brain, without exploring what the brain itself might do with those signals.

“My idea was to put a cortex on Bill’s thalamus, show the dorsal column projection as a rapid, precise feedforward system to activate psychological processes, with a feedback to the circle to modulate the input,” Melzack wrote. “Here, at last, was the beginning of a conceptual model in which brain processes can select, filter and modulate pain signals.”

Melzack expanded Noordenbos’ work by adding the brain’s cortex to the picture. He suggested that signals traveling quickly along the large fibers could activate higher mental processes, such as attention, memory, and meaning. These processes could then send feedback back down to the spinal cord to change how nociception is processed. 

In 1962, Melzack was an assistant professor in psychology at MIT working with Wall in developing and refining their theory. Wall, who had been studying the substantia gelatinosa, then proposed a presynaptic inhibitory system in the dorsal horn that could either block or allow nociception to pass to the brain.

Through many discussions and refinements (“where we consumed large amounts of duty-free whiskey and talked late into the night at Pat’s home,” Melzack wrote), Melzack and Wall combined their ideas into the gate control theory, which was published in 1965. It was widely accepted—and contested—where “it was not until the mid-1970’s that the gate control theory was presented in almost every major textbook in the biological and medical sciences,” Melzack wrote. “At the same time there was an explosion in research on the physiology and pharmacology of the dorsal horns and the descending control systems.”

In 1978, Melzack and neurosurgeon John D. Loeser from the University of Washington proposed the spinal cord’s dorsal horns up to the thalamus and cortex in the brain can act as pattern generators, meaning these areas can create repeated patterns of nerve activity on their own without needing constant signals from the body.

These regions’ activities can produce “nerve impulses which exceed a critical firing level per unit time…and project to other areas that subserve pain experience and the localization of pain at specific sites,” Melzack wrote. “Injury may produce high-firing levels that signal pain as well as…loss of input to central structures by deafferentation after amputation, root section or cord transection also produce high firing levels and abnormal bursting patterns that may provide the necessary conditions for pain. Thus, any input to the hyperactive central cells…can trigger abnormal, prolonged firing and produce severe, persistent pains in discrete areas of the denervated limbs or other body parts.”

In a 2013 editorial, Melzack and Dr. Joel Katz from the Department of Psychology of York University in Toronto described the “body-self neuromatrix” as a network of brain impulses that generate the sense of the body and self. This neuromatrix is made up of interconnected loops between major brain regions (thalamus, cortex, limbic system) that allow constant cycles of processing and feedback. 

This process produces a neurosignature, which are created within the neuromatrix, not by external stimuli. Melzack and Katz wrote that neurosignatures can only be modulated by sensory input or a “trigger.”

Portions of the neuromatrix, called neuromodules, specialize in processing specific sensory experiences, such as injury, temperature, or arousal, contribute smaller “sub-signatures” that attach to the entire neurosignature.

“The neurosignature, which is a continuous output from the body-self neuromatrix, is projected to areas in the brain—the sentient neural hub—in which the stream of nerve impulses is converted into a continually changing stream of awareness,” Melzack and Katz wrote.

They added that some of the neurosignatures branch into an “action-neuromatrix,” which drives movement that “activates spinal cord neurons to produce muscle patterns for complex actions.”

Overall, the self-body neuromatrix is how the brain constructs and maintains the person’s body experience as a whole. It combines sensory, emotional, and cognitive inputs to bring meaning to an experience. This includes body awareness and pain.

Inside the neuromatrix: The brain

Since the neuromatrix theory was proposed, scientists have identified brain regions that contribute to pain and other experiences. These regions overlap each other, and no single region is responsible for pain.

Thalamus: A central relay hub that transmits nociceptive signals from the spinal cord to higher cortical brain regions for further processing. The thalamus is also involved in descending modulation where it provides feedback to the spinal cord about nociception.

Somatosensory cortices S1 and S2: These regions help the brain process touch and body sensations, which involves context, memory, and decision-making. Studies on the primary somatosensory cortex (S1) in mice and humans show that different layers of this brain area handle sensory signals in specific ways. 

For example, researchers in a 2021 study found that neurons in layers 5 and 6 of S1 in mice affect how harmless and painful signals are felt. When layer 6 was activated, the mice became extra sensitive and showed pain-like reactions. This happened because layer 6 boosted activity in the thalamus while reducing activity in layer 5. When scientists turned off layer 5 directly, it caused the same pain-like effects, suggesting that layer 5 helps reduce pain.

The S2 uses past experiences to interpret sensations. Its activity is linked to how we actually feel and react to touch, meaning S2 helps turn raw sensory signals into perception. This suggests that communication between S1 and S2 may play a part in how one painful stimulus can reduce the feeling of another pain.

Insular cortex: This brain section is beneath the lateral sulcus of the brain. Research finds that it sits at a crossroads between systems that sense the body’s internal state (interoception) and those that detect external threats (exteroception). 

Its position allows it to switch between response to potential harm and pain management after an injury. It may also help turn unconscious nociceptive signals into conscious pain experiences, acting like a threshold or “gate.” When this system malfunctions, the threshold for pain may drop, leading to chronic pain and hypersensitivity.

Anterior cingulate cortex (ACC): Together with the insula, this region plays a key role in processing nociception and modulating pain responses. It receives nociceptive input from the thalamus and encodes its intensity. The ACC contributes not only to the sensory experience of pain but also to its affective components. This affects how people learn to avoid painful stimuli and avoidance behaviors. It’s also involved in descending modulation, adjusting spinal reflexes and pain sensitivity through connections with the brainstem and spinal cord.

Prefrontal cortex (PFC): The PFC is not only important for thinking and decision-making, it also helps the brain process pain. It does this through its connections with other brain areas like the ACC, hippocampus, thalamus, amygdala, basal nuclei, and the periaqueductal gray (PAG), which helps control nociception. In acute and chronic pain, the PFC undergoes changes in neurotransmitters, gene expression, glial cells, and neuroinflammation.

According to a 2020 review, the medial prefrontal cortex (mPFC), which includes the ACC, prelimbic cortex, and infralimbic cortex, helps process the emotional and cognitive parts of chronic pain. Brain scans show that people with chronic pain lose gray matter in these regions. The ACC tends to become overactive while the prelimbic and infralimbic areas become less active.

Brainstem and descending modulation areas: A 2022 review reported that the brainstem can modulate pain by enhancing or blocking nociception from the spinal cord to the brain.

Amygdala: The amygdala is involved in emotion regulation, particularly anger and fear. It receives nociception through two main pathways. One comes from the brainstem’s parabrachial area, which carries unfiltered nociceptive information. The other pathway delivers more complex sensory input from the thalamus and cerebral cortex where signals from different sensory input are combined.

Overall, the neuromatrix theory has helped shift manual therapy and pain research away from tissue-centric models and toward a brain-body-mind understanding of pain. In the last 20 years, some clinicians have embraced and used methods beyond pharmacology and surgery for treating chronic pain. These include:

• Pain education
• Referrals to mental health and exercise professionals
• Change the clinic’s environment
• Communication techniques

While there are still gaps in pain education and research with practice, modern pain medicine progressed since the days of Beecher with his combat veterans.

“We have traveled a long way from the psychophysical concept that seeks a simple one-to-one relationship between injury and pain,” Melzack wrote in 1999. “We now have a theoretical framework in which a genetically determined template for the body-self is modulated by the powerful stress system and the cognitive functions of the brain, in addition to the traditional sensory inputs.”