̽��ֱ�� of Cambridge - Ben Seymour

Identification of brain region responsible for alleviating pain could lead to development of opioid alternatives

sc604 — Tue, 27 Feb 2018 08:00:00 +0000

̽��ֱ��team, led by the ̽��ֱ�� of Cambridge, have pinpointed an area of the brain that is important for endogenous analgesia – the brain’s intrinsic pain relief system. Their results, published in the open access journal eLife, could lead to the development of pain treatments that activate the painkilling system by stimulating this area of the brain, but without the dangerous side-effects of opioids.

Opioid drugs such as oxycodone, hydrocodone and fentanyl hijack the endogenous analgesia system, which is what makes them such effective painkillers. However, they are also highly addictive, which has led to the opioid crisis in the United States, where drug overdose is now the leading cause of death for those under 50, with opioid overdoses representing two-thirds of those deaths.

“We’re trying to understand exactly what the endogenous analgesia system is: why we have it, how it works and where it is controlled in the brain,” said Dr Ben Seymour of Cambridge’s Department of Engineering, who led the research. “If we can figure this out, it could lead to treatments that are much more selective in terms of how they treat pain.”

Pain, while unpleasant, evolved to serve an important survival function. After an injury, for instance, the persistent pain we feel saps our motivation, and so forces us towards rest and recuperation which allows the body to use as much energy as possible for healing.

“Pain can actually help us recover by removing our drive to do unnecessary things - in a sense, this can be considered ‘healthy pain’,” said Seymour. “So why might the brain want to turn down the pain signal sometimes?”

Seymour and his colleagues thought that sometimes this ‘healthy pain’ could be a problem, especially if we could actively do something that might help - such as try and find a way to cool a burn.

In these situations, the brain might activate the pain-killing system to actively look for relief. To prove this, and to try and identify where in the brain this system was activated, the team designed a pair of experiments using brain scanning technology.

In the first experiment, the researchers attached a metal probe to the arm of a series of healthy volunteers - and heated it up to a level that was painful, but not enough to physically burn them. ̽��ֱ��volunteers then played a type of gambling game where they had to find which button on a small keypad cooled down the probe. ̽��ֱ��level of difficulty was varied over the course of the experiments - sometimes it was easy to turn the probe off, and sometimes it was difficult. Throughout the task, the volunteers frequently rated their pain, and the researchers constantly monitored their brain activity.

̽��ֱ��results found that the level of pain the volunteers experienced was related to how much information there was to learn in the task. When the subjects were actively trying to work out which button they should press, pain was reduced. But when the subjects knew which button to press, it wasn't. ̽��ֱ��researchers found that the brain was actually computing the benefits of actively looking for and remembering how they got relief, and using this to control the level of pain.

Knowing what this signal should look like, the researchers then searched the brain to see where it was being used. ̽��ֱ��second experiment identified the signal in a single region of the prefrontal cortex, called the pregenual cingulate cortex.

“These results build a picture of why and how the brain decides to turn off pain in certain circumstances, and identify the pregenual cingulate cortex as a critical ‘decision centre’ controlling pain in the brain,” said Seymour.

This decision centre is a key place to focus future research efforts. In particular, the researchers are now trying to understand what the inputs are to this brain region, if it is stimulated by opioid drugs, what other chemical messenger systems it uses, and how it could be turned on as a treatment for patients with chronic pain.

Reference
Suyi Zhang et al. ‘ ̽��ֱ��control of tonic pain by active relief learning.’ eLife (2018). DOI: https://doi.org/10.7554/eLife.31949

Researchers from the UK & Japan have identified how the brain’s natural painkilling system could be used as a possible alternative to opioids for the effective relief of chronic pain, which affects as many as one in three people at some point in their lives.

Pain can actually help us recover by removing our drive to do unnecessary things - in a sense, this can be considered ‘healthy pain’.

Ben Seymour

Penn State

Prescription bottle for Oxycodone tablets and pills on metal table

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Reconditioning the brain to overcome fear

ps748 — Mon, 21 Nov 2016 16:00:00 +0000

Fear related disorders affect around one in 14 people and place considerable pressure on mental health services. Currently, a common approach is for patients to undergo some form of aversion therapy, in which they confront their fear by being exposed to it in the hope they will learn that the thing they fear isn’t harmful after all. However, this therapy is inherently unpleasant, and many choose not to pursue it. Now a team of neuroscientists from the ̽��ֱ�� of Cambridge, Japan and the USA, has found a way of unconsciously removing a fear memory from the brain.

̽��ֱ��team developed a method to read and identify a fear memory using a new technique called ‘Decoded Neurofeedback’. ̽��ֱ��technique used brain scanning to monitor activity in the brain, and identify complex patterns of activity that resembled a specific fear memory. In the experiment, a fear memory was created in 17 healthy volunteers by administering a brief electric shock when they saw a certain computer image. When the pattern was detected, the researchers over-wrote the fear memory by giving their experimental subjects a reward.

Dr. Ben Seymour, of the ̽��ֱ�� of Cambridge’s Engineering Department, was one of the authors on the study. He explained the process:

" ̽��ֱ��way information is represented in the brain is very complicated, but the use of artificial intelligence (AI) image recognition methods now allow us to identify aspects of the content of that information. When we induced a mild fear memory in the brain, we were able to develop a fast and accurate method of reading it by using AI algorithms. ̽��ֱ��challenge then was to find a way to reduce or remove the fear memory, without ever consciously evoking it.

"We realised that even when the volunteers were simply resting, we could see brief moments when the pattern of fluctuating brain activity had partial features of the specific fear memory, even though the volunteers weren't consciously aware of it. Because we could decode these brain patterns quickly, we decided to give subjects a reward - a small amount of money - every time we picked up these features of the memory."

̽��ֱ��team repeated the procedure over three days. Volunteers were told that the monetary reward they earned depended on their brain activity, but they didn’t know how. By continuously connecting subtle patterns of brain activity linked to the electric shock with a small reward, the scientists hoped to gradually and unconsciously override the fear memory.

Scan of brain showing information associated with a fear memory Credit Ai Koizumi

Dr Ai Koizumi, of the Advanced Telecommunicatons Research Institute International, Kyoto and Centre of Information and Neural Networks, Osaka, led the research:

"In effect, the features of the memory that were previously tuned to predict the painful shock, were now being re-programmed to predict something positive instead."

̽��ֱ��team then tested what happened when they showed the volunteers the pictures previously associated with the shocks.

"Remarkably, we could no longer see the typical fear skin-sweating response. Nor could we identify enhanced activity in the amygdala - the brain's fear centre,” she continued. “This meant that we'd been able to reduce the fear memory without the volunteers ever consciously experiencing the fear memory in the process."

Although the sample size in this initial study was relatively small, the team hopes the technique can be developed into a clinical treatment for patients with PTSD or phobias.

"To apply this to patients, we need to build a library of the brain information codes for the various things that people might have a pathological fear of, say, spiders” adds Dr Seymour. "Then, in principle, patients could have regular sessions of Decoded Neurofeedback to gradually remove the fear response these memories trigger."

Such a treatment could have major benefits over traditional drug based approaches. Patients could also avoid the stress associated with exposure therapies, and any side-effects resulting from those drugs.

Koizumi et al. “Fear reduction without fear through reinforcement of neural activity that bypasses conscious exposure” Nature Human Behaviour: DOI:10.1038/S41562-016-0006

Researchers have discovered a way to remove specific fears from the brain, using a combination of artificial intelligence and brain scanning technology. Their technique, published in the inaugural edition of Nature Human Behaviour, could lead to a new way of treating patients with conditions such as post-traumatic stress disorder (PTSD) and phobias.

̽��ֱ��challenge then was to find a way to reduce or remove the fear memory, without ever consciously evoking it

Ben Seymour

Geoff Oxford

Large house spider on kitchen floor

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Cause of phantom limb pain in amputees, and potential treatment, identified

sc604 — Thu, 27 Oct 2016 10:49:19 +0000

Researchers have discovered that a ‘reorganisation’ of the wiring of the brain is the underlying cause of phantom limb pain, which occurs in the vast majority of individuals who have had limbs amputated, and a potential method of treating it which uses artificial intelligence techniques.

̽��ֱ��researchers, led by a group from Osaka ̽��ֱ�� in Japan in collaboration with the ̽��ֱ�� of Cambridge, used a brain-machine interface to train a group of ten individuals to control a robotic arm with their brains. They found that if a patient tried to control the prosthetic by associating the movement with their missing arm, it increased their pain, but training them to associate the movement of the prosthetic with the unaffected hand decreased their pain.

Their results, reported in the journal Nature Communications, demonstrate that in patients with chronic pain associated with amputation or nerve injury, there are ‘crossed wires’ in the part of the brain associated with sensation and movement, and that by mending that disruption, the pain can be treated. ̽��ֱ��findings could also be applied to those with other forms of chronic pain, including pain due to arthritis.

Approximately 5,000 amputations are carried out in the UK every year, and those with type 1 or type 2 diabetes are at particular risk of needing an amputation. In most cases, individuals who have had a hand or arm amputated, or who have had severe nerve injuries which result in a loss of sensation in their hand, continue to feel the existence of the affected hand as if it were still there. Between 50 and 80 percent of these patients suffer with chronic pain in the ‘phantom’ hand, known as phantom limb pain.

“Even though the hand is gone, people with phantom limb pain still feel like there’s a hand there – it basically feels painful, like a burning or hypersensitive type of pain, and conventional painkillers are ineffective in treating it,” said study co-author Dr Ben Seymour, a neuroscientist based in Cambridge’s Department of Engineering. “We wanted to see if we could come up with an engineering-based treatment as opposed to a drug-based treatment.”

A popular theory of the cause of phantom limb pain is faulty ‘wiring’ of the sensorimotor cortex, the part of the brain that is responsible for processing sensory inputs and executing movements. In other words, there is a mismatch between a movement and the perception of that movement.

In the study, Seymour and his colleagues, led by Takufumi Yanagisawa from Osaka ̽��ֱ��, used a brain-machine interface to decode the neural activity of the mental action needed for a patient to move their ‘phantom’ hand, and then converted the decoded phantom hand movement into that of a robotic neuroprosthetic using artificial intelligence techniques.

“We found that the better their affected side of the brain got at using the robotic arm, the worse their pain got,” said Yanagisawa. “ ̽��ֱ��movement part of the brain is working fine, but they are not getting sensory feedback – there’s a discrepancy there.”

̽��ֱ��researchers then altered their technique to train the ‘wrong’ side of the brain: for example, a patient who was missing their left arm was trained to move the prosthetic arm by decoding movements associated with their right arm, or vice versa. When they were trained in this counter-intuitive technique, the patients found that their pain significantly decreased. As they learned to control the arm in this way, it takes advantage of the plasticity – the ability of the brain to restructure and learn new things – of the sensorimotor cortex, showing a clear link between plasticity and pain.

Although the results are promising, Seymour warns that the effects are temporary, and require a large, expensive piece of medical equipment to be effective. However, he believes that a treatment based on their technique could be available within five to ten years. “Ideally, we’d like to see something that people could have at home, or that they could incorporate with physio treatments,” he said. “But the results demonstrate that combining AI techniques with new technologies is a promising avenue for treating pain, and an important area for future UK-Japan research collaboration.”

Reference:
Takufumi Yanagisawa et al. ‘Induced sensorimotor brain plasticity controls pain in phantom limb patients.’ Nature Communications (2016). DOI: 10.1038/ncomms13209

Researchers have identified the cause of chronic, and currently untreatable, pain in those with amputations and severe nerve damage, as well as a potential treatment which relies on engineering instead of drugs.

We wanted to see if we could come up with an engineering-based treatment as opposed to a drug-based treatment.

Ben Seymour

Osaka ̽��ֱ��

Measurement of brain activity in a patient with phantom limb pain

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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