Showing posts with label Injury. Show all posts
Showing posts with label Injury. Show all posts

Nov 22, 2023

Our brains are not able to 'rewire' themselves, despite what most scientists believe, new study argues

Contrary to the commonly-held view, the brain does not have the ability to rewire itself to compensate for the loss of sight, an amputation or stroke, for example, say scientists from the University of Cambridge and Johns Hopkins University.

Writing in eLife, Professors Tamar Makin (Cambridge) and John Krakauer (Johns Hopkins) argue that the notion that the brain, in response to injury or deficit, can reorganise itself and repurpose particular regions for new functions, is fundamentally flawed -- despite being commonly cited in scientific textbooks. Instead, they argue that what is occurring is merely the brain being trained to utilise already existing, but latent, abilities.

One of the most common examples given is where a person loses their sight -- or is born blind -- and the visual cortex, previously specialised in processing vision, is rewired to process sounds, allowing the individual to use a form of 'echolocation' to navigate a cluttered room. Another common example is of people who have had a stroke and are initially unable to move their limbs repurposing other areas of the brain to allow them to regain control.

Krakauer, Director of the Center for the Study of Motor Learning and Brain Repair at Johns Hopkins University, said: "The idea that our brain has an amazing ability to rewire and reorganise itself is an appealing one. It gives us hope and fascination, especially when we hear extraordinary stories of blind individuals developing almost superhuman echolocation abilities, for example, or stroke survivors miraculously regaining motor abilities they thought they'd lost.

"This idea goes beyond simple adaptation, or plasticity -- it implies a wholesale repurposing of brain regions. But while these stories may well be true, the explanation of what is happening is, in fact, wrong."

In their article, Makin and Krakauer look at a ten seminal studies that purport to show the brain's ability to reorganise. They argue, however, that while the studies do indeed show the brain's ability to adapt to change, it is not creating new functions in previously unrelated areas -- instead it's utilising latent capacities that have been present since birth.

For example, one of the studies -- research carried out in the 1980s by Professor Michael Merzenich at University of California, San Francisco -- looked at what happens when a hand loses a finger. The hand has a particular representation in the brain, with each finger appearing to map onto a specific brain region. Remove the forefinger, and the area of the brain previously allocated to this finger is reallocated to processing signals from neighbouring fingers, argued Merzenich -- in other words, the brain has rewired itself in response to changes in sensory input.

Not so, says Makin, whose own research provides an alternative explanation.

In a study published in 2022, Makin used a nerve blocker to temporarily mimic the effect of amputation of the forefinger in her subjects. She showed that even before amputation, signals from neighbouring fingers mapped onto the brain region 'responsible' for the forefinger -- in other words, while this brain region may have been primarily responsible for process signals from the forefinger, it was not exclusively so. All that happens following amputation is that existing signals from the other fingers are 'dialled up' in this brain region.

Makin, from the Medical Research Council (MRC) Cognition and Brain Sciences Unit at the University of Cambridge, said: "The brain's ability to adapt to injury isn't about commandeering new brain regions for entirely different purposes. These regions don't start processing entirely new types of information. Information about the other fingers was available in the examined brain area even before the amputation, it's just that in the original studies, the researchers didn't pay much notice to it because it was weaker than for the finger about to be amputated."

Another compelling counterexample to the reorganisation argument is seen in a study of congenitally deaf cats, whose auditory cortex -- the area of the brain that processes sound -- appears to be repurposed to process vision. But when they are fitted with a cochlear implant, this brain region immediately begins processing sound once again, suggesting that the brain had not, in fact, rewired.

Examining other studies, Makin and Krakauer found no compelling evidence that the visual cortex of individuals that were born blind or the uninjured cortex of stroke survivors ever developed a novel functional ability that did not otherwise exist.

Makin and Krakauer do not dismiss the stories of blind people being able to navigate purely based on hearing, or individuals who have experienced a stroke regain their motor functions, for example. They argue instead that rather than completely repurposing regions for new tasks, the brain is enhancing or modifying its pre-existing architecture -- and it is doing this through repetition and learning.

Understanding the true nature and limits of brain plasticity is crucial, both for setting realistic expectations for patients and for guiding clinical practitioners in their rehabilitative approaches, they argue.

Makin added: "This learning process is a testament to the brain's remarkable -- but constrained -capacity for plasticity. There are no shortcuts or fast tracks in this journey. The idea of quickly unlocking hidden brain potentials or tapping into vast unused reserves is more wishful thinking than reality. It's a slow, incremental journey, demanding persistent effort and practice. Recognising this helps us appreciate the hard work behind every story of recovery and adapt our strategies accordingly.

Read more at Science Daily

Aug 11, 2023

New orally available drug for spinal cord injury found to be safe and tolerable in healthy participants

New research from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King's College London has demonstrated the safety and tolerability of a new drug treatment designed as a therapeutic intervention for spinal cord injury (SCI).

The research, published in British Journal of Clinical Pharmacology, found that the KCL-286 drug -- which works by activating retinoic acid receptor beta (RARb) in the spine to promote recovery -- was well tolerated by participants in a Phase 1 clinical trial, with no severe side effects. Researchers are now seeking funding for a Phase 2a trial studying the safety and tolerability of the drug in those with SCI.

Global prevalence of SCI is estimated to be between 0.7 and 1.2 million cases per year, with falls and road accidents being the major causes. Despite incurring a cost of $4 billion per year in direct healthcare and indirect costs (i.e. inability to work and social care) in the US alone, there are no licensed drugs that can tackle the intrinsic failure of the adult central nervous system to regenerate, and thus remains a largely unmet clinical need.

Previous research by various groups has shown that nerve growth can be stimulated by activating the RARb2 receptor, but no drug suitable for humans has been developed. KCL-286, an RARb2 agonist1, was developed by Professor Corcoran and team and used in a first in man study to test its safety in humans.

109 healthy males were divided into one of two trial groups; single ascending dose (SAD) adaptive design with a food interaction (FI) arm, and multiple ascending dose (MAD) arm. Participants in each arm were further divided into different dose treatments.

SAD studies are designed to establish the safe dosage range of a medicine by providing participants with small doses before gradually increasing the dose provided. Researchers look for any side effects, and measure how the medicine is processed within the body. MAD studies explore how the body interacts with repeated administration of the drug, and investigate the potential for a drug to accumulate within the body.

Researchers found that participants were able to safely take 100mg doses of KCL-286, with no severe adverse events.

Professor Jonathan Corcoran, Professor of Neuroscience and Director of the Neuroscience Drug Discovery Unit, at King's IoPPN and the study's senior author said, "This represents an important first step in demonstrating the viability of KCL-286 in treating spinal cord injuries. This first-in-human study has shown that a 100mg dose delivered via a pill can be safely taken by humans. Furthermore, we have also shown evidence that it engages with the correct receptor.

"Our focus can hopefully now turn to researching the effects of this intervention in people with spinal cord injuries."

Dr. Bia Goncalves, a senior scientist and project manager of the study, and the study's first author from King's IoPPN said, "Spinal Cord Injuries are a life changing condition that can have a huge impact on a person's ability to carry out the most basic of tasks, and the knock-on effects on their physical and mental health are significant.

"The outcomes of this study demonstrate the potential for therapeutic interventions for SCI, and I am hopeful for what our future research will find."

Read more at Science Daily

Sep 4, 2022

From wound healing to regeneration

The phenomenon of regeneration was discovered over 200 years ago in the freshwater polyp Hydra. Until now, however, it was largely unclear how the orderly regeneration of lost tissues or organs is activated after injury. In its investigations of Hydra, an interdisciplinary research team at Heidelberg University was able to show how wound healing signals released upon injury are converted into specific signals of pattern formation and cell differentiation. Essential components are the mitogen-activated protein kinases (MAPK) and the Wnt signalling pathway -- molecular mechanisms that have remained relatively unchanged throughout evolution.

The ability to regenerate varies widely in animals. Most mammals and vertebrates have only limited regeneration capacity, while basal and simple animals that emerged early in evolution, like cnidarians and planarians, can regenerate their whole body. In all cases, the process of regeneration begins with wound healing. The cells at the site of injury proliferate and form an undifferentiated mass -- a blastema -- from which the missing structures are re-patterned. This activates genetic processes that also control embryonic development. To determine the molecular mechanisms involved, the research team led by Prof. Dr Thomas W. Holstein studied the freshwater polyp Hydra to understand the basic features of this activation of regeneration.

The core of their investigations is the doctoral thesis of Anja Tursch. She repeated the key experiment of Geneva naturalist Abraham Trembley (1710 to 1784) which led him to discover the regeneration phenomenon. The Hydra polyp is bisected, prompting the upper half to regenerate a new "head" and the lower half a new "foot" -- hence totally different body parts can grow from the exact same tissue at the cut surface in the middle. Building on their previous work on Hydra regeneration, the researchers at the Centre for Organismal Studies (COS) of Heidelberg University have now shown how this is possible.

Regardless of where it occurs, any damage triggers nonspecific signals for an injury response, i.e. wound healing, via calcium ions and the production of reactive oxygen species. The signals are transmitted intracellularly by three mitogen-activated protein kinases -- p38, JNKs, and ERK. Activation of these three molecules is required for both head and foot regeneration. Wnt signalling pathways are then activated that are important during embryonic development for the formation of rudimentary organs and the body axis. The generic signals of wound healing are thus transferred into position-specific signals of patterning and cell differentiation for regeneration.

"Our experiments show that the Wnt signalling pathway is a main component of the initially general injury response and, depending on signal strength, directs the tissue toward head or foot development," explains Prof. Holstein. This is why, in the case of MAPK inhibition, the otherwise absent regeneration can be induced by artificially generated, recombinant Wnt proteins. "It was also surprising that in middle body parts that had both head and foot removed, heads can be induced at both ends in this way," adds Dr Suat Özbek, a member of Prof. Holstein's "Molecular Evolution and Genomics" research group at the COS.

Read more at Science Daily