Stem Cell Promise Vindicated

Posted on by drjbdunphy

Stem Cell Promise Vindicated

 

With the publication of Professor Geoff Raisman’s spectacular achievement in repairing  the damaged spinal cord of a Polish knife attack victim in the journal Cell Transplantation, we are witnessing a paradigm shift of biblical proportions in the field of spinal cord repair – for the first time stem cell therapy has exceeded expectations. Humanity is on the verge of great advances in the understanding and repair of neurological disasters.

This week marks a significant milestone in our journey from the first bone marrow (stem cell) transplant to treat Leukaemia in 1956 (earning the Nobel Prize for Dr. Thomas and J.E. Murray in 1990) to Professor Raisman’s publication in 1969 on the ‘Plasticity of Nerve Cells’.

In just 10 years the possibility of neural regeneration has revolutionised our understanding of neural physiology and repair.

It all began when the canary (long used to warn coal miners of dangerous gasses in the mines) was found to grow 500,000 new neural cells in the process of learning a new song each spring time (it’s amazing what is done for love!!)

A few years later an inspired researcher did MRI brain studies on London Taxi drivers learning maps of London (known as ‘The Knowledge’). A repeat MRI nine months later showed that the hippocampus had grown in size by 14%.

Another study found that when rats learned to navigate a new maze, after only 5 trials they developed more than 20,000 new brain cells. The control group of rats that just ran around a ring for the same time showed no increase in brain cells.

So the brain can and does grow when stimulated. Professor Raisman’s research was the subject of an excellent cover story in the Sunday Times supplement circa 2007. I am personally pleased that I used his research findings and hypotheses in my presentations to the European Anti-ageing Conference on ‘The Potential of Stem Cell Therapy’ in Athens in 2007 and in Paris the following year.

In summary, the stem cell promise has been vindicated.

See below for comprehensive coverage of this exciting medical development from the ever-brilliant BBC.

 

 

Paralysed man walks again after cell transplant

Fergus Walsh

By Fergus WalshMedical correspondent

A paralysed man has been able to walk again after a pioneering therapy that involved transplanting cells from his nasal cavity into his spinal cord.

Darek Fidyka, who was paralysed from the chest down in a knife attack in 2010, can now walk using a frame.

The treatment, a world first, was carried out by surgeons in Poland in collaboration with scientists in London.

Details of the research are published in the journal Cell Transplantation.

BBC One’s Panorama programme had unique access to the project and spent a year charting the patient’s rehabilitation.

Darek Fidyka, 40, from Poland, was paralysed after being stabbed repeatedly in the back in the 2010 attack.

He said walking again – with the support of a frame – was “an incredible feeling”, adding: “When you can’t feel almost half your body, you are helpless, but when it starts coming back it’s like you were born again.”

Prof Geoff Raisman, chair of neural regeneration at University College London’s Institute of Neurology, led the UK research team.

He said what had been achieved was “more impressive than man walking on the moon”.

UK research team leader Prof Geoff Raisman: Paralysis treatment “has vast potential”

The treatment used olfactory ensheathing cells (OECs) – specialist cells that form part of the sense of smell.

OECs act as pathway cells that enable nerve fibres in the olfactory system to be continually renewed.

In the first of two operations, surgeons removed one of the patient’s olfactory bulbs and grew the cells in culture.

Two weeks later they transplanted the OECs into the spinal cord, which had been cut through in the knife attack apart from a thin strip of scar tissue on the right. They had just a drop of material to work with – about 500,000 cells.

About 100 micro-injections of OECs were made above and below the injury.

Four thin strips of nerve tissue were taken from the patient’s ankle and placed across an 8mm (0.3in) gap on the left side of the cord.

The scientists believe the OECs provided a pathway to enable fibres above and below the injury to reconnect, using the nerve grafts to bridge the gap in the cord.

 

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How the injury was treated

Spinal graphic

1) One of the patient’s two olfactory bulbs was removed and the olfactory ensheathing cells (OECs) were grown in culture

2) 100 micro injections of OECs were made above and below the damaged area of the spinal cord

3) Four strips of nerve tissue were placed across an 8mm gap in the spinal cord. The scientists believe the OECs acted as a pathway to stimulate the spinal cord cells to regenerate, using the nerve grafts as a bridge to cross the severed cord

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Before the treatment, Mr Fidyka had been paralysed for nearly two years and had shown no sign of recovery despite many months of intensive physiotherapy.

This programme of exercise – five hours per day, five days a week – has continued after the transplant at the Akson Neuro-Rehabilitation Center in Wroclaw.

Mr Fidyka first noticed that the treatment had been successful after about three months, when his left thigh began putting on muscle.

Six months after surgery, Mr Fidyka was able to take his first tentative steps along parallel bars, using leg braces and the support of a physiotherapist.

Two years after the treatment, he can now walk outside the rehabilitation centre using a frame.

He has also recovered some bladder and bowel sensation and sexual function.

Dr Pawel Tabakow, consultant neurosurgeon at Wroclaw University Hospital, who led the Polish research team, said: “It’s amazing to see how regeneration of the spinal cord, something that was thought impossible for many years, is becoming a reality.”

 

Darek undergoing physiotherapy
Mr Fidyka undergoes five hours of physiotherapy a day

Mr Fidyka still tires quickly when walking, but said: “I think it’s realistic that one day I will become independent.

“What I have learned is that you must never give up but keep fighting, because some door will open in life.”

The groundbreaking research was supported by the Nicholls Spinal Injury Foundation (NSIF) and the UK Stem Cell Foundation (UKSCF)

UKSCF was set up in 2007 to speed up progress of promising stem cell research – the charity has to date contributed ￡2.5m

NSIF was set up by chef David Nicholls after his son Daniel was paralysed from the arms down in a swimming accident in 2003.

To date the charity has given £1m to fund the research in London and a further £240,000 for the work in Poland.

The breakthrough

A key difference with Mr Fidyka was that the scientists were able use the patient’s olfactory bulb, which is the richest source of olfactory ensheathing cells.

This meant there was no danger of rejection, so no need for immunosuppressive drugs used in conventional transplants.

Most of the repair of Mr Fidyka’s spinal cord was done on the left side, where there was an 8mm gap.

He has since regained muscle mass and movement mostly on that side.

Scientists believe this is evidence that the recovery is due to regeneration, as signals from the brain controlling muscles in the left leg travel down the left side of the spinal cord.

MRI scans suggest that the gap in the cord has closed up following the treatment.

None of those involved in the research want to profit from it.

Prof Geoff Raisman said: “It would be my proudest boast if I could say that no patient had had to pay one penny for any of the information we have found.”

NSIF said if there were any patents arising, it would acquire them so as to make the technique freely available.

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The sense of smell and spinal repair

Generic image of a person smelling

The complex neural circuitry responsible for our sense of smell is the only part of the nervous system that regenerates throughout adult life.

It is this ability that scientists have tried to exploit in stimulating repair in the spinal cord.

Every time we breathe, molecules carrying different odours in the air come into contact with nerve cells in the nose.

These transmit messages to our olfactory bulbs – at the very top of the nasal cavity, sitting at the base of the brain.

The nerve cells are being continually damaged and must be replaced.

This process of regeneration is made possible by olfactory ensheathing cells (OECs), which provide a pathway for the fibres to grow back.

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Mr Nicholls said: “When Dan had his accident I made him a promise that, one day, he would walk again. I set up the charity to raise funds purely for research into repairing the spinal cord. The results with Darek show we are making significant progress towards that goal.”

Prof Wagih El Masri said: “Although the clinical neurological recovery is to date modest, this intervention has resulted in findings of compelling scientific significance.”

The consultant spinal injuries surgeon, who has treated thousands of patients in the UK, added: “I have waited 40 years for something like this.”

All those involved in the research are keen not to raise false hopes in patients and stress that the success will need to be repeated to show definitively whether it can stimulate spinal cord regeneration.

The scientists hope to treat another 10 patients, in Poland and Britain over the coming years, although that will depend on the research receiving funding.

Dr Tabakow said: “Our team in Poland would be prepared to consider patients from anywhere in the world who are suitable for this therapy. They are likely to have had a knife wound injury where the spinal cord has been cleanly severed.

Sir Richard Sykes, chair of the UK Stem Cell Foundation, said: “The first patient is an inspirational and important step, which brings years of laboratory research towards the clinical testbed.”

“To fully develop future treatments that benefit the 3 million paralysed globally will need continued investment for wide scale clinical trials,”

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The researchers

BBC undated handout video grab of Professor Geoffrey RaismanProf Raisman

Prof Raisman has spent more than 40 years studying how to repair the spinal cord.

In animal studies he showed that OECs injected into the rat spinal cord could reverse paralysis.

In 2005, Prof Raisman was approached by a Polish neurosurgeon who had begun researching how to apply the technique in humans.

BBC undated handout video grab of Dr Pawel TabakowDr Tabakow

Dr Tabakow carried out an initial trial involving three paralysed patients who each had a small amount of OECs injected in their damaged spinal cords.

While none showed any significant improvement, the main purpose of the study was achieved, showing that the treatment was safe.

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Healthy Brain Month

Posted on by drjbdunphy

Multiple recent developments have inspired us at Dunphy Medical to focus on healthy brains this month, here are a few of them.

  • Trinity College in association with the EU recently launched Hello Brain, a website and free app that promotes mental agility, brain health and understanding of this fascinating organ, follow a link to their site here http://www.hellobrain.eu/en/
  • This October Bank Holiday weekend (25th-27th October), Muintir na Tíre is organising a National Active Community Weekend in conjunction with Console to promote mental health.
  • TedTalks, (a favourite reference on this site as frequent visitors know) have a great playlist this week called How Does My Brain Work which features 9 videos on separate aspects of brain function.

Here’s one of those TedTalks by Daniel Wolpert  called The Real Reason For Brains, I hope you find it as interesting as I did.  It also greatly supports and explains the rationale of a physical therapy which I use in my practice (Neural Organisation Technique – N.O.T.) which I have found of great benefit in head, spinal and other physical injuries, and also unexpectedly in dyslexia and learning disorders over the past 30 years. Further information on N.O.T. can be found on this blog by clicking on Neural Organisation Technique under Categories, a section that shows on the left side of our home page.

 

 

We’ve added more videos from this TedTalks series on our Facebook pages https://www.facebook.com/dunphymedical and http://www.facebook.com/pages/Dr-Sean-Dunphy/173021722744006?ref=hl and there is always endless content on http://www.ted.com/ too.

In 2006 I had the unique experience (for a short time) of using umbilical cord stem cells in a range of chronic diseases. Because of this experience I was invited as a guest speaker to the European Anti-ageing Conference in Athens, Greece in 2007 and to the World Anti-ageing Conference at the Palais de Congres in Paris the following year.

A fellow speaker from Oxford presented some fascinating new information on how spectacularly adaptive and regenerative the brain is, this quality is called plasticity. Brain plasticity was believed to be impossible as recently as approximately 10 years ago, so all medical textbooks more than 10 years old are 100% wrong in relation to brain plasticity and are best thrown on your next bonfire!!

We can thank the humble canary bird for our first scientific breakthrough in this regard, it generates 500,000 new neural (brain) cells learning a new song every spring – neural stem cells are a key player in learning and memory.

A study of London taxi-drivers who memorised and learned the ‘knowledge’ ie a map of London’s many streets like an internal GPS, showed a  14% growth of the hippocampus (the area of the brain responsible for memory) after just 9 months.

Another study found that when rats learned to navigate a new maze, after only 5 trials they developed more than 20,000 new brain cells. The control group of rats that just ran around a ring for the same time showed no increase in brain cells.

Here’s a video neatly summarising neuroplasticity courtesy of http://www.HelloBrain.eu

 

 

 

Here’s a video from http://www.HelloBrain.eu summarising the best ways to keep your brain healthy

 

Breakthrough for Dyslexia and Learning Disabilities

Posted on by drjbdunphy

Dr John B. Dunphy

One of the most frustrating, and in many cases, debilitating conditions (both emotionally and socially) that has plagued mankind, is a condition known as Dyslexia. Dyslexia is the best known terminology for a group of conditions dealing with the inability to properly process language, be it written, spoken or symbolic (numbers, for example). It does not manifest solely in the academic world of school, but involves every part of our existence. Just consider the following possibilities:

  • Difficulty with reading, writing and mathematics.
  • Difficulty in understanding words in normal conversation.
  • Poor or non-existent sense of direction.
  • Little or no concept of time.
  • Inability to concentrate, even when involved in a particular activity, such as a game.
  • Disequilibrium (balance dysfunction).
  • Poor motor co-ordination.
  • Constantly bumping into things or dropping things.
  • Stuttering, hesitant speech, poor word recall.
  • Inability to remember names.
  • Sharp emotional or mood swings.
  • Need to reread the same word or phrase to get any meaning out of it.
  • Difficulty following sequential instructions or events.
  • Difficulty in following motion or moving things (balls, people, traffic).
  • Various phobias including height, motion-related (escalators, elevators, bridges, etc.).
  • Gets lost easily or all the time.
  • Unable to, or unsure in making decisions.
  • Feelings of inferiority, stupidity or clumsiness.
  • Inability to organise daily activities, particularly in allotting proper time.
  • Doing opposite of what was told.
  • Get drowsy, or tend to fall asleep while driving on a highway or open road.
  • Any many, many more. This is a multifaceted condition, which escapes detection many times because of its diverse symptomatology.

Unfortunately, until recently, Dyslexia was not recognised as a specific problem, but was labelled Minimal Brain Damage, Psychosis of one sort or another, Inferior Mentality, Dumb, Lazy, Inattentive, etc. Some ideas die slowly. The concept that the various problems found in our school systems and society in general, are indeed Dyslexia in origin, has been ignored in many educational, law enforcement and other circles. Parents were told by paediatricians and educators alike that nothing was wrong. “He’s just immature.” “She’s not trying hard enough.” “He’s not paying attention.”  Parents were confused, teachers were frustrated and the child was tormented by failure, isolation, and the knowledge of being different. Nowhere was any help available.

Eye-tracking problems were recognised, and eye exercises, and/or special lenses were tried. Equilibrium faults were recognised, and various drugs were used to suppress these symptoms, and hyperactivity and attention deficits. Co-ordination faults were noticed and special exercises were devised. Allergies were finally recognised as contributory factors, and modified diets have been prescribed. Special educational protocols have been instituted with very limited success, in most cases. Any gain was considered a major breakthrough, and was hailed as a ‘cure’. For some it seemed to be, but nothing to date has been of any meaningful or lasting benefit. As soon as the special activity or drug was stopped, the symptoms returned with a vengeance. The child or adult always had to modify or over-compensate his or her lifestyle, to accommodate the limits imposed by this disability.

The majority of the investigators have determined that this complex disability is a bewildering combination of disorganisation within the nervous system.

Neurological Kinesiology…A Neural Organisation Technique

Applied Kinesiology, a speciality within Chiropractic, was discovered, researched, and developed by Rd. George Goodheart, D.C. et al., since 1964. It specifically deals with the integration of the nervous system and the body functions. It is ideally suited to give the best answer to this perplexing problem. Researchers have taken a giant step beyond the medical and other professionals involved in this and other conditions (Scoliosis, T.M.J, etc).

In 1982, Dr. Carl Ferrari, D.C., in researching the Applied Kinesiology concepts in relation to the survival mechanisms of the human species, recognised the relationship between his Neural Organisation Techniques, and the symptomatology of Dyslexia and all learning disabilities. Combining the organizational effects of the centering and righting reflex systems of the Cloacal, Labyrinthine and Ocular reflex mechanisms; the specific cranial faults found in all dyslexics and learning disabled; and a unique eye muscle fault found only in Dyslexics and the learning disabled, has led to an astounding reversal of all the problems  found in the Dyslexic and learning disability condition (to further confound the experts, as early as the first or second treatment, patients often report selective results).

Of course, in most cases, a series of treatments is necessary to refine and stabilise the initial corrections. However, no one has to wait a long time to know that changes have been made, and normal function is being, or has been established. The number of treatments varies with the individual patient. It is important to note that this procedure is done by hand, and no drugs or other foreign substances are ever used.

Outlook And Follow-Up….What To Expect

Although in most cases, once the corrections are made and stabilised, further treatment is rarely necessary. There are things that may cause loss in stabilisation and return of some symptoms. Any condition which is accompanied by high fever may cause destabilisation, as may allergies which were not stabilised. Emotional and physical trauma, particularly head injuries, should always be a reason for a complete re-evaluation. It is also recommended that after the initial treatment protocol has been completed, the patient returns every month or two for the first year, to make sure that all procedures were completed. Another consideration is that research is on-going, and since the original protocol was devised, many refinements have been added in an effort to make this procedure as complete as possible for every nuance the patient may present.

Catch-Up…How You Can Help

Once the proper neurological and structural corrections are made, the patient is able to learn what he or she was not able to learn before. Therefore, ‘catch-up’ is the name of the game.  It seems that approximately 10 hours of activity (reading, writing, speaking, etc.) are necessary to “programme the computer” for each function.

Because disorganisation and easy distraction have been part of their problem, the patient does not know how to study and learn. Structured time for studying and learning must be provided by the parents, or set aside by the adult to learn. There is no radio, TV, eating, going to the bathroom, etc. JUST LEARNING TIME. The family must co-operate . Cross pattern exercises, either in place, or as a march-type activity (right arm-left leg, left arm-right leg) are extremely beneficial, and in the beginning should be done 20 minutes per day. Because diaphragm control is usually weak, blowing balloons is a good exercise. Buy 100 balloons, blow one up, then blow it up again until it breaks; do one a day for 100 days.

With some effort and proper treatment, dyslexia and learning disabilities are treatable.

The Cranial or Head Injury

Posted on by drjbdunphy

The Cranial or Head Injury

The Problem:

You may have any number of chronic health, emotional or structural problems that could be the result of a cranial injury that has gone undetected. The injury to your skull may have occurred long ago or very recently, but the symptoms you are now experiencing have not been associated with it. Cranial or head injury is probably the single most undiagnosed, and therefore untreated physical problem on the face of this earth. That may sound like an overstatement of fact, but lets look at the record.

You hit, or were hit on the head. You were in an accident or fell and struck your head. Whatever the circumstances, the bruise or laceration healed and it was assumed that everything was then all right. But since then, has your overall function been as it was before? Think about it.

Except for the more severe head injuries, the obvious problems of cranial injury go undetected. There is little real information in the literature on the after-care of a head injured person, and almost no discussion on the lesser injuries. There are almost no examination procedures available to determine if a deficit exists in relation to the injury and there is no treatment protocol for resulting problems. You have to know there is a problem before you can treat the problem. With the exception of some Cranial Osteopaths and Cranial Chiropractors, no noe is even attempting correction of the many problems. The Cranial Injury Complex is essentially an unknown entity.

Some of the Known Facts…

When the skull is injured there may be – unconsciousness, disorientation, memory loss or lapses, confusion, motor dysfunction or disorganisation, alterations in speech patterns, the sense of taste or smell changed or lost, and disturbance of gait, balance, equilibrium, and postural functions. There may be mood and personality changes; concentration and decision-making may become difficult; the person is easily distracted, and time awareness is lost. The list could go on for pages. All these are known to be some of the results of injury to the skull, to a greater or lesser degree, when obvious damage has occurred.

In the book Total Recall by Joan Miniger, Ph.D., a report of a study done at the University of Virginia Medical Centre revealed some startling statistics. Of the 424 post-traumatic cranial injury patients released as neurologically normal, a survey indicated that within 3 months 79% had daily headaches, 54% suffered memory loss and 34% could no longer maintain their jobs.

The Lesser Injury

What about the average person with a lesser variety of injury? Most people hit their head on something or were hit on the head at least once in their lifetime. They did nothing about it because it wasn’t considered important at the time. If we “see it coming” so to speak, our defence system can be somewhat prepared to lesson the effect of the blow, and depending on the extent of the injury, may have no permanent effect on us. In more primitive times, this injury would most likely during a fight/flight situation. The ensuing physical activity would have probably cleared the circuits, and if no severe damage was done to the head, no residual effects would have prevailed. Today, this does not happen and the effects from these so-called minor injuries can imprint in the nervous system and go totally undetected. Any deficiency is usually attributed to something else, or accepted as a chronic condition one has to live with.

Cranial Bones Move

It is now accepted in many scientific circles that cranial bones move, in specific and synchronous respiratory motion. This movement is essential for the circulation of the cerebrospinal fluid which nourishes and cushion the brain in the skull. It is also responsible for the balanced circulation of blood in the skull and the drainage of blood and lymph from the skull. Any disturbance to that rhythm can cause either neurological or physiological dysfunction. If the bones DO move – then they can be moved, either by a blow to the skull to DISRUPT the harmony, or a corrective force of a doctors hand to RESTORE the harmony. The fact is dramatically important in the understanding of and treatment of any cranial or skull injury.

The Defence System for Survival

We were created to survive in a primitive and hostile environment. When a dangerous situation or possible injury presents itself, the body’s reflex system must react to protect it from serious injury, if it can. The first order of business is to protect it from serious injury, if it can. The first order of business is to protect the central nervous system from damage and to hold the head on the body. The nervous system is what makes the body work, and in a sense is “us”.

The nervous system is encased in a movable body housing called the skull and spine. Being movable, this body protection mechanism is subject to damage or derangement.

The body has three primal defence systems designed to hold it together and to minimise damage as much as possible.

  1. The reactive muscle system of survival; this system in defence situations, is designed to hold the bones of the skull and spine together, and to literally hold the head on the body. The extensor muscle groups which are our fight/flight muscles – particularly those in the neck – contract to muscularly hold the head in place. If the rhythm of the cranial bones signal a dysfunction, this system remains in place until signalled otherwise. The combination of the labyrinthine and ocular righting reflex systems and the vestibulo-ocular righting reflex system, and their relation to the tonic neck righting reflex system, are the neurological mechanisms involved in this signalling phenomenon. This results in a chronic reactive muscle system imbalance if these reflex systems are not corrected and balanced. The first symptoms noticed are usually chronic posterior neck tension. This causes headaches, eye and special senses problems and chronic weakness of the flexor muscle groups including the anterior support muscles of the neck and abdomen. If a muscle is in a chronic hypertensive state, it cannot rest properly and fatigues easily on stress. The support muscles of the spine, both internal and external, are extensor in nature. If they are compromised by hypertension we lose the stability of the spine on activity.
  2. (a) The defence system of the TMJ – the muscles of mastication (chewing) particularly the masseter muscles in this case, lock the jaw externally to prevent dislocation if struck. The temporalis muscle contraction holds the side joints (sutures) of the skull together. The buccinator muscles tighten over the teeth for protection. Both sets of the pterygoid (internal muscles) are activated to lock the jaw on the inside and to stabilise the sphenoid (centre bone of the skull) on the inside. This muscle action mechanically stabilises and holds the skull together if stuck. The pulling action of the pterygoid muscles flexes the bone causing an increase of tension of the stabilisation to this most vital organ and a resilient wall to facial and dental pains, scalp and head pains, ringing in the ears, dizziness or loss of equilibrium, and a host of other symptoms may be present.

(b) The contraction of the ptygeroid muscles activates the coccyxegeal group muscles on the outer end of the spine. These muscles contract pulling the sacrum and coccyx forward. This action, because of the way the dura is attached, increases the tension of the spinal dura (covering the cord) which stabilised the cord in the canal, pulls the spine together for structural integrity, and again because of the way the dura attaches, holds the head to the body and specifically stabilises the upper neck (cervical) bones. This is the Dural Defence System.

(c) The Facial Defence System…When danger is imminent the muscles of the skin and body fascia contract to hold the body and the joints together, restrict peripheral blood flow, and hold the head on the body. If this system is not released, circulation, joint problems and endocrine problems may ensue. If the defence system is not neutralised because of the continued cranial distress signals – bowel, digestive and sexual problems will become chronic health problems which no one will place in proper perspective.

Successful Treatment

The cranial injury disrupts the synchronous motion of the cranial function, activating the reactive muscle and the dural and facial defence systems to protect the body. The motion and balance of the cranial bones and the balance of the reactive muscle system is restored through proper treatment of the labyrinthine and ocular righting reflex systems of the skull itself, along with the neck righting reflex system which will stabilise the head on the neck.

The muscles of the Temporo-Mandibular System and their reactive Coccygeal Muscle system, if treated properly, will release the dural tension.

The fascia at the base of the skull, if reset and stretched, will release the fascial and skin reflex.

This treatment protocol, researched at the Ferrai Institute, will clear the defence system and restore the structural and functional integrity of the skull, neck, spine and pelvis. With the correction of the confusing signalling from these structural and functional problems, neurological integrity can be restored and most if not all of the chronic problems related to cranial injury can be eliminated. This is particularly true of the subtle head injury, which for the most part is unrecognised and therefore untreated. If there is profound head injury without brain damage, the process is slower but most function will eventually be restored. In the case of brain damage, there are additional cranial and other protocols which can be employed to enhance and/or restore normal neural function.