Job Alchemy

My primary school teacher told me my favourite word had been loquacious. That doesn’t obviously lead well to my choice of mainly somnolent patients. But there are times, like now, where thankfully the profession and the NHS is telling us all her stories. 

When I think about my happiest times in medicine they weren’t the easiest or the least emotionally intense. They were on teams. I had two things – time in one place to familiarise myself – and an anaesthetic room. I was given, and  didn’t have to create a safe space. I had a few minutes alone with someone I knew to talk about life. When I left I was given a book, with an inscription. I was happy to be moving home, but sad to be leaving. There are many many good places to work within the NHS, because there are many resonantly compassionate and humane people. For some reason it attracts them! So imagine finding myself in the position of receiving message after message of what I would call cruelty. If not malicious then certainly negligent. 

At first I assumed these were probably just extreme examples of workplace conflict. And then more followed. And more. I didn’t invite them! But expressing myself on the internet had created a safe space for them. The physicist in me would call it a “story vacuum”. It brings them in from high pressure to low pressure. 

When we think of ourselves as human, what is the quality that sets us as a species apart? Language. Verbally or behaviourally it allows us to express and receive the thoughts and hearts of others. It is part of theory of mind, a developmental process. Yet somehow, in a world that is built of human, we have forgotten to really speak to each other. 

How can it be possible that someone is called into work despite their partner committing suicide that day? How can it be possible someone is mercilessly mocked, humiliated and bullied, yet called unprofessional when they wish to change team. How is it possible that a young doctor is expected to start a placement when their parent just passed away from a common diagnosis in that specialty…and again called weak and unprofessional for wanting to swap or delay. How is it possible that last October a junior doctor hung himself mid shift on a Friday and was found three days later…HR and colleagues assumed there had been a rota error rather than checking in. 

It scarce seems possible an organisation designed to care for the sick and dying, can wear the face of such cruelty. Moreover with callous claws tear into its own heart and leave the workforce bleeding. 

 This isn’t just a moral issue, or a workforce one. This is a patient safety issue. We know that errors increase, and protocols aren’t followed, and there is reduced patient centred discussion, when the team is fractured. Civility Saves Lives is a campaign that demonstrates in real terms, what even one rude interaction can do to patient outcome. 

But despite this I have seen the poetry of doctors and other professionals, and the public, fusing together to condemn such acts and provide support for one another. When you have such a mass of people, there is a certain force involved…in physics we call it gravity. The problem with gravity is that you can use it for both these ends; to build planets…and black holes. I think we all need to take a moment to consider where we are taking ourselves and what a future in this climate actually looks like. 

For me, being invited to spend the day and shown histology slides, going to events as an equestrian doctor, an invitation to an aviation medicine base and a hyperbaric chamber showed me the fun and immense privilege of the profession, and only having to turn round to look at the face of someone who cares immensely. 

Thank you so much for everyone’s huge support and the conversation that has burst into life; I am touched and overwhelmed and so grateful that these brave trainees have had an audience. I have never been more honoured to call myself a doctor.

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Post Mortem of a Career

From the age of 9 I remember my dad sitting down on a summer day whilst I was on the swing on the apple tree and communicating in one of those poignant father-child ways that one of his greatest wishes in life if I could go to Oxbridge. He himself was from a working class family and had apprenticed during university holidays, and had gone to a grammar school, after doing well on the 11+ which his parents were thrilled by. My mum was first a nurse then a midwife then finally a band 8 (although I am biased she is both smart and lovely), even though her family was also poor and the neighbour paid for her school uniform.

Then I, always keen to make people (and my dad) proud of me, was a super geek at school and applied to Oxford (for my partner at the time). To my absolute surprise I got in; albeit to the college so academic it was called where fun goes to die and they shut the games room during exam time. I was told off for coming 7th in my year because that wasn’t the way of my college. 

Half way through I went to London for clinical training. Having had no hospital experience and still fairly shy of people I did very badly in the practicals, though written was still easy but they didn’t contribute to the year. My parents were paying a lot to support me through London rents and catching the tube between zones 1-6 for med school. (As in £1500/month), so I thought I better buck up. Finally I left with distinction and started off an academic job in Oxford deanery (academic was wonderful) but like all new juniors it was hard work. It turned out the years above us however were taking bets on which F1s they could sleep with, lovely. Suddenly the offers of help and advice from seniors became quite sinister! Accommodation nearby was expensive so I stayed somewhere rather rough until I called the police for a women being attacked in the house next door and then came home to find all my windows broken the day after. Though nearly all consultants are helpful they were rather busy, and so the odd ones who threw ringbinders at you or told you to go back to med school, or you were going to fail at at medicine because your supervisor had gone on a month cruise and things wouldn’t be signed in time, occasionally made you think twice. But medicine is rewarding and satisfies your curiosity.

Fast forward to anaesthetic training. I moved up north for two years for a partner I broke up within a month of the move. I knew very few people but got to, worked hard, decided to focus on exams, travelled back 3-4 hours each way to see friends and my mum when she was poorly , dealt with some of the casualties from the terror attack. signed everything off, passed my exams, focused on getting a clinical fellow job because I didn’t feel ready for reg posts. Then when the Rotas were one in two weekends with a lot of single days off , but a six hour round  trip to see anyone new, I turned that down (feeling absolutely guilty – who was I to turn down an opportunity in medicine for boring family reasons?) luckily got a reg job where people were suddenly jumping off the hospital and slitting their throat which was wildly out of my comfort zone but you get on with the job . 

I find it interesting people rarely ask how your first shifts/night shifts are even though they are often absolutely far beyond the scope of a normal person’s entire life experience. We ask about first days of school, a new job, but rarely about first day in a new hospital. I got engaged (but no one knew because there are hundreds of anaesthetic consultants and you are only there for three months at a time/on nights/see people either never or max three times and you can’t wear a ring at work). Only my peers knew as well, when my dad fell down a twenty foot concrete trench. We don’t really ask each other about our weekends between consultant/trainees which I think is partly lack of familiarity and partly an opaque hierarchy.

Once my aunt had a large heart op and had a spell in icu but I couldn’t go see her. Then a colleague let me know I’d been missed on an email regarding us all starting at a completely new trust in two months. Suddenly that annual leave I had been collecting could not be debited, because too many other people were off over January. 

Then before rotating I was coming in between night shifts (despite also living an hour away) to get things signed off. But it comes with the territory. Then on my next block I had to go to induction on my annual leave days. I was paying £25/shift to park initially until I figured out cheaper places because despite living forty miles away they’d run out of permits. Expenses cost the same as my mortgage payments for petrol, parking and the four new tyres I needed in eight months of motorway driving. 

My grandad passed away (my aunt rang me saying the carers had found his body what should she do). I was at work so I mentioned the ambulance and called the gym where my mum was to get reception to go and get her so we could tell her that her father had passed away. I then worked the twelve hour shift, with only the midwives being sweet. I didn’t feel compassionate leave would be acceptable so I tried to swap shifts to go to his funeral 250miles away.

Once I had an incredibly traumatic death of a young person.  Even the consultant was distraught at 2am. No one had cleaned the body even though the family were in the room. I did it, and it was incredibly frightening and gory even though I am pretty inured to the frights of trauma and death. Three months later I was having nightmares about it, and for a two day spell would be speaking to people, and seeing their eyes dilating and then passing away, even though we were just sat in clinic and it was a complete illusion. Luckily that was short lived and i still went to work, driving the hour and back from shifts, leaving the house at 06:30 and returning at 9pm, or vice versus on nights. Twice I slept in the car at services, once I tried to but a kindly traveller had knocked on the window thinking I was dead. I was so guilt ridden about a journey one day in the snow, I walked forty mins to a station, caught two trains and a taxi to work (which took about three hours), felt horrific I was late, but then all the patients had cancelled.

I love medicine and my colleagues are smart, funny, caring and inspiring. But none of my seniors, who I get on well with, knew about my engagement, my dad, my grandad, either because of the rota pattern, busy shifts or we aren’t designed to ask. We all get asked how our shifts were but not the viscera of our lives.

I am not depressed, I wouldn’t give it up, but I am tired that medicine in the UK at the moment has created a system that is systematically designed to separate us from our real lives, erode the mentor/trainee relationship, move us round hundreds of miles and perform a constant circus of acid rain on our self esteem,deep rooted desire to please, and ability to conduct ourselves as a daughter, partner or parent. Medicine is unfortunately one of those careers you have to prostate yourself before/marry. I’m not sure I understood completely what I was sacrificing at 18. I accept that For healthcare you do just have to sacrifice, but realistically there is a fleet of small, inconsequential things, like the omission of small talk, missing people off emails and registers, coming up with complex and circuitous methods of claiming annual leave, that would transform my world were they to undergo a humane metamorphosis.

There is that remnant shard of infant inside me that is still curious, enjoys exams, feels comforted that with the world in catastrophe I still have a job that is pleasurable and well remunerated, and sets goals that I will chase as avidly and enthusiastically as a spaniel with its ball. My colleague, more business-like than me negotiated kinder working conditions. He wryly observed that after honing myself  writing essay after essay on things such as whether and how memories last forever, the evolutionary bioengineering of the knee (the locking mechanism is a highly efficient way of maintaining a standing position in terms of energy) and whether pain was “all in the head” in med school, I was fully able to communicate the minute, vague and petty tortures of a colossal machine like the NHS, and why goodwill matters. I myself still feel a little confused that I felt compassionate leave was cheeky. Why?? If the NHS wants to employ people in a lifetime career then it needs to make it that career sustainable. That includes allowing for precious moments in the lives of staff. I find emails about resilience galling because they seem to say that it’s our fault we find it hard sometimes, and the environment can not be altered. It’s not that I feel burned out, it’s that despite exchanging some of the most pivotal events in my life to work, I am continually missed off emails about my own life (eg rotas, the hospital I will actually be working at); and clearly so anonymous no one would actually realise you were gone until the first time you didn’t turn up for a shift. 

Why are we treating professionals who have cost thousands to train, dreamed of the career often since a child, work at the expense of their health and personal life, in such a disposable way?


Your gut and Parkinson’s

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/ – in depth review of alpha synuclein

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/ – the appendix/Parkinson’s study in full

Why?

My partner recently mentioned to me a study had revealed a putative link between appendicetomies and a reduction in Parkinson’s disease. An epidemiological study, but one with convincing numbers involved and a potential mechanism.

I have always been quite interested in protein based disease because as an adolescent I remember reading that the point at which DNA based life started to develop was when proteins learned how to reproduce and store themselves – in the form of genes. Protein production is heavily regulated by cellular machinery because they are the players by which the script – genes – produce living, breathing organisms.

Prion diseases have been a possible consequence of proteins’ ability to manipulate and reproduce in their environment. The most infamous being ‘mad cow disease’ or CJD. Abnormal ‘infectious’ proteins are able to make other neighbouring proteins pathogenic and spread. It’s fairly devastating because there is no cure, and it happens rapidly. Other protein based diseases such as amyloidosis, Alzheimer’s and Parkinson’s also seem to march to an inevitable destination.

Alpha-synuclein

The protein that seems firmly entrenched in the pathophysiology of Parkinson’s in one called alpha synuclein. In health it is often present in synapses – in between communicating cells. It seems to play a role in helping to regulate transmitter release, and possibly also transport up and down neurons (brain cells) as well as calcium homeostasis (a key signalling molecule in the central nervous system). A complete absence of alpha synuclein has a devastating effect on the development of animals in whom it has been genetically erased.

Additionally, transfecting one individual with alpha synuclein from an individual who has Parkinson’s disease, does not confer the disease upon the recipient. At least in animal studies. Additionally there are people who have the presence of alpha synuclein protein aggregates at autopsy, who never displayed Parkinson’s.

However in heaviliy hereditary parkinson’s; which is rare, the most common form is sporadic, gene defects affecting alpha synuclein are the common finding. The more aberrant copies of this gene they have, the earlier onset and severity of Parkinson’s. Alpha synuclein is found in all patients displaying Parkinson’s disease.

Image result for alpha synuclein structure[from degruyter.com]

Thus it is clear alpha synuclein is associated with Parkinson’s. It could be causative – the hereditary version would suggest so. However it could also be an unfortunate byproduct of another disease process going on – a symptom of cellular or synaptic metabolism gone wrong and causing toxic build up. A feature of synuclein present in Parkinson’s versus healthy brain, is abnormal folding of its protein structure, causing it to clot and form aggregates called Lewy bodies. Abnormal folding is a feature of many prion diseases as well as amyloidosis – a protein’s function is heavily related to its structure; think of enzymes, of charged amino acids interacting at various surfaces, how well it fits its upstream and downstream targets in order to effect a response. Thus it is no surprise a change in structure causes a change in function leading to mayhem in the precariously balanced environment at the junctions between brain cells.

The Appendix

What is fascinating about the appendix hypothesis is an idea that the gut microenvironment – in this case that found within the appendix, can influence the alpha synuclein of the brain. There is infact one nerve, whose branches I had to memorise for my anaesthetic exam, that directly arises from the brain and descens into the gut. It also carries signals, upwards. This nerve is number X of XII cranial nerves, so called because they arise directly from the brain unlike every other nerve in the human body, which originates from the spine. These nerves are responsible for vision, hearing, balance, sensation on the face, movement of the face, the tongue, the eye, and shrugging of the shoulders. They also help regulate certain essential physiology such as blood pressure. None descends quite so far or seems to cover quite so many organs as the vague nerve. It travels out of the skull and down the neck by the jugular vein, under the first rib and into the thoracic cavity, over the lung hilum and through the diaphragm, throwing off multitudinous branches as it courses. It splits into an anterior and posterior part and supplies the viscera of the abdomen, including the gut.

[

[from medscape.com]

It has already been suggested that two places the badly behaved alpha synclein originates is In the olfactory bulb (Cranial Nerve I) and the nerve root of the vagus (X). A postulate for this has been some sort of airborne pathogen, ingested via the swallowing of nasal secretions, that then track back up the vagus nerve. There is some gentle evidence for this in that extra cranial alpha synuclein has been found in the stomach and vagus nerve of animals with prodromic Parkinson’s. Pathogenic alpha synuclein has been injected into the stomach of rodents and witnessed to ascend into the brain where it has caused features of Parkinsonism.

Image result for dorsal root vagus

[The University of Western Ontario Department of Anatomy and Cell Biology]

Thus, alarming as it is, there is a potential trafficking route by which gut pathogens can transfect the brain. As the appendix is somewhat enrolled in establishing the local gut flora and fauna (significant changes in dominant bacterial species occur post appendiectomy) and alpha synuclein deposits are found in the appendix it is quite feasible this could be a protective procedure.

Equally because pure alpha synuclein is not causative of Parkinson’s, there is likely to be more to this picture. Appendiectomies are also protective against certain inflammatory bowel diseases (ulcerative colitis) and likely have a gubernatorial role to play in enteric inflammation. The production of cytokines, free oxygen radicals and mitochondrial dysfunction that also contribute to the pathogenesis of Parkinson’s disease. Having an appendiectomy is also likely secondary to appendicitis; there may be genes that are protective against Parkinson’s yet predispose to appendicitis. Thus the correlation between appendicectomy and Parkinson’s would reflect a pre-existing genotype rather than a true causation.

Conclusion

The epidemiological studies were conducted across nearly 2 million health records matched for age, sex, location. Not only was the incidence of PD reduced in the appendicetomy group, the age of onset was several decades later, most pertinently in the rural groups. Thus these especially may end up exposed to an environmental agent (either biological eg bacteria, or chemical – a pesticide), which installs the appendix as an agent of neuroinflammatory change. I’m less impressed that they have ‘corrorborated these findings’ in a database of 849 american patients. With a prevalence of just 0.3% in the UK population, you’d need studies with tens of thousands of cases to find a statistically valid difference in Parkinson’s rates between appendiectomy and non appendicectomy patients. 0.3% of 849 is probably about 2.5 patients altogether. (probs)

I think big data is key to mining the answers to some of our most widespread and least lucid human diseases. And the age old dichotomy of the brain/body interface is slowly being eroded.


Anaesthesia, the brain, and a pinch of salt

We might all be able to describe what it means to be unconscious. However to ask the meaning of ‘consciousness’ is to catch mist with one’s bare hands.

The human nervous system is, on a global level, rather organised and succinct. Like most fish, birds, reptiles and other mammals we possess a brain and a spinal cord. The spinal cord flares off into peripheral nerves in a segmental and symmetrical fashion, and the brain has its own set of 12 nerves that control the head and neck. One nerve descends from the skull deep into the abdomen; the vagus; a proponent of various shenanigans in medicine. Anaesthetist’s generally pre-prepare four key emergency drugs prior to delivering unconsciousness, and two of these are antidotes to the vagus nerve’s actions. One, atropine, is actually derived from belladonna, a plant featured in both Harry Potter and Ancient Egyptian hieroglyphs. Dinosaurs were in possession of vagus nerves, and presumably belladonna would have its role in anaesthetising a T.rex as much as a human. So much of what we use and manipulate in medicine is indutably prehistoric.

Spinal cords are business like, braided structures that carry messages, akin to telephone networks. They communicate between thought and limb, hand and eye. The brain itself can be broadly classified into a primitive hindbrain, regulating a beating heart and sub-conscious breathing, and a more prestigious forebrain; the architect of thought and reflection, planning and emotion. There is a midbrain somewhat connecting the two. It is indeed possible to be born without a midbrain and hindbrain and survive in terms of functioning organs, however developmentally ‘anencephalic’ infants are considered to be blind, deaf, unaware of pain or surroundings and anatomically incapable of forming autonomous thought or emotion In addition there is a gate somewhere in the mid/hindbrain called the Reticular Activating System that contributes a switch between awareness and asleep and generally monitors the flow of traffic, bi-directionally, between brain and spine.

 

hind (https://cerebralcomponents.weebly.com/forebrain-midbrain-and-hindbrain.html)

It is on a microscopic and sub-cellular level that neuronal signalling actually appears more chaotic and random. Tumultuous surges of charged particles oscillate in and out of brain cells (neurons) which transfer messages amidst a constellation of shepherd cells (glial cells), who have an immune function and tightly regulate toxins, waste products, fresh resources and to a mediocre extent, growth factors, amidst a forest of neurons.

Most of us are familiar with the grosser aspects of electrical messaging; a ‘current’ which flows and conveys energy from a source to recipient. In our household sense, electricity is a stream of charged particles; electrons. In the body these charged particles are ions i.e. basic elements such as sodium, chloride, calcium, potassium, hydrogen. In their possession of a charge they can not only transfer energy, they are reactive, and can be baited, captured, collected, leaked, lured down tunnels and passages, and explosively released and deployed in order to incite metabolic reactions that have a desired macroscopic outcome.

 

channel (https://www.cytherapharm.com/research.html)

In the nervous system, positive charge i.e. sodium and calcium tends to excite and switch on the brain, whilst chloride tends to switch off and settle neural networks, with its negative charge. These ions cannot freely pass cell membranes and have little tunnels called ion channels that bore through a fatty cell membrane and allow flow inside/outside or both. These act as switches because according to electricity, natural signalling molecules such as hormones, and drugs , they will open and close. All anaesthetic drugs have a propensity to mess with the on switches; calcium and sodium, and/or the off switch, chloride.

Whatever one’s beliefs about the origin of life, if one considers 2/3 of the earth is covered in water, namely salt water, and that life may have blossomed in this primordial soup, I find it fascinating that our own nervous systems have taken salt (sodium chloride) as the elementary basis of thought.

The ‘switched on’ circuits of the brain are balanced by a counterweight of chloride. Chloride channels are faulty in epilepsy, psychosis, bipolar, schizophrenia, insomnia, chronic pain and migraine. On and off switches seem an elegant and mathematical principle by which to run an organism, indeed this binary approach is similar at first glance to the 10101 binary code used in non quantum computers. However this appetising brain=computer logic quickly begins to fail when one considers it is not in the nature of computer software to corrode, reshape or destroy the physical hardware. A disc may become scratched however it is not the string of 1’s and o’s imparting such a defect in the tangible world.

The opposite is true for our electrical currents. In switching on and off messages and neighbouring neurons, all these electrical fluxes and also the direct interaction of the elements like calcium themselves on an atomic level, re-manufacture the neuron. New genes are expressed. New genes that make or break down proteins. Proteins that activate other proteins or even proteins that become new ion channels, influencing the ‘switched on-ness’ of a cell or its sensitivity to its neighbours. Rafts containing ion channels float around beneath the cell membrane ready to be activated and installed at will. Proteins and components that cause little hands called dendrites to reach out in the direction of signalling molecules outside the cell, all the better to grasp them; like flowers turning to face the sun. Two neurons may form such close dendrites that a signal in one is guaranteed to incite another, instead of an arbitrary 70 percent of the time. Just one mechanism in the basis of forming memory.

 

Image result for dendrites (http://www.mult-sclerosis.org/dendrite.html)

Thus a nerve is not a passive wire transmitting a current. The very transmission of a current alters its chances of receiving and responding to the next current. And the absence or presence of subsequent currents changes the neuron again. Sometimes it might receive a sodium and chloride current together but one may override the other depending which ion channel is open to more traffic in that nanosecond.

A series of balletic ion fluxes is unremittingly present at all times of day in all neurons. A percentage of these currents are completely whimsical; subject to the laws of physics and mathematical chance. Ions can enter at random; they are just not likely to. The brain somehow teases out which currents are meaningful responses to stimuli and which are nonsense background noise.

It is not a leap to understand why electrical impulses can regulate something regular and mechanical such as breathing. It is a more mind-bending task to consider why and how such impulses can generate spontaneous thought and philosophy. Why should a brain cell decide to ponder its own existence. Why should a global ego, consisting of thousands of individual neurons yet able to survive the death of many, ascend from the random electrical gibberish of salt passing in and out of phospholipids.

Noone appears to satisfyingly express consciousness. And anaesthetists, as practitioners in the delivery of unawareness, are no wiser as to what they are switching off and restoring, than anyone else. At some juncture our drugs are able to separate body and mind. We artfully dispense with what is one of the most prominent questions in human history – what makes us human? We have no idea. But humanity responds to propofol.


Optogenetics, the immortal cells of Henrietta Lacks, and one’s future cure for Alzheimer’s

Back in the days of learnedness at university, where it was incumbent upon us to learn about the flaws and fallacies of laboratory research techniques in order for us to challenge the currently held models of  the human body, I spent a year dedicated purely to neuroscience. In the years since my  time has been sent stocking up on redundantly google-able facts such as the antigen causing heparin induced thrombocytopaenia. I have therefore forgotten to check up on the progress of a field so swiftly-ambulating that someone can publish a paper on the same research you are conducting before your experiments have finished.

 

I remember at the time, not being a techie, and never failing to maim my own experiments to the extent the lab supervisors would give me antibiotics to grow my long-suffering cells without a significant population of flora and fauna. Of note these cells were formidable ‘immortal’ HeLa cells taken from the tumour of a lady called Henrietta Lacks whose tumour was controversially resected and used in medical research, to this day, sixty years post her death, since they are unrelentingly alive. Nevertheless I killed them.

However along the way I became entirely entranced with some novel genetic techniques that were to the field of Neurobiology as revolutionary as Fleming’s penicillin to microbiology. (Incidentally you are to be thanked Sir Fleming, your penicillin did indeed save my experiment.)

37280_447166451006_3092695_n **writing initials  with a laser on the nuceli of HeLa cells. A laser than you must turn off overnight or it starts to burn (for future reference.) Of related note the nuclei will re-assemble to form the same letters after division – show some anonymous microstructure organises the chromosomes quite purposefully. This was postulated when I ran my experiments but has quite geekily been confirmed by researchers at MIT http://news.mit.edu/2016/study-molecular-motors-shape-chromosome-structure-0610

The technique is known as “Optogenetics” – the idea being you can turn on individual brain cells selectively using light.

Prizes in medicine and biology have been won a dozen times over for work in this field. It beats other techniques hands down since unlike CT and MRI or even PET scanning, one can see individual neurons change in real time on a millisecond time scale, allowing us to visualise how neurones communicate and crucially, we can view them without interfering in the affairs of the networks themselves.

So what does the technique involve?

Neurones signal to each other using an array of techniques. Originally we felt they were just bits of ‘thought string’ running from hand to brain etc like a puppeteer’s rein (greek philosophers) moving to electrical bursts (true) and then identified as movements of charged ions across a permeable membrane (yay GCSE biology) discovered in squid tentacle axons in the 1930’s by Hodgkin and Huxley whom my tutors were obsessed with and appeared in essay questions incessantly. So cells signal using ‘charge’ a fundamental property of matter measured in coulombs, transferring energy, and this triggers an armada of biochemical, enzymatic, genetic and hormonal fluxes and more recently discovered quantum mechanical effects, eliciting effects such as thought, movement and memory.

Since every neuron seems to have effects on its adjacent neurones as well as those it is wired to, it has been exceptionally difficult to understand WHICH reaction inside brain cells actually conveys the requisite information in a medley of chaotic millisecond flux.

However the simple insertion of a light sensitive channel into a cell membrane allows us to turn one cell on at a time like an electrical switch. These ion channels are similar to those found in the retina of the mammalian eye, and were sourced from blue-green algae, who are photosensitive in that they are galvanised to move towards light. Channelrhodopsin is one such. It likes blue light, and opens to admit a swathe of charged ions into its resident cell, activating a signal.

stanfordheart2**picture copyright www.kurzweilai.net

SO we learned to switch on discrete networks, we also learned how to use these channels to turn OFF networks. Thus in live animals (no more brain dissecting!) you can expose them to a learning event and switch on or off tiny little circuits of neurons to see which ones directly affect the behaviour of recall, learning and number of attempts to memorisation. Then you can even see where the memory is stored! Then you can switch off the stored memory, and watch the mouse have to relearn something  it knew by heart a moment before. Then turn it on again.

optogenetics-neuron-640x353

The implications are enormous. Sight has been restored to blind mice. Hearing to deaf mice. You can demolish fear/traumatic memories. You can accelerate learning by replaying the learning circuit whilst the mouse sleeps.

 

And my personal current favourite is the discovery published in Nature doi:10.1038/nature.2016.19574 regarding Alzheimer-like mice. In Alzheimer’s memories are lost and it can become difficult to form new memories. However in the Alzheimer’s mice, optogenetics showed the lost memories are actually retained../but the networks that access them are lost. Thus if blue light is used to stimulate the old memory, the memory returns. When the light is turned off, it vanishes.

I find this staggering. With an aging population and a highly academic but remarkably inefficacious field of brain medicine, some of these techniques may represent an actual solution to some dementias and head injuries. Possibly even developmentally challenged children.

 

The current limitations are quite harsh – the cranial vault must be opened to expose the relevant neuronal networks and some are buried deep requiring a carefully positioned probe. Genetic engineering is controversial and generally unethical in humans with our limited knowledge on unwanted effects (note X-men), but there are fields that harness its potential – cystic fibrosis sufferers can have new genes inserted into their airways through inhalers and some hereditary blood disorders have been partially managed using gene therapy.

index **from this paper explaining how to reduce tissue damage vs selectivity in optogenetics http://www.nature.com/articles/srep13289

Therefore I will not leave it quite so long before checking out neuro advances again, the definitions and physiology are lost to me, until I find a way to shed light on them again.

 

🙂


An Ode to On-Call

Apprehension
Anxiety
Looking at the clock
Flicking through the patient lists
Quickly taking stock

With military precision the bleep
Goes off
Several times a minute
Like a ten gun salute
A fanfare hailing doom
Scribbling jobs on my handover, rapidly
Running out of room

Chase these bloods
His potassium is too high!
It might be a PE, can’t do an ABG
Take it from his thigh!

Await the CSF results,
His cannula’s not working doc,
I need some more fluids doc,
His regular meds aren’t written up,
My patient’s throwing up,
I called you an hour ago!
I feel like giving up.
Just to let you know, our patient has encephalopathy
You might want to do something when results back from laboratory.
The D-Dimer back at 300, troponin back at 50,
My writing less legible, characters getting thrifty
Started aspirin, begun clopidogrel,
This lady wants senna, lactulose, fibrogel

ABC, ABC
Acute heart failure, some furosemide
More oxygen and then again decide
Meanwhile bleep still shrieking,

Doctor! These late night relatives are here…
“I’m a bit busy; I’m not speaking”
They’re getting really angry,
by the way
The patient’s cannula is leaking!
No local sanicloths, no needles,
no tourniquets, just wheedles
After you’ve done this…
“I have another sick patient to review”
The relatives want to speak to you!
-adjourn in treatment room for respite-
Bleep still bleeping.
Keeping, keeping bleeping.
Our patient needs his methadone,
“Why is he on methadone?”
I don’t know.
After prescribing methadone.
Doc pharmacy won’t release the methadone.
“I can’t make them”
The patient wants to know, can he collect it from Tesco
…NO!

Bleeping, shrieking, bleeping
Pulses leaping, IVs seeping
Desaturating! Hypotensive! No urine output
Cannula failed! Needs antibiotics for his foot
We don’t know the name, we don’t know the age
I’m just starting my shift, let me read you the page…
By the way his respiratory rate is 55
“How long has he been this alive?”
It started going off earlier today
“And his day team ignored it anyway?”
They made a DNAR. No escalation. Withdrawing care.
“And what would you like me to do?”
I think he needs ITU. And review.

CTPA back, diagnosis on track,
Treatment dose fragmin prescribed
Patient survived.

Heart failure less failing,
From here it’s all plain sailing.
You’ve been ages doc!
I asked for this hours ago!
The relatives have left now!
Patient with a smile,
Thank you doctor.
All worthwhile.


What drives us? Harness the horsepower

Motivation bridges the gap between desire and action. It derives from one of the Latin roots motivus (to set in motion) and motare (to stir/agitate). Our human happiness is the net product of how many of our desires, spiritual and instinctive, we able able to placate. Motivation delivers us from one to the other, and many of us wish we had more of it.

In keeping with a law of physics I’ve forgotten about, accelerating an object from standstill to motion requires more energy than keeping it moving. Similar seems to be true for many inner desires; starting a diet, quitting smoking. The decision to walk to the kitchen to retrieve a biscuit when we are in bed and it’s cold out there.

Any action we take requires neurons firing when a critical threshold is reached. A series of inputs of variable weights collaborate to produce a common output. When it comes to what motivates us, what are these variables?

It is generally agreed there are primary and secondary motivations. Primary are instinctive, such as food, sex and warmth. Secondary are more cognitive; money, awards, weight loss. Each of these hold a different importance depending on personal preference (the taste of bacon may weigh against our moral prejudice against eating meat) our mood (PMS anyone?) and our physical state e.g. Hungry. Each of these goals thus have a range of values dependent on a range of complex interactions with other desires, primary or secondary. Thus there is no way for a brain cell to code a discrete ‘value’ for each goal, because from second to second they are in flux.

Once we have settled on the value of a goal for the time being, we must weigh this against the predicted probability and also ease of getting it. Experiments show that monkeys (and you will recognise this phenomena in people!) when asked to push a selection of levers, will push one with a longer delay in getting food, as long as that reward is bigger. However there is a maximum time delay, at which regardless the amount of food offered, monkeys are willing to wait. In a similar vein, large rewards that are only delivered 20% of the time when a lever is pushed may be superseded by a much smaller reward that is consistently delivered.

In people, our degree of experience (ability to predict risk) and degree of risk aversion affects how willing we are to proceed with a goal orientated task. We recognise the two extremes in thrill seekers, gamblers and bank traders vs health and safety standards, mothers with young children and public sector workers.

When we weigh up a decision, in the very simplest terms it involves two intersecting circuits. we have a reward system, which dictates reward value in that time and place; instant gratification, and a decision maker which assesses risk and also delayed gratification – the bigger picture. This is classically the ‘I want a yummy biscuit but I will get fat’ conflict.

The opinion is personal but I think of these as a primitive circuit and a more sophisticated circuit. The instant gratification circuit was given to us, by Mother Nature, to reinforce certain behaviours, to maximise survival. Such behaviours include high calorie food (we evolved in a food scarce world) and sex. Our less animal circuit, the decision maker, enabled us to thrive by planning ahead, rather than living just another day.

The reward circuit is driven at a basic level by dopamine, the release of which in this area, the nucleus accumbens, is experienced as a rush of pleasure. The degree of pleasure we feel correlates with the quantity of dopamine unleashed. Soon dopamine is liberated by cues related to the original source of pleasure, such as a place or time of day. This is reminiscent of Pavlov’s dogs and operant conditioning.

Meanwhile the decision maker consists of inputs to the orbitofrontal cortices and the ventral tegmental area. These may be memories, morals, fears, emotional cues and higher cognitive processes e.g. This won’t help me achieve ‘X’. According to the Hebbian rules of neurocircuitry ‘what fires together wires together’ and the more the reward circuit us tapped the more cemented certain pathways become, and may even fire an action with minimal modulation by the decision maker. Variations on this theme is implicated in addictive substance abuse, despite the profound detriment to physical and social achievements.

Ultimately there are mental tricks to improve motivation. One can increase the value of a goal eg by frequently imagining it, bolstering it’s value in terms of mental prominence and tangibility, or equating it with money eg by giving children gold stars for homework exchanged for toys at a later date.

One can lessen the effort required to achieve a goal (and therefore the relative risk of squandered effort), for example by breaking it down into smaller pieces. One can also add in a reinforcing reward for small chunks of success, remembering that delayed gratification is less stimulating than instant reward.

Finally, remembering that motivation is simply a mechanistic effort of a unity of cells to achieve action in the real world, it does to think of the mechanism; fluxes of charged atoms from closely apposed neuronal dendrites. The more we repeat behaviours, the easier they are to repeat; desired or otherwise. Anecdotally it takes 30 days to break a habit or introduce one….so how do you propose to start?