Leaflea. Sorry for delay in answering but been away. Thanks for the question about how this study fits in with the others. Bit of background first then I will give my opinion on the study, though others may disagree.Before I go on let me say for the 100th time what is meant by the " hyperexcitabiliy stage in ALS. " It is a phenomenon that has absolutley nothing to do with BFS, it has NOTHING to do with the 6.7% study either, and it has nothing to do with peripheral hyperexcitability cases on here....it has to do with the progression of ALS established disease.etc etc. It is a phenomenon seen in ALS patients and is a symptom DOWNSTREAM of their diagnosis, not prediagnosis. It was studied by Prof Cav and others. They noted that in ALS patients whose upper limbs were affected, an EMG of their remaining strong lower limbs(TA), would still detect abnormality such as increased jitter and fasciculation before clinical weakness in that muscle developed by about 6 months. It is almost like a way of mapping its progression and their hope was it could be a prognostic factor. ( let the patient know how long they had until lower limb failure). This they called the hyperexcitability phase just before onward spread of disease. Other studies have backed this up including one in which stem cells from ALS patients at various points in disease were differentiated into neurons and electrically studied. For those that keep asking over and over please please read the email.....the.hyperexcitability phase talked about here is in post diagnosis ALS patients, probably as part of the damage already done. In fact their pool of bfs sufferes with peripheral hyperexcitability were used as control healthy subjects. Therefore the statement in that paper of "fasciculation before weakness ". has been misinterpreted over and over on here ever since the paper was published almost 2 years ago. To those doing this please stop, and reread what has been written at length in previous posts, because your bias interpretation of the studies are harmful. I understand some people have health anxiety, but there comes a point of silliness, you cant walk into a packed building and shout " FIRE" because someone is smoking 10 streets away. Health anxiety or not you have to get hold of your facts. Using facts is like trying to construct a jigsaw from random pieces, you just get a load of *beep* unless they are put together in the right order i.e. like saying with nine women pregnant, you can get a baby in a month.So now to the paper mentioned in this thread. Agsin these are just my views. Look at its title and break it up. ( note motor_neuron interchangable with moto_neuron ie both are a neuron with motor function).Quote"Early intrinsic hyperexcitability .........does not contribute to motoneuron degeneration .......... in amyotrophic lateral sclerosisFélix LeroyCorresponding Author, Boris Lamotte d'Incamps, BeckyBecky D Imhoff-Manuel, Daniel ZytnickiSo at no point does it say there is NO hyperexcitability phase in ALS. It is not asking or challenging or disagreeing with Eisen and all the others. Instead the study is asking the next logical question.... Is this hyperexcitability phase:a) contributing to the neurotoxicity and death of the motor neurons in ALS, hence increasing progression rate in the patientsb) or of no consequence, and just a byproduct of the disease and not contributing to the neuron degeneration.c)or controversially is the hyperexcitability of the neurons protecting them from damage during ALS spreading.The main reason I feel for driving the study was to explore the first option, was hyperexcitability phase DIRECTLY pathological in ALS through a process called excitotoxicity. "Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate". So the process of excitotoxicity goes something like this.... Step 1.a neurotransmitter glutamate sits on cell.Step 2......this causes a thing called depolarisation of neuron cell membrane......., this means that sodium can flow out of neuron cell ...........and as a consequence the calcium concentrations inside the cell begin to build. ( like a seesaw when sodium gets low, calcium gets high vice versa). Step 3....Anyway this high calcium level activates all the cell machinery inside and all the signaling, .....basically neuron goes absolutely nuts starts to fire randomly..makes things it shouldnt...even tries to migrate and turn into other cells....its gone totally cookoo.Step4 : this " turn everything on behaviour uses up all the cells energy, it gets super tired, it gets exhausted...byproducts and toxins build up.....MAKE IT STOP shouts the poor neuron, but it doesn't and instead cell starts to become damaged, neuron dies, loss of neurons. Epileptic fits is one example of this overstimulation. ( note glutamate excitotoxicity does not occur in bfs, our neurons don't die, we are more likley to have ( intrinsically or aquired ), slightly unstable neuron cell membranes or sodium channels, antibodies against the channels. Etc. The fact is we don't get cell death through our hyperexcitability, we just twitch and recover as our emgs do not progress to losses.So back to the study. The group took a mouse model of ALS and recorded changes in two types of motor neutrons called F and S. They deduced that the hyperexcitability occurred in the S- type ( which are spared in ALS). Thst is why they say. Quote " we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration. ". The paper then goes on to state that because the S-type are protected perhaps their intrinsic hyperexcitability is actually protecting them rather than being excitotoxic. If true this is disappointing news for ALS patients, because if the hyperexcitability phase had been proven to directly contribute to ALS degeneration we have licences drugs for epilepsy which can control excitotoxicity. They may have held a potential to slow down or halt the damage to neurons by stopping the excitotoxicity.......but since the hyperexcitability phase doesn't contribute to disease progression, what is the point of trying this approach. If this study is to be believed that avenue is dead.Ah but here is where good and bad science research comes in. I personally feel this paper has too many drawbacks to throw out the possibility of a clinical trial of above mentioned drugs. Mainly it uses one mouse model with only one gene mutated. In reality ALS is probably the end product of various genes, environmental, hormonal and pathogen interactions. i.e many roads lead there and this study examines only one. The study would have been better using humans, but where not possible more realistic nervous systems can be studied in zebra fish etc. Mouse models of ALS have been credited as a reason for slow progress in ALS research. Really the title should beEarly intrinsic hyperexcitability does not contribute to motoneuron degeneration in the mSOD1model of ALS.Lastly this is published on elife, on which the jury is out on how stringent its checking procedures are.Quote " this desire to be quick may lead eLife to cut corners and accept poor studies for publication. The fact that, unlike paper journals, eLife has no restrictions on the number of papers it can publish monthly only compounds the temptation to publish anything in order to establish eLife as a publishing titan. Indeed, eLife’s current initial acceptance rate is 30%, meaning that a quarter of the manuscripts submitted to eLife are passed on to reviewers and, most likely, eventually published. The journal Science, by comparison, accepts fewer than 6% of its submissions.Anyway just my thoughts.Bottom line as all others have said " the hyperexcitability phase " discussed in these papers is to do with ALS patients. Just as a headache in migraine does not have the same physiological bases as a headache in brain cancer. Now go beat yourself up with a feather duster it will be more productive than spending anymore time reading my rubbish. Said "rubbish " because I will get beeped out if I say *beep*......ah see what I mean....crap.Let it go .......pleeeeeeeeeeeeeaaaaaaaaaaaaasssssssssssssssseeeeeeeeeeeeee. See even my words have fas fas fasci fasciculations now.
