The paper that you shared actually says nothing. It is useless with respect to the question posed. It only increases your RG score.

Dear Muneeb, I like your frankness and my score is very poor, as my English!

It is my strictly personal opinion: I found different behaviour of electrophysiological responses between NTG and Optic Neuropathy that can explain with the following assumption: in NTG, like POAG, the pathogenesis start to the soma of RGC, so it happens an anterograde degeneration, contrarily to Optic Neuropathy in which occur retrograde degeneration. Perhaps, the role of the lamina cribrosa in POAG pathogenesis is debatable...

Dear Dr. Mavilio,

Thank you for your reply. And sorry for my blunt words.

In fact there were a few people who just pasted links of some papers which had these words in the title (they have perhaps removed their answers as i am no more able to see them). These papers had nothing to do with the question I asked. And these people were not even distantly related to the question asked in the professional sense. I believe, when we ask question, we want to know something we don't know already. And by asking a question here, we are seeking help from others who know more than us or at least can guide us to come nearer to the answer. When someone sends me an irrelevant paper, it wastes my time to read the paper and find nothing related to the question I asked. They are actually harming me and wasting my time. It is a fashion for some people to just paste links in response to the questions you ask. They do a google search with the terms in the question and copy-paste the links in the response tab. The only good it does is that it increases their RG score (which has no meaning whatsoever).

Coming back to your answer:

Thank you. It is very much helpful. But I do have some reservations in buying your hypothesis as some of the latest papers have demonstrated degenerative changes in visual cortex even before the vision loss and RGC apoptosis ensues in glaucoma. For example the Murphy et al., paper published in Scientific reports (https://www.nature.com/articles/srep31464). I think it would be better if we differentiate the two on the basis of etiology and pathogenesis (which you have already done) but latest research seems to change the picture.

I would love to know your take on this.

Thank you

Muneeb

Dear colleague, I am very grateful for your feedback.

I know the paper you attached to me and I do not know why so many populations of neurons in glaucoma are affected.

I study the oscillatory phenomena of retinal neurons by steady-state pattern electroretinogram and I have found that in healthy subjects these signals are perfectly ordered. In neurodegenerative disease, including glaucoma, bioelectrical potentials are more chaotic and this seems to be an expression of RGC dysfunction that precedes apoptosis.

I performed a blinded trial, and I discovered, for example, that in preclinical Alzheimer's disease (MCI), unlike frontal dementia, I have observed electrofunctional responses similar to glaucoma.

In short, I think that neurodegenerative diseases are not confined to the inner retina, hippocampus, VTA, but perhaps they are generalized, as a systemic disease, but with a different expression. For example, the efficacy of metformin in Alzheimer's has been debatable. In literature, there are hundreds of papers on these issues.

I have seen that demyelinating, inflammatory, ischemic and traumatic causes of optic neuropathy have different responses in my studies about oscillatory phenomena.

I have developed a procedure that I called RE-PERG which in my clinical practice helps me to make a differential diagnosis between, for example, glaucoma and healthy subjects in difficult cases, frontal dementia and Alzheimer's disease, inflammatory and compressive optic neuropathy. Of course, in chiasmal compression is described ganglion cell complex loss, but it takes months, or even years, while in NMO or MS the RGC dysfunction is immediate! I see RGC dysfunction in Alzheimer's disease but not in frontal dementia.

So, anterograde and retrograde degeneration is a different phenomenon that can help you understand where the disease starts, in the soma of neurons or in the synapses. Some papers by authors who inspired my passion for electrophysiological studies:

Article Dysfunction of the magnocellular stream in Alzheimer's disea...

Article The spatial tuning of steady state pattern electroretinogram...

Article Retinal Ganglion Cell Dysfunction in Asymptomatic G11778A: L...

I hope I have not said useless things and I wish you to continue your research that are really interesting. And...I'm sorry for my poor English, I'm learning...

Your sincerly

Dear Dr. Alberto Mavilio,

Thank you for your thoughtful reply.

At the outset, I agree to most of what you have written.

Alterations in electrophysiological patterns may be among the earliest changes that could be observed and used to diagnose (of deferentially diagnose) various diseases involving deficits/change in neurons (or may be glia as well). This is very much relevant in clinical settings as it is a relatively non-invasive procedure and there are no surrogate markers of early degenerative changes in the neuronal integrity due to functional plasticity of neurons.

The circuitry, sub-circuitry, micro-circuitry and integrated circuitry of neuronal electro-signalling operates on many levels an is not noise (as far as I understand). I would rather consider it a yet unrecognized but definite pattern (more or less like music) with precise signatures for each functional domain. That means a particular mechanism of neuronal death may affect the electrical patterns in a unique and distinct way (which may be exploited for proper diagnosis given the development of comprehensive algorithms). If electrocardiography is used to diagnose and deferentially diagnose many heart ailments why can't electrophysiological probes be used in diagnosis and differential diagnosis (and probably prediction and treatment) of disease of a more electrically circuited organ like brain and the nervous system. Why optic nerve is a tissue of choice to start with is because it is accessible.

On an additional note, I think synchronous vs non-synchronous patterns of the electrophysiology may be one of the keys to early diagnosis of neurodegenerative or neuropathic syndromes (including glaucoma and Alzheimer's disease). Perhaps the old adage "neurons that fire together, wire together" has something fundamental to do with this. Neural plasticity and development and dendrite pruning presumably works through this mechanism. If this is true then, then early changes picked up by various electroimaging modalities (for example RE-PERG as you pointed out) may prove to be a useful tool not only for differential diagnosis but also for predictive diagnosis as well. I would take the liberty of using this modality in combination with electrical brain stimulation to treat such diseases. This looks quite plausible.

If synchronous pulses are given regularly in a systematic and well designed (well synchronized) fashion, they may prompt the required neurons to fire together and hence wire together. Development of new synapses could be initiated and redefining and de-novo development of dendritic arbor could be envisioned. This may reverse synapse degeneration and may re-purpose various neuron-synapse junctions to salvage the functional loss. And may be apoptosis is delayed or stopped.

A well designed clinical trial can have definite answers. I would love to do such a trial. Such a trial may be conducted for glaucoma as well as various forms of dementia including Alzheimer's disease. A prospective randomized controlled trial with PERG, visual field, visual evoked potential and vision related quality of life as primary/secondary outcomes and an intervention of brain stimulation (electrical brain stimulation or trans-cranial brain stimulation or may be meditation based brain training- as we have done in many trials) may yield clinically translatable knowledge.

Hope this is useful.

Thank you

Muneeb

Dear Dr Muneeb Faiq I think that in glaucoma we consider always the outcomes of the disease and sometimes we forgot that the pathology starts in the inner retinal layer. So, in these cases, if we don't see PERG impairment, is not glaucoma. Of course, we do consider all conditions can compromise PERG response and all test, like visual field and OCT, but, in my opinion, without a sign of inner retinal dysfunction, we can't think about glaucoma. Also about Alzheimer's disease, I think that we can see the pathology through the inner retinal dysfunction at a very early stage, and so in the MS and Parkinson disease. We have to consider neurological medications that can alter PERG outcomes, so electrophysiology can help in naive patients. Regarding variability of phase, I think that morphology is an aspect of reproducibility of the response of bioelectric potential and due to signal to noise ratio (type or position of electrodes, gain etc) and in part to signal quality. Morphology as a result of the average of the events acquired, it will be better as the repeatability of the events is greater. Increasing temporal frequency of the stimulus, the peaks gradually approach each other until a sinusoidal wave is obtained. Therefore if the events are not perfectly repeatable the morphology of the sinusoidal wave will be altered as transient potential using a low-frequency temporal stimulus. Thus analysis of the intrinsic phase variability is an expression of the variability of the events. Variability of the events can be results of neurological performance impairment.

Article Inhibition of the classical pathway of the complement cascad...

..."While the optic nerve head is considered a primary and critical site of damage in glaucoma [2, 6, 8, 9, 62] early damage may also manifest at other locations including the retinal ganglion cell soma, dendrites and synapses [3, 10–12,16, 63–67]. In this study, we use both a genetic (DBA/2 J mice) and an inducible (rat bead) model of glaucoma to show that significant changes occur to retinal ganglion cell synapses and dendrites prior to optic nerve degeneration."...

Article The Role of Microglia in Retinal Neurodegeneration: Alzheime...

..." Microglial cells are important for the normal functioning of neurons in the CNS. They provide trophic support to neurons and regulate synapses. The altered microglial behavior could induce neuronal degeneration in AD (Southam et al., 2016). During development, microglia are involved in synapse elimination and these mechanisms may be aberrantly reactivated in the aged brain, contributing to the synapse loss in AD. The synapse loss in the hippocampus and association cortices is an early hallmark of AD and strongly correlates with cognitive impairment (Hong et al., 2016). "...

Article Physiological significance of steady-state PERG losses in gl...

..." Dendritic modifications typically precede neuronal loss and result in reduced responsiveness of RGCs in glaucoma. 41 Reduced responsiveness of RGCs includes reduced ability to follow stimuli of increased temporal frequency, implying a slower temporal dynamics and longer latency. A phase delay without amplitude attenuation could arise from synaptic and transport delays.42 "...

Article Looking into the brain through the retinal ganglion cells in...

..."Retinal ganglion cells offer a more accessible part of the living brain than other cerebral areas. Retinal architecture and function have been widely studied, and results from animal studies are transposable to humans (Baden et al., 2016; Sand et al., 2012; Yu et al., 2013). Both functional and imaging techniques for investigating ganglion cells are relatively rapid, non-invasive, easy-to-use, inexpensive, and amenable to research with standardized protocols (Bach et al., 2013; Staurenghi et al., 2014). The retinal ganglion cell layer is clearly identifiable and isolated, so measurements derived from these techniques make it easy to detect architectural and functional anomalies of retinal ganglion cells without the interactions with other retinal layers or other cognitive functions that can happen in the brain."...

Tell me what do you think all these. Thank you for your interest. Yours sincerely