We recently ran a couple of blog posts about the possibility of a link between post-SSRI sexual dysfunction (PSSD) and small fibre neuropathy:
The posts recapped some of the things we had previously discussed on the blog and also included new information about a Finnish PSSD support group – many of their members had undergone skin biopsy for small fibre neuropathy and tested positive.
Small fibre neuropathy is certainly consistent with many aspects of PSSD. Some people with small fibre neuropathy experience numbness in one area of the body while for others it’s more widespread – similar to PSSD. Although small fibre neuropathy is often described as involving tingling or burning sensations, particularly in the hands and feet, this isn’t the case with all sufferers.
There is an interesting paper from 2018 which described two patients with unexplained genital numbness (not related to medications) who tested positive for small fibre neuropathy. One of the patients had two biopsies – one near the ankle and another on the thigh. Nerve fibre density was much worse in the biopsy taken from the thigh. This suggests that small fibre neuropathy can be worse in a particular area of the body, in this case closer to the genitals, and may not conform to the typical burning sensation in the hands and feet.
Some people with small fibre neuropathy also report a variety of other symptoms, some of which overlap with problems experienced by people who have come off SSRIs such as fatigue, cognitive impairment, and urinary and gastrointestinal issues.
However, testing for small fibre neuropathy isn’t universally available and can be difficult to arrange. Patients who complain of skin numbness are often sent for nerve conduction studies instead. This is where small electric shocks are sent through the arms and legs to test how well the nerves conduct electrical signals. It predominantly assesses the function of large nerves and isn’t useful for investigating small fibre neuropathy. Unfortunately, neurologists sometimes misinterpret a negative result as meaning that the patient doesn’t have neuropathy.
An important point highlighted by the Finnish group is that even if patients have a skin biopsy, it requires expertise to interpret the results, and the age of the patient needs to be taken into account.
Getting tested on the NHS
Dr Channa Hewamadduma is a neurologist with expertise in small fibre neuropathy, based in Sheffield, UK. He has spoken with Professor Healy and is happy to dedicate a small fibre neuropathy and skin biopsy clinic to 5 PSSD patients. The clinic happens on a Tuesday morning – the first Tuesday of the month.
Suitable patients need to be based in the UK – ideally not too old, and ideally on no other medications. You will need to get a printout of your medical history summary from your GP – basically to show you have no other conditions and no recent blood tests showing other problems. You also need to get your NHS number.
Men or women can take part. The group can be a mixture of both.
You won’t need a referral from your GP. Professor Healy would make the referral to Dr Hewamadduma. The testing will all be done on the NHS. However, you will need to pay for your own travel to and from the hospital in Sheffield, and as the clinic is on a Tuesday morning, this might involve staying overnight.
Dr Hewamadduma will aim to carry out the following investigations:
Assessment of sweat gland function using Impeto Medical’s Sudoscan device with feet and hand plates. This is a non-invasive procedure that evaluates the function of sweat glands by measuring the electrical conductance of the skin. You can read more about this on the Sudoscan website. It isn’t the same as nerve conduction studies (mentioned above).
Quantitative sensory testing (QST). This is a non-invasive procedure in which a probe is attached to the hands and feet. The probe gets warm or cold to varying degrees and you are asked whether you can feel it. This determines the threshold at which your skin can detect temperature changes. Here is a leaflet about QST from Sheffield Teaching Hospitals.
Skin biopsy at the ankle and maybe lower thigh. A few millimetres of skin is removed for testing in the laboratory to determine how many intraepidermal nerve fibres are present and whether this is normal for your age. Skin biopsy is regarded as the gold standard for detecting small fibre neuropathy.
Blood tests for genetic screening.
How to apply
If you would like to apply for the testing, the first step is to complete and return this form with details of your case. The cases will be reviewed for suitability, and you will then be contacted for any further information such as your NHS number and the printout of your medical history summary.
The aim is to get people into the clinic for the first Tuesday in January or February 2023. Five people would take up one whole clinic.
It is very generous of Dr Hewamadduma to offer one of his clinics for PSSD patients, and it will only go ahead if enough people come forward to take part.
If there are any pointers from the testing, the results will be written up into a research paper and published in a medical journal. Obviously, your details will be anonymous with no indication of who you are. Dr Hewamadduma would also be willing to write a grant to make it possible to test a further 25 people or so.
Sarah says
This is an incredible opportunity, amazing that this doctor has shown an interest in this and is willing to dedicate a clinic for these patients. Great support to have Dr Healy able to make the referrals also. It will be revealing to hear of the results and fingers crossed the grant goes through so more people can be involved in this in the future. I imagine a lot of people would be interested in this. Amazing all round.
mary H says
I agree, Sarah.
I think I read, correctly, that patients need to be clear of “any other medication”. I wonder if that is going to rule out a number of patients? From what we are told, it would surely be quite unusual for them to not have been prescribed other medications too? I fully understand the reasons behind this rule of course – the need for a clear body to produce acceptable results. It would be such a shame if the number putting their names forward is too low for the tests to be carried out. Would it, possibly, have been an idea to freely ask for volunteers first and bring in that particular clause later?
I hope that all who would be willing, even if on other medications, will at the very least show their appreciation of this excellent all-round offer.
I wish the whole effort the very best success rate.
susanne says
Summaries
Here is one template used in an English practice:-
Information for new patients: about your Summary Care Record
Dear patient,
If you are registered with a GP practice in England, you will already have a Summary
Care Record (SCR), unless you have previously chosen not to have one. It will
contain key information about the medicines you are taking, allergies you suffer from
and any adverse reactions to medicines you have had in the past.
Information about your healthcare may not be routinely shared across different
healthcare organisations and systems. You may need to be treated by health and
care professionals who do not know your medical history. Essential details about
your healthcare can be difficult to remember, particularly when you are unwell or
have complex care needs.
Having a Summary Care Record can help by providing healthcare staff treating you
with vital information from your health record. This will help the staff involved in your
care make better and safer decisions about how best to treat you.
You have a choice
You have the choice of what information you would like to share and with whom.
Authorised healthcare staff can only view your SCR with your permission. The
information shared will solely be used for the benefit of your care.
Your options are outlined below; please indicate your choice on the form overleaf.
Express consent for medication, allergies and adverse reactions only.
You wish to share information about medication, allergies for adverse
reactions only.
Express consent for medication, allergies, adverse reactions and
additional information. You wish to share information about medication,
allergies for adverse reactions and further medical information that includes:
your illnesses and health problems, operations and vaccinations you have had
in the past, how you would like to be treated (such as where you would prefer
to receive care), what support you might need and who should be contacted
for more information about you.
Express dissent for Summary Care Record (opt out). Select this option, if
you DO NOT want any information shared with other healthcare professionals
involved in your care.
If you chose not to complete this consent form, a core Summary Care Record (SCR)
will be created for you, which will contain only medications, allergies and adverse
reactions.
Once you have completed the consent form, please return it to your GP practice.
You are free to change your decision at any time by informing your GP practice.
Copyright © 2017Health and Social Care Information Centre. The Health and Social Care Information Centre is a
non-departmental body created by statute, also known as NHS Digital.
Summary Care Record patient consent form
Having read the above information regarding your choices, please choose one of the
options below and return the completed form to your GP practice:
Yes – I would like a Summary Care Record
□ Express consent for medication, allergies and adverse reactions only.
or
□ Express consent for medication, allergies, adverse reactions and additional
information.
No – I would not like a Summary Care Record
□ Express dissent for Summary Care Record (opt out).
Name of patient: ………………………………………………..……………………….
Date of birth: …………………………… Patient’s postcode: …………………
Surgery name: …………………………… Surgery location (Town): ………………………
NHS number (if known): …………………………..……………………………………………..
Signature: ……………………………. Date: ………………………………
For more information, please visit [https://www.digital.nhs.uk/summary-carerecords/patients], call NHS Digital on 0300 303 5678 or speak to your GP Practice.
For GP practice use only
To update the patient’s consent status, use the SCR consent preference dialogue box and select the
relevant option or add the appropriate read code from the options below.
And
This is separate to t he Summary
Breaking news EMIS and TPP halt NHS app records rollout due tomorrow
Costanza Potter
31 October 2022
This is separate to the Summary as refers
to the whole medical record…..(Be prepared in case this great opportunity snowballs.) It can seem daunting to request records even these days which often needlessly unfortunately can put people off.
So It may be an idea to get hold of a copy of medical notes asap. There’s a lot of obstructive activity going on from GPs but Using the APPs is not the only way to get a copy A simply request in writing to the practice manager is good enough and no reason is necessary. Some practices have advice on info leaflets or online similar to the one above
The two main suppliers of GP IT systems – EMIS and TPP – have confirmed they will not switch on automatic patient access to their records via the NHS app tomorrow.
Patients were set to be given automatic access to their prospective patient records through the NHS app from 1 November – starting with EMIS and TPP, and with other smaller suppliers to follow at a later date.
However, the RCGP has advised GP practices to consider opting patients out of the programme on the grounds of patient safety.
And the BMA last week suggested that system suppliers who turn on automatic patient access to their records without the explicit consent of practices may be acting illegally.
In order to roll out access through the NHS app, IT suppliers will have to allow this through practices’ systems.
But EMIS said on Saturday that it ‘will not be making any practice-level system changes’ on the planned go-live date.
It said this comes as ‘many’ GP practices have asked it not to switch on automatic patient access to their records ‘due to GDPR and/or patient safety concerns’.
In a post on an EMIS Facebook group seen by Pulse, country director for England at EMIS Group plc Karen Bonnett said: ‘We have received requests from many GP practices asking us not to make the system change due to GDPR and/or patient safety concerns.
‘This is a complex issue and we have been in constructive dialogue with NHSE, over the past few days, on an appropriate way forward.’
She added: ‘We continue to be in dialogue on these matters and we can confirm that we will NOT be making any practice-level system changes to EMIS Web until we have a clear path forward.
‘We will continue to update you as we know more.’
TPP (SystmOne) said it will take the same stance, in a statement posted today on an internal daily noticeboard for TPP practices, seen by Pulse.
It said that it too ‘will not be making any practice-level system changes to SystmOne’ until it has ‘a clear path forward’.
It added: ‘For all stakeholders in this process, patient safety and compliance with GDPR are important priorities.’
TPP has also received ‘many’ practice requests not to go ahead, with lots saying that ‘they require more time to be ready for the proposed change’, it added.
The BMA’s GP Committee for England said it was ‘pleased’ with the news.
Deputy chair Dr David Wrigley said: ‘Patient safety is at the heart of what we do, which is why any changes to the system – particularly default ones – should be carefully thought through.
‘We hope that following EMIS and TPP’s decision, NHS England will now also rethink how this roll-out is going to work, and ensure that every practice is given the time and resources it needs to properly prepare in the interests of both patients and practices, especially at a time of intense pressure on general practice. We remain keen to engage with NHS England on this project going forward.
‘In the meantime, the BMA is compiling new guidance for practices on what to do going forward and in support of patients.’
Meanwhile, one local commissioner has recommended that practices apply an ‘opt-in’ approach to automatic records access following a ‘clinical safety review’.
In an email sent to practices on Friday, North Central London integrated care board (NCL ICB) said that its ‘clinical safety report’ concluded that ‘the safest option is to enact an opt-in solution’.
It added: ‘When patients then request access, you will then have the opportunity to review records for any content that may cause harm to the patient or disclose third-party information.’
The ICB said local practices should take ‘immediate action’ to allow an opt-in process and ‘prevent global access being automatically activated’ by applying a SNOMED code to the full practice list before 1 November.
NCL ICB is ‘confident’ that this decision is ‘in keeping’ with practices’ contractual obligations, it added.
However, practices will not currently need to take this action if all suppliers delay the scheme’s launch.
NCL ICB said the principle of records access is ‘a good thing’ and that it will issue ‘further guidance’ to practices ‘in the next few weeks’ about how it can be rolled out ‘in a safe way that is manageable in primary care and protects our most vulnerable patients’.
Helen says
A data point?
My son has PSSD. He noted recently that, although everything is now muted and numb and he no longer responds to the world like he used to, he is still sensitive to smells. He has mentioned a couple of occasions where he has had a ‘normal’ emotional reaction on catching an aroma, e.g. a perfume that someone was wearing.
From what I understand, the sense of smell has a direct route to the brain and doesn’t rely on the same indirect nerves as the other senses do, so I was wondering if this might be common with other PSSD sufferers and whether this hints at the neuropathy that is being explored.
I will ask him if he is willing to apply for your study.
Thank you for the work that you are putting into getting this terrible injury recognised.
Helen
susanne says
Doing the Quick Step . A Day later than above things have changed. re Summaries and Access to Records
Records access to go ahead after system supplier U-turn, BMA suggests
Costanza Potter
01 November 2022
Exclusive Patient records access in the NHS app will be switched on this month, despite system suppliers informing GP practices they were holding fire, the BMA has suggested. (as above comment)
The functionality, which will enable all patients to view their prospective GP record, had been due to go live today.
But both EMIS and TPP said in recent days they would not be making any practice-level system changes, after ‘requests from many GP practices’ with ‘GDPR and/or patient safety concerns’.
But today the BMA suggested that the system suppliers have made a U-turn.
BMA IT policy lead Dr Mark Coley told LMCs, in a message seen by Pulse: ‘There appears to have been a change of approach in recent hours and that prospective access is going to be turned on imminently for any practice that hasn’t sent in a template letter, despite the messages from system suppliers yesterday saying they are not doing anything until a clear way forward has been found.’
Those who have not sent letters instructing their system supplier not to switch on the functionality will have it turned on ‘imminently’, while it will be turned on ‘regardless’ after a four-week delay on 30 November for those who have, he added.
‘For those that have sent in letters, we’re hearing access is going to be turned on regardless on 30 November (after a four-week delay),’ the message said.
In response, the BMA reiterated advice to bulk opt-out patients out of the automatic access until sufficient safety checks are completed.
Dr Coley said: ‘The only options for stopping an uncontrolled and chaotic rollout (without even considering the safety implications) is to send in a template letter or bulk add the enhanced review indicated code to your patient population.’
Practices that are ‘happy to have access turned’ on ‘don’t need to do anything’.
‘We will send more information when we have it,’ he added.
Pulse has approached BMA, NHS England, EMIS and TPP for comment.
BMA last week suggested that system suppliers who turn on automatic patient access to their records without the explicit consent of practices may be acting illegally.
The RCGP has also advised GP practices to consider opting patients out of the programme on the grounds of patient safety.
Yesterday, Pulse reported that one local commissioner has recommended that practices apply an ‘opt-in’ approach to automatic records access following a ‘clinical safety review’.
Spruce says
This is great news that this is finally happening now, after 4 years of frustrating setbacks, since late 2018.
Hopefully we can now find a way forward to getting the hard physical evidence to prove PSSD exists; and hopefully we might be able to find some insight into the mechanism of action behind PSSD too.
I have been waiting for this moment for many years.
This month of November also marks the month where I have suffered from PSSD for a total of 15 years.
I first took Citalopram in November 2007, and got PSSD with the first tablet I took. So exactly 15 years ago.
Let’s hope the small fibre neuropathy tests, lead to more help and support for people with PSSD, which is so desperately needed.
Justin Oxley says
I think this sounds like a sensible thing to do.
Wouldn’t it be a good idea to take periodic biopsies of a skin area say every month and apply a possible curative intervention over the days inbetween those biopsies ? If you did that you could assess if there is an improvement in the c-fibres functioning over time.
I have now had the burning hand and feet experience which occurred during and following a second flare up in my symptoms which began quite abruptly on 1st August 2022. This flare up transition was almost like someone had flicked a switch with symptoms becoming noticeably worse very quickly.
I had been tapering using the liquid Fluoxetine starting with the standard 70ml bottle at 20mg/5ml using the end of week water replacement method to create a non linear taper. From 1st April 2022 I began feeding myself a 0.625ml dose of the liquid which equates to taking 2.5mg each day. At the end of the first week I replaced the removed liquid with 7 x 0.625 = 4.38ml of water. Weekly dilution has the effect of reducing the concentration in the 70ml bottle from 4mg/ml in a non linear way. There is no reason why you couldn’t replace the 0.625ml dose removed each day with the equivalent dose of water to make things even smoother, however I decided topping the bottle up with water at the end of each week should be sufficient.
On the 1st August 2022 I had arrived at a 0.8mg dose (according to the spreadsheet my Dad produced) I found it difficult to function as I had a swirly head when I walked around my house and was extremely unsteady on my feet. I think this is called ataxia. I decided my marbles might be trying to escape from my head so I stayed in bed for most of it. On some days during the first two weeks of August 2022 I noticed that I had burning hands and feet. I also had an odd sensation of movement even when I was lying perfectly still in bed. I remember Monday 15th August was particularly bad after that date the severity of the symptoms gradually diminished. During this second flare up in the first two weeks of August I sometimes took a larger dose of Fluoxetine than the 0.8mg to counter the severe symptoms.
I cannot remember when the early waking started but I am still experiencing this now and I have noticably burning hands and tinnitus when I awaken sometimes. I was waking up very early in the morning for example at 2am and found myself unable to get back to sleep. The early waking is occurring even though I am eating my dinner early at around 7pm and taking my sleeping supplements at this time. To sleep I was taking lemon balm, magnesium glycinate, montmorency cherry, magnolia bark and apgigenin capsules with my dinner. Taking these capsules gets me to sleep fairly reliably before 9pm but it doesn’t stop my early waking and being unable to return to sleep.
In mid October I decided that I had clear symptoms of elevated histamine levels, I had a runny nose, sneezed occasionally, chesty cough and most noticeably I was getting short of breath with any exercise. I decided some of the food I had been eating was probably encouraging elevated histamine levels most notably fresh spinach with my lunch, sausages, mayonaise and I was having plain greek yogurt following my dinner in the evening. I then decided to switch to a low histamine diet and I began taking a DAO tablet in the morning. I now take some antihistamines like quercetin and nettle leaf in the morning plus I take 10mg loratadine in the evening.
I had a theory that the early waking up events might stop occurring if I could bring my histamine levels down to a more sensible level. At this time I am still waking up too early but I now have no runny nose or chesty cough. I am still getting breathless when walking, so I just tend to walk slowly with my walking stick. I don’t need to rely on the stick so much now but I acquired it in August to prop myself up sometimes when I was in the queue for the checkout in my local Coop.
I also decided to begin taking sulforaphane and calcium d-glucarate again in mid October as I think as well as impeding the release of the natural histamine moderator DAO the Fluoxetine was probably encouraging raised estrogen levels. The histamine and estrogen are related very intimately so it mades sense to me to try and flush estrogen from my body.
I am in a better condition now than I was in mid October. I am curious to see if my newly introduced methods cause my early waking to stop. Apparently it should take around 30 days to return histamine levels to normal so I would hazard a guess that my early waking may stop around mid November.
I also decided it would be a good idea to drink 200ml of tart cherry juice before bedtime in the second week of October. I later wondered if doing this had made my histamine reaction worse and stopped doing it in mid October. I don’t think drinking the tart cherry juice has an effect on histamine so I am starting to drink this at bedtime again and when I wake up early in the morning. I am still taking 0.8mg Fluoxetine and will not continue to taper until my early waking stops and I feel ready.
In order to slow down the rate of tapering from 0.8mg I created 140ml liquid Fluoxetine at 1mg/ml in a 250 medicap bottle. I will continue to taper at roughly 64% of my previous rate using the water replacement method. This will mean I take a 0.8ml dose from this bottle each morning and I top up the bottle with 5.6ml at the end of each week. This creates a shallower non linear tapering curve, I still think it will take me all of next year to taper off the Fluoxetine using this bottle. I recently acquired a second 70ml bottle of Fluoxetine from my local Boots Chemist and syringed 35ml into a second 250ml medicap bottle and added 105ml of water so I have a backup bottle should I accidently spill my existing 250ml bottle. I topped up the remaining 35ml in the 70ml bottle with 35ml of water so I have a constant 0.4ml=0.8mg source. At the moment I am using this constant bottle.
I predict given the pattern of my past two flare ups that I might see a third flare up occur around June 2023. I would hope that my efforts to keep my histamine and estrogen levels lowered combined with a more gentle tapering schedule would reduce the severity of any third flare up. I shall have to wait to find out if this is true or not.
Last year I tapered from 5mg down to 2.5mg from July to early October 2021 linearly reducing the amount of liquid I took each day from 1.25ml down to 0.625ml reducing the dose by 0.05ml each week.
Following this linear taper I remained at 2.5mg to wait and see what would happen further downstream. Around 27th November I had the first flare up begin which was less severe than the second I described above. I was really rather anxious during this first flare up but I didn’t have the burning hands and feet. I did have PoTs symptoms which were especially noticable when I would wake up too early in the morning and go downstairs into my kitchen wearing my pulse oximeter. My pulse would then increase quite alarmingly from a steady 80bpm upto 160bpm, this also occured during the day when I walked to the Coop which made the short walk feel a bit scary. During this second flare up I have not had the PoTs symptoms, I’ve not seen a raised pulse with walking. My early waking persisted for around two weeks in December 2021, this time it has been occurring for over two months.
I am still feeling a bit unusual when walking around and taking exercise doesn’t feel refreshing like it used to. I’m still experiencing the burning hands a bit and occasionally I get paraesthesia occur on the left side of my scalp which gets a bit unnerving.
I’ll be sticking to my low histamine diet from now on.
I think I would struggle to complete a train journey upto Sheffield currently.
Zach says
It is obvious that this kind of syndromes are neurologic damage, even if not all people would have SFN detectable.
Sexual dysfunction as such is an autonomic neuropathy symptom. It is “funny” that research has not even connected that dot in all these years, especially since often people have additional autonomic neuropathy symptoms and additionally numb genitals (with vulnerable sensory fibers)
Humphrey says
To whom it may concern,
The discovery of a clear physiological biomarker would be a milestone. Evaluation of peripheral neuropathy by intraepidermal nerve biopsy is clearly the way forward. This initiative represents a chance for all sufferers to gain greater recognition.
I wanted to draw your attention to a study that may be relevant to the current topic: peripheral neuropathy. I initially wanted to post my comment in the neuropathy section of the PSSD research forum but comments are disabled. The study is : Identification of touch neurons underlying dopaminergic pleasurable touch and sexual receptivity (DOI: https://doi.org/10.1101/2021.09.22.461355) (this is a pre-print).
0/ INTRODUCTION
This study aims at identifying a sublineage of neurons involved in touch reward. This is of course relevant in the context of PSSD. Indeed, one of the characteristics of PSSD is the decrease of genital sensations, in particular the decrease/loss of erogenous sensations. Individuals with PSSD often report loss of the sensation of comfort or lack of reward from hugging a partner or loved one. This study aims to understand the underlying mechanism that leads to this rewarding sensation and the peripheral pathways that transmit this pleasurable touch. The understanding of the study requires knowledge in genetics (promoter region, transcription, protein recombinase …) and some knowledge in neurobiology (structure of a neuron, action potential, different neurotransmitters, peripheral nervous system, optogenetics …). I don’t have any expertise in these fields so I may have misunderstood some elements. Please be indulgent with me.
1/ WHAT IS THE GOAL OF THIS STUDY ?
The goal of the study is to induce an action potential only in Mrgprb4-lineage neurons to observe both the mice behavior upon activation and the brain area involved in response to the activation of these neurons. By Mrgprb4-lineage neurons, we refer to neurons which has a “parent” cell which has transcribed the Mrgprb4 gene at least once. This raises two problems : how do we target specifically Mrgprb4-lineage neurons ? how do we induce an action potential among those neurons ? :
How do we induce an action potential ?
To induce an action potential in a neuron they used a technique called optogenetic. Neurons that we want to be activated will express sensitive ion channel channelrhodopsin proteins (ChR2). The idea is that neurons expressing ChR2 which is sensitive to blue light (fixed lengthwave) will induce an action potential if it is in contact with blue light. This will permit to “activate” the neuron by sending a specific light signal.
How do we select Mrgprb4-lineage neurons ?
A problem remain, how do we achieve to target only Mrgprb4-lineage neurons (in other how do we manage that only Mrgprb4-lineage neurons contain ChR2+ neurons)? This problem is solved by using a Cre recombinant technic. Mouse which promoter region of the Mrgprb4 gene has been activated will express a protein Cre-tomato which is a site specific recombinase. This recombinase will cleave a DNA region which prevent the ChR2 gene region to be transcribed. Therefore ChR2 will be transcribed within the cell and all its descendants (this means Mrgprb4-lineage neurons ). This is explained in the supplement figure 1. A.
Therefore, Using optogenetic and recombinant techniques, the authors of the study succeeded in inducing an action potential only in Mrgprb4-lineage neurons.
2/ ACTIVATION OF MRGPRB4 NEURONS INDUCES A REWARD RESPONSE IN FEMALE MICE
Female mice whose Mrgprb4-lineage neurons are sensitive to blue light, as described above, had their backs shaved so that the light could reach their skin. Two chambers were presented to the mice: one with blue light and one with green light (Figure 2.A). Observer noticed that the mice preferred to stay in the blue chambers. This means that activation of blue light-sensitive Mrgprb4-lineage neurons induces reward hence the preference of mice to in the blue light chamber. It has been shown in the study that this phenomenon is specific to Mrgprb4-lineage neurons (see the study for more details). This is interesting because the activation of first-order (or afferent) neurons will induce an action potential that will be transmitted to the CNS, which will ultimately lead to reward. This shows a peripheral pathway leading to reward which is relevant in regard to PSSD.
3/ ACTIVATION OF MRGPRB4 LINEAGE NEURONS INDUCES LORDOSIS.
Mice, with blue light sensitive Mrgprb4-lineage neurons, showed lordosis behavior when these neurons were activated (by exposure to blue light). They further showed that this behavior is specific to the activation of Mrgprb4-lineage neurons (see study for details). Here’s how these results could be interpreted: “Because this response resembles the sexual receptivity lordosis posture and occurred in female mice with optogenetic stimulation directed to the back, we hypothesized that Mrgprb4-lineage neurons might play a role in sexual receptivity and other touch-dependent socially rewarding behaviors.”.This observation is very interesting because it shows that Mrgprb4-lineage neurons activation induce sexual behavior. This confirms that Mrgprb4-lineage neurons are involved in peripheral sexual stimuli.
4/ NEURONS OF THE MRGPRB4 LINEAGE CAUSE DOPAMINE RELEASE IN THE NUCLEUS ACCUMBENS.
How to monitor dopamine release in the nucleus accumbens?
To monitor dopamine release in a certain area of the brain, they used a technique called a genetically encoded fluorescent sensor (see the graphic summary of this article for a visual explanation: https://www.cell.com/cell/pdf/S0092-8674(18)30845-6.pdf). Using a viral vector, they implanted a GRAB_DA dopamine sensor into nucleus accumbens (NAc) neurons (GRAB_DA is a G protein-coupled receptor). When the ligand (dopamine) binds to GRAB_DA, light (a fixed wavelength photon) is emitted. This permits to monitor the release of dopamine in the synaptic cleft of dopaminergic neurons in the nucleus accumbens.
The study found that dopamine release in the NAc seemed to depend on the site stimulated (by blue light):
– “When we analyzed the GRAB_DA signal upon optogenetic back stimulation of Mrgprb4-lineage neurons, we did not observe a significant increase in dopamine release (Supplemental Figure 7).”
– “We next turned to the Mrgprb4-lineage neurons innervating the skin surrounding the genitalia, which are expected to be stimulated during male intromission into the vagina during mounting. Intriguingly, blue light stimulation to skin surrounding the genitalia, but not green, was sufficient to raise GRABDA deltaF/F significantly from baseline levels (Fig 5b-e). This demonstrates that the Mrgprb4-lineage neurons in the anogenital skin are sufficient, in otherwise socially-isolated mice, to induce dopamine release. ”
Based on these observations, it was hypothesized that reward during sex might be mediated by Mrgprb4-lineage neurons. This was proven in an experiment detailed in the study (Figure 6).
5/ HOW DO THESE RESULTS APPLY TO PSSD ?
Patients with PSSD very often report numbness in their genitals and an absence of erogenous sensation. Numbness has also been reported in other parts of the body. However, this does not entirely contradict the hypothesis that numbness may be mediated by Mrgprb4-lineage neurons, as they also play a role in sexual behavior elicited by a non-genital body part (paragraph 2 of this text). Hence, we can speculate that the peripheral neuropathy seen in PSSD may be mediated by Mrgprb4-lineage neurons. Cell death of Mrgprb4-lineage neurons in dorsal root ganglia may explain the observed peripheral neuropathy. However, this remains speculative.
Similarly, abnormal functioning of the NAc when PFS patients are exposed to erotic images compared with controls has been reported (Characteristics of Men Who Report Persistent Sexual Symptoms After Finasteride Use for Hair Loss; doi: 10.1210/jc.2016-2726). Therefore, we can speculate that NAc may be involved in the pathophysiology of PSSD/PFS. However, this remains speculative.
6/ SOME QUESTIONS REMAIN
However, as mentioned in the study, Mrgprb4+ fibers seem to innervate only the hairy skin. This is in agreement with a previous immunohistochemical characterization of Mrgprb4 (https://www.nature.com/articles/nn1937). Therefore, the Mrgprb4+ fiber does not seem to be involved in the observed sexual stimulation. According to the study, we can only assume that neurons of the Mrgprb4 lineage are involved, although it does not specify which exact neurons are involved. It would be interesting to determine more precisely which exact neurons in this lineage of Mrgprb4-lineage neurons are involved. Perhaps this would be an interesting question to ask to the authors of this article?
6/ CONCLUSION
We have presented here a possible explanation of the physiopathology of the peripheral neuropathy observed among PSSD patients (it remains to be confirmed though). Mrgprb4-lineage neurons impairement might explain the sensory symptoms experienced among PSSD patients and the observed peripheral neuropathy. However everything said here remain speculative. Thank you for reading. Let me know what you think.