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New brain scan study in depersonalization.


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#1 Mayer-Gross

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Posted 22 January 2021 - 07:34 PM

I have overlooked this brain scan study of 6.patients from Switzerland with some germans co authors from 2020. Until 2013-15 there was two small research units doing research into depersonalization. One in New York and one at King´s College in London. These were very poorly staffed with around 4-5.people working permanently there and some ph.d students and external researchers from other places coming there for a specific study. The studies were all very small in size likely due to the lack of funding as depersonalization is so mis and under-diagnosed until recently. So, almost every publication coming out had relation to these to units for nearly two decades. Now, they are closed. The positive side of it is that there are coming studies from other countries. One angular gyrus trial in France, one scan in Japan, two structural MRI/DTI scans in Germany and now this small study from Switzerland. So, there is increased awareness about the disorder in other countries and that is positive.

 

Brain scans of depersonalization is closely related to rTMS as a potential treatment. If a location, network can be found to be over or underachieve it could in theory be stimulated with rTMS and the state would normalize. Both former research units tried to find such locations and do some very small trials at them with the rTMS technology available back then. That excluded many locations as they were to deep for stimulation with conventional rTMS back then.

 

The study from Switzerland brings  challenges to locations also the models previously used. The former model thought of a model with a overactive prefrontal cortex that suppressed the limbic system (area for emotions) This overactivity should make a state of numbing/having no emotions, detachment, unreality. With rTMS is was thought the inhibition of such a overactive area would take depersonalization away.

 

The German studies put this model in to question. They also said the the size of the studies previously done was very small. Below a minimum of 20.patients. They agreed though that rTMS would likely be the intervention.

 

This study was done with a scanner called ALS-MRI that is similar to a fMRI but uses the iron in the blood of the brain as a tracer for brain metabolism.

 

They found a significant under activity in the left orbitofrontal cortex that is involved in sensory integration in pre-psychotics with DP/DR symptoms. They think that it this under-activity or failure of this area to make a integration of sensory input that makes some part of the disorder. The emotional numbing do not come from emotional supression but a failure to integrate them.

 

They also found a overactivity in the very dopamine rich area in the brain called the left Caudate nucleus that is a location deep in the brain that is also very affected in states like obsessive compulsive disorder. So, an element of having OCD like symptoms in depersonalization is likely related to this.  

This can likely be changes with the type of rTMS equipment used in research.

The study is very small as all previously studies done but it puts a major challenge to the models previously used in depersonalization. It can be read here. It is very small but points towards the need for more newer and larger brain scans done.

 

.https://www.frontier...020.535652/full

 

There was a review of the brain studies done to date in depersonalization last year and they pointed towards the conflicts about locations, networks that have only become worse with this study. They recommended to do a study were a combination of advanced rTMS with rMRI was used. So, a location coming up as over or underachieve was stimulated to some sessions in 10-15.patients to see if there was any reductions in symptoms and then scan them again and see if some of the brain had normalized or changed.An area could also be ruled out as having any relevance.  It could also be that some locations works in 50% and not in the rest and people with depersonalization in reality have some differences in their emotional regulation done by the brain-

 

There is a need for a research unit that can work with this continuously with many patients. The germans wrote they had difficulties finding sufficient number of patients, The French angular gyrus trail have been under way for 6.years likely also due to the lack of patients in a Paris area. The Swiss study wrote that they difficulties finding people with "pure" depersonalization (many have is secondary to another disorder and can not be used). Many with "pure" depersonalization they contacted in Switzerland declined to take one hour out for a brain sca.  So, a research unit can likely only be in the London area or New York/Boston as many likely there have been seen by the former research units and many local psychiatrists are aware of the disorder.A research unit shall be in an area with 300-500.people with "pure depersonalization" who will be a part of research  For legal reason a research unit can only take nationals of the authorities that have approved the research.   



#2 Mayer-Gross

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Posted 23 January 2021 - 06:34 AM

I Denmark where I live there is a research programme between two companies from Danmark and Germany and some research institutions to make more advanced rTMS equipment. The ambition is to develop equipment that can treat refractory depression but also other conditions that have few treatment options today. A professor in psychiatry who is a part of the programme said that the ambition is to develop more indivualistic treatments for patients and use fMRI scans in the individual patient to find locations for rTMS interventions. This programme that should run until 2023 and I expect them to start some testning in Denmark and Germany around 2022 of their hardware. I could likely try to contact this professor I have spoken to years back to see if they would give depersonalization a try to test the new equipment. It would likely involve several rMRI scans do in a process. This development could if it succeeds could also open up for many individual case studies of patients with depersonalization in countries that adopt this equipment. 



#3 Frederik

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Posted 23 January 2021 - 09:55 AM

Dear Mayer-Gross,

 

first of all, I'd like to thank you for the information you delivered in the forum about research topics. I have been a passive reader so far and I highly appreciate the efforts you make to constantly sum up the lastest developments.

 

I am a medical student from Germany, currently in my last year of medical school and I'll, hopefully, start working as a physician in autumn of this year. I suffer from DPDR for around three years (I am already 34, medicine is my second studies). Anyway, I will give more details about my history in the "Introduce myself" board and not here.

 

The reason why I mention my background is because I learned what a gamechanger in regards to diagnosis, treatment and theoretically also research it could be if you work in the medical field and especially if one is connected in this area. For example, I am in contact with a physician (friend of a fellow student) who is a close friend to the head of neurology in a major university hospital in Germany. They might be interested in performing imaging studies. There already was the discussion to perform an fMRI scan with me as part of a single case study to get more insights. However, most of us know that individual brain scans are not really helpful in DPDR if they are not part of a study and therefore not comparable. M-G, you explained this in one of your posts I think. In the future, I will rather try to use my contacts (which hopefully will get more and more over time) in the medical field to convince the right people to consider more studies in imaging and/or rTMS. I hope, also for my own good, that I will have some success. It is always worth trying and I had to experience the hard way how rarely known DPDR is in the medical field. This needs to change (and it slowly is). I will dedicate a huge amount of my medical future/career into the field of DPDR. Experiencing the symptoms of this disease on my own, I know how important proper care and especially further research is. The current medical care for DPDR is a disaster in most countries and not enough physicians and researchers are aware. This needs to be changed.

 

I am personally convinced that either selective opioid antagonists or rTMS will make a huge difference in the treatment of this disease in the future. I am trying to get deeper into rTMS and imaging topics since some days and I was shocked when I read that not enough participants could be recruited or even declined to take one hour for a brain scan. Maybe online self-help forums and groups would be a way to reach more participants for future studies. There needs to be more contact between (possible) researchers and patients.

 

M-G, you wrote

 

I could likely try to contact this professor I have spoken to years back to see if they would give depersonalization a try to test the new equipment.

 

Please do so. We need to try each option for possible progress. Could you give us/me more details about the involved research institutions in Denmark/Germany?

 

Also, if you have the time, could you kindly provide the titles or DOI (if completed) or otherwise weblinks to more information regarding the mentioned studies in France, Japan and Germany?

 

You mention that, in your opinion, further research needs to be performed in a DPDR research unit, which probably needs to be in London or NY/Boston again in order to reach enough participants. Could you elaborate why you think imaging studies performed in university clinics might not be sufficient (without creating specific DPDR units) here?

 

Thank you!



#4 Mayer-Gross

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Posted 23 January 2021 - 09:43 PM

The German scans are both structural. A MRI and a DTI.

The DTI here; https://www.ncbi.nlm...les/PMC6158023/

The MRI here; https://pubmed.ncbi....h.gov/25285875/

 

The one from Japan I can not remember as it was posted by other. I remember it focused on dopamine. 

 

The French angular gyrus trial is unpublished but has been going on since 2015 -so likely difficulties to find a 100.subjects. The trial is here. https://clinicaltria...how/NCT02476435

 

I have tried two opiopate antagonists- naltrexone and nalmefeme without any effect. I do not think that is plays a central role. There are people here who have tried buprenorphine/subuxone that is highly antagonistic for the kappa receptor with some slight reduction. I do not think it makes the disorder.

 

In all medicine you have e replication crisis. Only 50% of studies can be replicated. I think that number might be higher in depersonalization because the studies are small, the trails are also very small. So, you might end up with using time on something that is useless and colored by your own hope. I have been there for years.

 

rTMS as it is used right now is very limited due to stimulation dept in the prefrontal cortex. You did not have coils that could go deeper that 1.cm and many areas in many with depression could not be tried and in depersonalization many areas are also too deep to try back then when these trial was done. A deep coil that is currently used in research can go to a dept of 2-2.2.cm so many areas can now be tested. I do not know if the current research programme can develop a coil that can go much deeper. Perhaps 3.cm. The new coil will be developed in Denmark while "Localite" in Germany will make software for network localization. Program here. It is still very early into development.   https://www.drcmr.dk...tant-depression

 

In research in depression this coil is used for deeper locations like the dorsomedial prefrontal cortex and the orbitofrontal cortex. It could alternatively be used. Both locations comes out as active in depersonalization and are also OCD locations.  

 

https://www.magventu...oils/cool-d-b80

 

If you could find a sufficient number of patients with "pure" depersonalization to do research that should not be a problem. The problem is this "stop-go" with one small trial here and there. You really need something that have good scannings capacity and in an area with people who have been correctly diagnosed with depersonalization in it primary form. It shall work continuously.A  research facility similar to what Jonathan Downar have for depression research would be ideal. A combination of fMRI and advanced rTMS to isolate locations and networks in the disorder.  http://rtmslab.com



#5 Frederik

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Posted 24 January 2021 - 08:40 AM

Thank you for the links, I'll look into it later today.

 

The French angular gyrus trial is unpublished but has been going on since 2015 -so likely difficulties to find a 100.subjects. The trial is here. https://clinicaltria...how/NCT02476435

 

Do you know if the trial is still ongoing, if they are still recruiting or if there are any information about the progress? Last update was 10/2017. If you don't know more, I have a very kind visiting professor from the University of Lyon here, who I could ask. Maybe she knows someone in Paris who could give further info.

 

For legal reason a research unit can only take nationals of the authorities that have approved the research. 

Do you know for sure if this is valid in the European Union as well? Asking especially because of the unknown status of the French trial.

 

 

I have tried two opiopate antagonists- naltrexone and nalmefeme without any effect. I do not think that is plays a central role. There are people here who have tried buprenorphine/subuxone that is highly antagonistic for the kappa receptor with some slight reduction. I do not think it makes the disorder.

 

In all medicine you have e replication crisis. Only 50% of studies can be replicated. I think that number might be higher in depersonalization because the studies are small, the trails are also very small. So, you might end up with using time on something that is useless and colored by your own hope. I have been there for years.

I'd agree only partially. I think there are patients out there which still might benefit from opioid antagonists. Naloxone and Naltrexone have only low affinity for kappa opioid receptors and most patients don't tolerate the dosages needed. I remember you were also not able to get beyond 100mg. Nalmefene acts partially agonistic on KOR which probably makes it a competitive antagonist in the end. I think pure kappa antagonists with high affinity could still make a difference, at least in a subgroup of patients, in the future. But, as far as I know, only Aticaprant is in the pipeline so far.

 

I read that you tried Nalmefene with max. 26mg and had a reduction in derealisation and a glimse of emotions back then. You wrote that you needed to stop because side effects were too strong. Would you say those effects on DR and emotions were mainly placebo (if you can still remember)?

 

 

While, personally, my biggest hope is definitely future progress in rTMS, I do think that the symptoms of DPDR can have different pathophysiological causes in different patients. Otherwise I can't explain why we have this huge replication crisis in DPD and why some drugs have an effect in some patients and no effect in others. For example, I saw somebody who had a severe decrease in DPD symptoms from Vortioxetine (serotonine modulator). Now, of course, we could say that this is only anecdotal and might be placebo and/or secondary DPD with primary depression, but it still does not fully explain why this person, for example, took several SSRI before - which decreased depressive symptoms but not DPD symptoms, whereas Vortioxetine then decreased depressive symptoms and DPD symptoms. Same for the opiod antagonists. Few, but some patients, were in full remission after one of the studies was completed and stayed without symptoms for a long time in follow-up. Might be placebo, but usually placebo is short-term in DPD. There is case study where a DPD patient had a major long-term decrease in DPD symptoms after amphetamine salts, whereas SSRI and other drugs previously had no effect in the patient except anti-depressant. I also saw Lyme disease patients with DP or DR symptoms, so maybe inflammatory processes can also play a role. It seems like, pathophysiologically, opiod receptors (mainly kappa), NMDA receptors, serotonine and dopamine might play a role at least in some patients and depending on the co- or primary morbidities of/with DPD. By the way, do you know if there has been anybody trying opiod anatgonists together with lamotrigine (and maybe SSRI) to taget opiod and NMDA receptors at the same time?

 

However, I still think there is a main mechanism (or main brain area) which is causative in the majority of people. I am just not sure if we found it yet.

 

rTMS as it is used right now is very limited due to stimulation dept in the prefrontal cortex. You did not have coils that could go deeper that 1.cm and many areas in many with depression could not be tried and in depersonalization many areas are also too deep to try back then when these trial was done. A deep coil that is currently used in research can go to a dept of 2-2.2.cm so many areas can now be tested.

Just to get it right: With the coils that we have at the moment, let's say 1cm or max. 2.2cm, would it make sense to start a trial? Or is an fMRI/rTMS trial only relevant if we could go deeper that 2cm?

 

The new coil will be developed in Denmark while "Localite" in Germany will make software for network localization.

 

So, the team from DRCMR will use the coil from Magventure, which currently is FDA approved for OCD only, in order to treat depression (correct me if I'm wrong). I hope you will have success in contacting the mentioned professor. It would be great if they would extend the program for DPD. I saw that Munich is involved as well. I know someone who has contacts to LMU Munich neurology (maybe also psych). I'll see what I can do there, but it will take some time. I am currently in Romania.

How deep will the new coil be able to reach?

 

If you could find a sufficient number of patients with "pure" depersonalization to do research that should not be a problem.

Theoretically, this should be possible in Germany as well. There is a psychosomatic unit in Mainz which is specialized on DPD. Prof. Michal is working there. I was a patient there in 2019. I also remember that I saw posters in the lobby which were about MRI scans in DPD but I can't find any study from them about that. However, in Mainz they are very reluctant to use anything besides psychotherapy to treat DPD. But at least they have hundreds of patients per year which, theoretically, could be part of a study in another university in Germany. As soon as I am back I will talk with the neurology contacts that I mentioned before. It is always worth trying...

 

Last question regarding rTMS: With unlimited time and financial resources (or no costs) and a 2.2 cm coil and neuronavigation, would it theoretically be possible to try all of the possible causative regions in the brain (which are reachable so far) always for 8-10 sessions on each region? Or are we limited with known adverse effects here and therefore need to know the most relevant area identified in studies?



#6 Mayer-Gross

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Posted 24 January 2021 - 10:20 AM

Some wrote to the French researchers at this time last years and they said that they were in a process of reviewing the data and would finish around sept 2020. As I wrote a research unit is typically restricted for people who are nationals of the authority who have approved the research. In reality they are often more restricted. Jonathan Downars research rTMS clinic in Toronto for depression is very open to people in that area but closed to the rest of Canada. When the "Depersonalization research unit" was active your could get a referral directly to them if you lived in the London area. If you lived in other areas in England you had to get the referral by a the area you lived under. They also had to pay the founding for your referral to the London area. So, it is very unlikely that any research done in one European country will accept nationals from another. 

 

As I wrote buprenorphine have had some slight reductions in some that also had problems with opioid addiction. Buprenorphine is a antagonist for the kappa receptor with high affinity. So, that is settle for me. It is also very unlikely that a selective kappa antagonist will be approved. They have failed in some trials and likely dropped. . Because you can have depersonalization secondary to many states doesn't mean that they are the same. Your can have depersonalization secondary to depression as many will respond with a typically antidepressent intervention. People with depersonalization in its primary form will not. Those who respond to rTMS at the left or right DLPFC typically have depression with secondary symptoms of depersonalization. 

 

A conventional rTMS coil can stimulate at the dept of 1.cm.That is the one approved for clinical use.  A coil for deeper stimulation was developed around 2015 and only used for research in Europe. It is not approved for clinical use yet. Magventure is with danish researchers trying to make another coil as part of the development. Jonathan Downar adresses in this text different locations in the prefrontal cortex and their stimulation. Most of them are highly dependent of a deep coil.https://dribrahimyil...emik-Makale.pdf

 

 You could likely test the diffrent locations with a Magventure D-b80 coil. Jonathan Downar have done that is depression since 2015. If there is a register in Germany with people who have been diagnosed with depersonalization disorder in a sufficient number it could likely be used. But, in the DTI scan they wrote it was difficult to find many and they wrote it was due to it was under diagnosed. It could also be related to it was both strutural brain scans and they likely wanted people who had been symptomatic for a long time as they are looking for small changes in sizes of the brain. Newly diagnosed would likely not make any data. . I think the average was 15.years.     



#7 Mayer-Gross

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Posted 24 January 2021 - 10:36 AM

Here is a video done by Jonathan Downar with neuronavigation stimulation done with a deep coil at the dorsomedial prefrontal cortex in depression.

 

https://www.ncbi.nlm...les/PMC4692428/

 

This is also found overactive in depersonalization along with the anterior cingulate. In some scans in left dorsomedial prefrontal cortex should be larger/ most active. This location is also a OCD location in some. There is connections to the caudate nucleus from this location. So, it could be a location to explore. 

 

In dissociative subtype of PTSD a structure deep in the midbrain called the periaqueductal gray had shifted into a an area that is related to immobilization. They are working with a model where this shift is done by the right ventromedial prefrontal cortex that makes inhibition of anxiety and emotions and makes this shift in the Periaqueductal gray. To see in the midbrain for this and look for networks in there to other structures you need a fMRI at 7.tesla- not 3.tesla the is normally used. Everything is to small. In depersonalisation this shift in the Periaqueductal gray is likely also seen. But, the areas in the prefrontal cortex might not be the same as in the dissociative subtype. 



#8 leminaseri

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Posted 25 January 2021 - 07:38 PM

hey mg

is a 3 tesla fmri enough to figure out which parts of my brain are overactive? i have also an options to make a dti. which one would give me more details about the activity in my brain?

#9 Mayer-Gross

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Posted 26 January 2021 - 03:13 AM

No, even with a sample size of 10-20.persons they have the difficulties finding the correct locations. That is why a combination with rTMS should be considered to test the different locations showing up as active on a scan.  

 

There will likely not be such individual brain scans as long there is not more advanced rTMS equipment that can intervene in many of these locations. That is why there are some dependence on development of more rTMS equipment. 



#10 leminaseri

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Posted 26 January 2021 - 06:14 AM

No, even with a sample size of 10-20.persons they have the difficulties finding the correct locations. That is why a combination with rTMS should be considered to test the different locations showing up as active on a scan.

There will likely not be such individual brain scans as long there is not more advanced rTMS equipment that can intervene in many of these locations. That is why there are some dependence on development of more rTMS equipment.


my question was if a fmri or dti scan of my brain would show the overactive/underactive areas.

#11 Mayer-Gross

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Posted 26 January 2021 - 06:53 AM

It will show over and underactive areas in all living people depending of what the brain do. So, to explore depersonalization you always have a group with depersonalization and a normal group of similar age to compare with. it is in the differences between those two groups you find where depersonalization is abnormal. A scan of your brain as with what we know is close to useless. 



#12 leminaseri

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Posted 26 January 2021 - 08:54 AM

It will show over and underactive areas in all living people depending of what the brain do. So, to explore depersonalization you always have a group with depersonalization and a normal group of similar age to compare with. it is in the differences between those two groups you find where depersonalization is abnormal. A scan of your brain as with what we know is close to useless.


i think it wont be difficult to find scans of healthy people. another point what i want to reach with this considering is to figure out, if i in general have the same abnormalities as in the depersonalization scans. maybe my prefrontal cortex is not overactive, and this would be mean i have not primary depersonalization. just an idea.




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