Early-life trauma endophenotypes and brain circuit–gene expression relationships in functional neurological (conversion) disorder, 2020, Diez et al

Andy

Retired committee member
Not a recommendation.
Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition whereby individuals present with sensorimotor symptoms incompatible with other neurological disorders. Early-life maltreatment (ELM) is a risk factor for developing FND, yet few studies have investigated brain network–trauma relationships in this population.

In this neuroimaging–gene expression study, we used two graph theory approaches to elucidate ELM subtype effects on resting-state functional connectivity architecture in 30 patients with motor FND. Twenty-one individuals with comparable depression, anxiety, and ELM scores were used as psychiatric controls. Thereafter, we compared trauma endophenotypes in FND with regional differences in transcriptional gene expression as measured by the Allen Human Brain Atlas (AHBA). In FND patients only, we found that early-life physical abuse severity, and to a lesser extent physical neglect, correlated with corticolimbic weighted-degree functional connectivity. Connectivity profiles influenced by physical abuse occurred in limbic (amygdalar–hippocampal), paralimbic (cingulo-insular and ventromedial prefrontal), and cognitive control (ventrolateral prefrontal) areas, as well as in sensorimotor and visual cortices. These findings held adjusting for individual differences in depression/anxiety, PTSD, and motor phenotypes.

In FND, physical abuse also correlated with amygdala and insula coupling to motor cortices. In exploratory analyses, physical abuse correlated connectivity maps overlapped with the AHBA spatial expression of three gene clusters: (i) neuronal morphogenesis and synaptic transmission genes in limbic/paralimbic areas; (ii) locomotory behavior and neuronal generation genes in left-lateralized structures; and (iii) nervous system development and cell motility genes in right-lateralized structures. These circuit-specific architectural profiles related to individual differences in childhood physical abuse burden advance our understanding of the pathophysiology of FND.
Paywall, https://www.nature.com/articles/s41380-020-0665-0
Sci hub, https://sci-hub.se/10.1038/s41380-020-0665-0
 
If they found that physical abuse causes physical problems in the brain that are measurable then it is not a conversion disorder caused by emotional distress. So they have shown these patients have not got FND, instead they have discovered a neurological syndrome associated with physical abuse in childhood.
 
  1. If half the FND patients were on ADs, then either the drugs don’t work, or the symptoms can’t be related to mood disorders. Just saying.
  2. Why no analysis of ELM of non-psychiatric, non-FND people? Just saying.

My symptoms are definitely mediated by anxiety, AD's are given not as primary treatment, but to treat comorbid conditions, GAD in my case.

@Mithriel: with the latest batch of imaging studies showing subtle structural changes, the label FND will undoubtedly evolve. Some of these studies:

Cortical thickness alterations linked to somatoform and psychological dissociation in functional neurological disorders
https://onlinelibrary.wiley.com/doi/full/10.1002/hbm.23853


Reduced limbic microstructural integrity in functional neurological disorder
https://www.cambridge.org/core/jour...cal-disorder/83DE1499B3E6EF3FEE6A195EBE1F47B6

Grey matter changes in motor conversion disorder
https://jnnp.bmj.com/content/85/2/236

Corticolimbic fast-tracking: enhanced multimodal integration in functional neurological disorder.
https://jnnp.bmj.com/content/90/8/929

WHITE MATTER IS ALTERED IN FUNCTIONAL NEUROLOGICAL DISORDER.
https://advances.massgeneral.org/neuro/journal.aspx?id=1455


and in the trials registration, I just came across this one:
Neuroimaging Biomarkers of Prognosis in Motor Functional Neurological Disorders
Neuroimaging Biomarkers of Prognosis in Motor Functional Neurological Disorders
https://ichgcp.net/clinical-trials-registry/NCT03398070/


Things are changing, and indeed the changes in functioning have detectable organic correlates.
 
with the latest batch of imaging studies showing subtle structural changes, the label FND will undoubtedly evolve.
Will it though? In my opinion, what currently seems to be the case is that observable structural changes are taken as proof that, paraphrasing, faulty thinking can lead to physical changes that then lead to the physical symptoms that get called FND, rather than the more obvious, and more likely, causality, that there are structural changes from some yet unknown biological process that lead to the physical symptoms that get called FND. It's pretty much the same issue that ME patients have had with the BPS researchers, and it will need researchers who are willing to honestly look at the evidence rather than trying to force the evidence to fit into their pet, magical, beliefs.
 
Will it though? In my opinion, what currently seems to be the case is that observable structural changes are taken as proof that, paraphrasing, faulty thinking can lead to physical changes that then lead to the physical symptoms that get called FND, rather than the more obvious, and more likely, causality, that there are structural changes from some yet unknown biological process that lead to the physical symptoms that get called FND. It's pretty much the same issue that ME patients have had with the BPS researchers, and it will need researchers who are willing to honestly look at the evidence rather than trying to force the evidence to fit into their pet, magical, beliefs.

I see what you're saying, and some will undoubtedly follow that route, and that is unfortunate. I still feel progress has been made esp over the last few years for a number of reasons:

- Much of the new research is being done by neurologists instead of psychiatrists.
- The recognition that FND can occur without prior trauma or stress.
- Tangible structural changes in the brain.
- Some small-scale studies with significant results from experimental neuromodulation treatments (which I am pursuing currently).

I believe these will slowly push FND back towards neurology.
 
Can you explain how you can be sure that your symptoms are mediated by anxiety?

Literally a 1 on 1 relationship between my anxiety and symptoms. A lack of anxiety does not eliminate my symptoms completely, but is sure does exacerbate them immediately. Can I be sure there is no confounder, no. But my lived-in experience tells me the two are inextricably linked in my case.
 
I see a correlation between feeling poorly, low and irritable mood and diarrhea. Many people would see that as confirmation that the root problem is depression, and that the other symptoms are somatic expression of depression. I also see that these symptoms are often triggered by certain foods so I interpret them as food sensitivity. I think it's just a milk allergy and/or reaction to some additives commonly found in processed foods.

That some things occur together doesn't mean that one can be sure that one of them causes the others. When I see someone say that their physical symptoms are expression of for example anxiety, I wonder if that is merely based on the observation that certain symptoms occur together.
 
I see a correlation between feeling poorly, low and irritable mood and diarrhea. Many people would see that as confirmation that the root problem is depression, and that the other symptoms are somatic expression of depression. I also see that these symptoms are often triggered by certain foods so I interpret them as food sensitivity. I think it's just a milk allergy and/or reaction to some additives commonly found in processed foods.

That some things occur together doesn't mean that one can be sure that one of them causes the others. When I see someone say that their physical symptoms are expression of for example anxiety, I wonder if that is merely based on the observation that certain symptoms occur together.

Ah, yes but my premise is not that anxiety causes my FND, but it directly affects my symptoms. That is a big difference. And I'm well aware of correlation vs causation, hard evidence would be nice to have, but in this case I have to make do with inferences based on my own observations. I have found nothing else that mirrors my symptoms as exact and swift as my anxiety levels. Could there be event triggering both, possibly, but given the positive effect on my symptoms of the SSRI's I'm betting it's the anxiety.
 
@Mithriel: with the latest batch of imaging studies showing subtle structural changes, the label FND will undoubtedly evolve.

Haven't they been saying that for the last two decades though, yet understanding has not yet evolved?

What makes the new research any different? It's the same sorts of hyped findings that have too low sensitivity and specificity to be of value in the clinic.
 
I don’t think so. Previously they’ve been saying there are functional changes but no structural changes in FND

Perhaps I wasn't clear. They've been performing brain imaging and surface scanning for several decades.

Example:
"Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement" Lancet 2000.
https://www.sciencedirect.com/science/article/pii/S0140673600020961

What has changed? They're still insisting there is no structural lesion in FND.

The following is from Begue et al. "Structural alterations in functional neurological disorder and related conditions: a software and hardware problem?"
Caution should be taken to not over interpret the structural neuroimaging literature outlined here, particularly given that the neural mechanisms of FND and SSD remain distinct from lesional neurological conditions.
https://www.sciencedirect.com/science/article/pii/S2213158219301482#bb0605
 
They say there is no relevant lesions.

They are quite happy to diagnose FND even if you have positive signs of neurological lesions if they think they are not the "proper" ones. Jonathon Edwards gave the example of a stroke victim who has left side weakness but right side vision deficit. I see what he means and he is a decent doctor not an FND *** but I think that I would need strong positive proof that such a patient had psychological problems before I accepted FND.

Being cured of one of the problems with CBT would be a good clue but otherwise I would consider things like "Did the patient fall when they had a stroke and damage the other side of the brain" or could this be a strange biology of the embryo or infant using one part of the brain for both sides for each eye or something. Remember that penicillin was discovered because someone did not throw out a contaminated agar plate.

FND infuriates me because it assumes an answer so closes the door on further investigation.

In a worse case, you can have all the symptoms of Paroxysmal Dyskinesia but the neurologist can decide that you have a psychogenic disease by looking at your circumstances. There are lists of these things to watch out for and one of them is coming to the appointment with a caring husband!

These studies which are showing brain damage they do not consider to be showing that damage in places relevant to your neurological problem so they assume it is the parts of the brain responsible for FND completely ignoring the complexity of brain function.

The only good thing about all this is it makes it harder to say that FND is deliberate deception.
 
Perhaps I wasn't clear. They've been performing brain imaging and surface scanning for several decades.

Example:
"Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement" Lancet 2000.
https://www.sciencedirect.com/science/article/pii/S0140673600020961

What has changed? They're still insisting there is no structural lesion in FND.

The following is from Begue et al. "Structural alterations in functional neurological disorder and related conditions: a software and hardware problem?"

https://www.sciencedirect.com/science/article/pii/S2213158219301482#bb0605
The difference is in the increased resolution of MRI imaging as well as new imaging techniques such as Diffusion Tensor Imaging. DTI is particularly useful for creating connectivity maps of the brain. Clear differences between FND and controls are visible here.
 
new imaging techniques such as Diffusion Tensor Imaging.

New? Weren't the key papers of that technique published around 1985?
I guess big difference since then is increased computational power (which is what enables the increased resolution and broader scope of analysis), but I haven't yet seen any major breakthroughs for FND or any other disease.
 
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