Cortisol and α-amylase awakening response in children and adolescents with functional neurological (conversion) disorder, 2022, Chung et al

[Andy]

Abstract

Objective:
Stress system dysregulation is considered to have an important role in the aetiology of paediatric functional neurological (conversion) disorder. This study examined salivary cortisol and α-amylase awakening responses in children with functional neurological disorder to determine activation patterns of the hypothalamic–pituitary–adrenal axis and sympathetic system. A healthy cortisol awakening response involves a robust increase in cortisol within 30 minutes of awakening. Alpha-amylase awakening response is variable in children.

Methods:
Cortisol and α-amylase were measured in saliva from 32 patients with functional neurological disorder (26 girls and 6 boys, aged 11.3−16.1 years) and 31 healthy controls (23 girls and 8 boys, aged 8.6–17.7 years). Saliva samples were collected using a Salivette sampling device at two time points – upon awakening and 30 minutes after awakening.

Results:
Patients with functional neurological disorder showed a decrease in cortisol awakening response (–4 nmol.min/L) and controls showed an increase (107 nmol.min/L), t(55) = –.4.6, p < 0.001. Within the functional neurological disorder group, 57% showed an attenuated cortisol awakening response and 43% showed an obliterated/reversed cortisol awakening response: Cortisol awakening response was negatively correlated with adverse childhood experiences, r(58) = –0.6, p = 0.002, and subjective distress (total Depression Anxiety and Stress Scales score), r(58) = –0.4, p = 0.050. In controls, cortisol awakening response showed no correlation with adverse childhood experiences and a positive correlation with subjective distress, r(56) = 0.4, p = 0.023. Total cortisol remained similar between the functional neurological disorder and control group. No significant differences were observed between the functional neurological disorder and control group in any of the α-amylase analyses.

Discussion:
The results suggest dysregulation of the hypothalamic–pituitary–adrenal axis in children with functional neurological disorder. Hypothalamic–pituitary–adrenal dysregulation in children with functional neurological disorder may contribute to comorbid symptoms of fatigue, sleep disturbance and subjective loss of well-being because circadian rhythms and energy metabolism are disrupted. Hypothalamic–pituitary–adrenal dysregulation – and changes in glucocorticoid (cortisol) signalling at the molecular level – may also contribute to increased vulnerability for functional neurological disorder symptoms because of epigenetically mediated changes to neural networks implicated in functional neurological disorder.

Paywall, https://journals.sagepub.com/doi/10.1177/00048674221082520
Now open access

 

[Snow Leopard]

This can also be an artifact of sleep-activity cycles. If the "FND" participants usually sleep in later and have lower daily activity levels. If they were tested at a time they would normally be sleeping, this sort of result is expected without having any pathological disturbance in the HPA axis.

Cortisol is a feed-forward metabolic hormone, rather than a "stress" hormone. Stress reactivity is just an artifact of the fact that it is associated with anticipation of energy use.

 

[bobbler]

This can also be an artifact of sleep-activity cycles. If the "FND" participants usually sleep in later and have lower daily activity levels. If they were tested at a time they would normally be sleeping, this sort of result is expected without having any pathological disturbance in the HPA axis.

Cortisol is a feed-forward metabolic hormone, rather than a "stress" hormone. Stress reactivity is just an artifact of the fact that it is associated with anticipation of energy use.

Indeed. Unfortunate about the paywall but I'd assume that any research into cortisol really has to note that an issue with the adrenal gland could be just as likely as a 'neurological' until proper testing is done. Goodness knows how you can start asking about negative childhood experiences and be either reliable and count it as an objective measure or think that you've got any business relating it to measures taken without any detailing of where the fault in the HPA lies.

Are we really getting to the point where BPS is now calling the entire HPA axis 'mind', when how much of it actually lies outside the 'brain' and the feedback mechanisms are physiologically explained and therefore those interactions need to be just as discussed in any explanation?

 

[Mithriel]

They are busy gobbling everything up. Soon medicine will be entirely FND.

 

[Arnie Pye]

Are we really getting to the point where BPS is now calling the entire HPA axis 'mind'

Yesterday I read a post on a thyroid forum (which I now can't find to get the exact wording) where a hypothyroid patient was told by an endocrinologist that levothyroxine [a hormone replacement] was a vitamin. It would appear that minimising everything health-related is part of a nationwide plan by the NHS to save money.

 

[bobbler]

Yesterday I read a post on a thyroid forum (which I now can't find to get the exact wording) where a hypothyroid patient was told by an endocrinologist that levothyroxine [a hormone replacement] was a vitamin. It would appear that minimising everything health-related is part of a nationwide plan by the NHS to save money.

Yikes. At what point can we stop calling them medicine because they have become something else if that trajectory continues - some aren't far off. And what and how will spring up to replace the non-science they become, picking and choosing when and what for they are one or the other isn't being what they think they are either. 'vitamins' - why would someone do that?

 

[livinglighter]

They are busy gobbling everything up. Soon medicine will be entirely FND.

This is what I also meant about FND appearing to take over microscopic brain injury which causes impaired neurological functioning of the brain.

The name FND confuses things even more like CFS/CF, etc.

 

[Mithriel]

It is worse when you realise they explicitly say that FND is the new name for hysteria. So all those WW1 soldiers who were said to have hysteria rather than bombardment brain injuries now have ... hysteria!

Stone has written a paper admiring the likes of Beard and Freud and the rest and said what a pity it was that their work was ignored for much of the 20th century.

 

[livinglighter]

Even worse than that is NICE is currently creating a brain injury guideline that includes FND.

So far from what I've read, sequelae brain injury symptoms are not completely understood but are well recognised by neurology. However, psychiatry argues the cause are somatic/conversion disorder instead.

Abnormal cortisol awakening response is also a recognised result of ABI.

It is worse when you realise they explicitly say that FND is the new name for hysteria. So all those WW1 soldiers who were said to have hysteria rather than bombardment brain injuries now have ... hysteria!

Exactly, it doesn't make sense.

 

[bobbler]

Even worse than that is NICE is currently creating a brain injury guideline that includes FND.

So far from what I've read, sequelae brain injury symptoms are not completely understood but are well recognised by neurology. However, psychiatry argues the cause are somatic/conversion disorder instead.

Abnormal cortisol awakening response is also a recognised result of ABI.



Exactly, it doesn't make sense.

Just a riff but .. however many years ago (suspect some GPs did it earlier than others who were nudged by rules) GP became test for these red flags and dump all chronic illness in a bucket. Worse, label that bucket and make getting out of it very hard indeed. 'we don't do chronic illness'.

This just sounds like neurology's bucket. We do these bits, shove all these parts off to psychiatry and now need our own little labels for the chronic/stuff we don't do.

For all their talk about 'wellness' being their new mission, the reality is they've stopped 'health' for many and focus on programmes that 'make them act normal'.

Now we've all been in jobs with workload management issues or where the staff are only sufficient to cover 'part of the job done a certain way', hoops are inserted to 'manage queues/demand'. If it were just that you'd get it. Is it like the focus on prescriptions so some GPs would have 5 appts (starting with assume stress or nothing and come back in 2 weeks) over barn door diagnosis in order to avoid giving out a cheap prescription on the first round. When we are short on GPs.

How long before it pops because everyone is on that same book? Bit of a giveaway of 'mass 'medicine'' when most of the population is on the same 'treatment'. I think once they start saying that 35-50% of GP appointments are 'MUS' in their literature and footnotes I'm shocked that instead of 'explosion of x' you'd be wondering whether it is 1. a bucket and 2. why these 'treatments' aren't leading to a reduction.

Someone I know came back from abroad (several countries) with among other diagnoses one for an autoimmune arthritis, and despite going private was put through re-diagnosis akin to NHS guidelines and told their spine wasn't yet deformed enough for treatment - even though they'd been on higher level stuff for many years hence still working and lack of deformity spreading to their spine. To me this indicates it isn't 'just' fuzzy illnesses either.

Are thyroid drugs not cheaper than all of the charade (and certainly when you count the costs of lack of productivity/care etc)?

The unforgivable bit is messing with what science is and making black white etc. and calling it a step forward

 

[livinglighter]

It would appear that minimising everything health-related is part of a nationwide plan by the NHS to save money.

Looks like what's going on to me. NHS Improvements even stated themselves if challenged on the grounds of ethics they can refer to the recommendations within the NICE guidelines.

That's probably why when post covid neurological symptoms and Long Covid emerged as a result of this pandemic a group of UK neuroscientists went out of their way to study the effects on the brain. I can loosely quote one's involvement as an attempt to stop conditions suffering the same fate as earlier ones had. The NHS does not want to link this stuff I'm sure it would constitute medical negligence.

 

[livinglighter]

For all their talk about 'wellness' being their new mission, the reality is they've stopped 'health' for many and focus on programmes that 'make them act normal'.

I couldn't have said it better myself. Plus, blaming those who cannot 'act normal' as hypochondriacs.

 

[Hutan]

The paper is now open access.

Difference in collection environment

The children with FND collected the samples while admitted into the Mind-Body Program, and controls collected the samples at home. All children collected samples immediately on waking up – according to their normal schedule (including attendance at hospital or census school) – and were expected to stay in bed, reading or engaging in some quiet activity, until they took the second sample half an hour later. They were also asked to refrain from going to the toilet, eating any breakfast, or brushing their teeth until both samples had been taken. Saliva samples were stored at –40°C before assaying.

That is a major difference between the groups, collection at home (controls) and collection during the residential programme (FND group). It seems possible that the FND young people's natural sleep/awakening processes may have been disrupted by being away from home; it is possible that they were woken up to a schedule, it is possible that they had to wait to be given the sampling kit. A delay in the first sample would be consistent with a result of a reducing cortisol level, as in the 'increase to the peak' phase was missed and instead the 'decrease from the peak' phase was captured.


Sample size

Fifteen participants (9 patients and 6 controls) were excluded from the analysis because one or both of their saliva samples were insufficient to run the analysis or because the sample had been mistakenly compromised (e.g. by addition of acid by pathology staff).

They started with 41 young people admitted to an inpatient Mind-Body program who agreed to participate and 37 healthy controls. 9 FND patients and 6 controls were excluded because one or both of their samples was 'insufficient to run the analysis or because the sample had been mistakenly compromised'. So there were 32 FND participants and 31 control participants.

All sorts of data comparisons e.g. on child adversity are given on these two groups.

Mandatory shutdowns during COVID-19 disrupted the analysis process, resulting in missing cortisol data for 4/32 patients with FND and 2/31 controls,

But then, for the cortisol analysis, further participants are excluded (4 FND, 2 controls), further participants were also excluded from the amylase analysis. Therefore, the demographic, symptom and history information presented is not exactly for the young people who contributed samples that were used. There is a lot of potential here for bias in what is reported.

There were 57 paired samples suitable for cortisol analysis, comprising 28 patients with FND and 29 controls.

Use of the word 'complex'
Table 5 reports that 81% of the FND sample is reported to have 'Complex (functional) pain'.

 

[Hutan]

Cortisol results

Unexpectedly, 12/28 FND group participants and 2/29 control participants had a 30-minute salivary cortisol level lower than the awakening cortisol level.

The mean cortisol level of the FND group was 10.5 at first measure and 10.3 at second measure.
The mean cortisol level of the control group was 6.2 on the first measure and 13.7 at the second measure.

It's not that the young people with FND were not producing cortisol at all. It seems likely that there were problems in the timing of the sample collection, with the FND samples often taken close to or after the peak.

I think the authors may have been worried about the same thing, because they did a sub-analysis of only the young people with a positive CAR.
The mean cortisol level of the positive CAR FND group (16 participants) was 7.2 at first measure and 10.9 at second measure (30 minutes later).
The mean cortisol level of the positive CAR control group was 6.2 on the first measure and 13.9 at the second measure (30 minutes later).

They aren't so different. And the problem is that they only present means, not actual individual data. If the the baseline collection tended to be late in the FND group, that could account for the differences. Also, there is a massive standard deviation in the 13.9 figure (6.7), suggesting that the inclusion or exclusion of a few participants would have made a big difference to the mean.

I think the problems with this study make the results pretty much uninterpretable.

 

[Hutan]

The finding that almost half of our patients with FND had a reversed CAR was unexpected. Notwithstanding, this finding does cohere with the clinical and research experience of our multidisciplinary team. As corroborated in our research studies, patients with FND who are admitted for treatment to our Mind-Body Program present in a state of high arousal and neurophysiological dysregulation (see summary of studies in chapter 4) (Kozlowska et al., 2020). For example, when these patients (vs healthy controls) attempt to utilise slow-paced breathing to down-regulate autonomic arousal, their autonomic measures show a paradoxical increase in arousal (a further decrease in heart rate variability) and not the expected increase (Chudleigh et al., 2019). Likewise, hyperventilation – with breathing rates of 30+ breaths per minute – is common, and in the subset of children with functional seizures, hyperventilation increases cortical arousal and may trigger functional seizures (Kozlowska et al., 2017b). In a study looking at the immune-inflammatory component of the stress system, we found that children with FND (vs healthy controls) had elevated high-sensitivity C-reactive protein (hsCRP), suggesting a systemic shift of balance towards an inflammatory body state.

Some of the 'FND' patients had only been ill for two weeks, over half were not able to mobilise themselves and had to use a wheelchair. I think if I was such a young person, having experienced that stress, along with the probing to find any childhood trauma, and then having been placed in a residential Mind-Body program away from my parents and my home, I might also find it stressful when someone is instructing me on how to breathe.

 

[Hutan]

From the discussion

To make things even more complex, the pattern of stress system dysregulation can shift across development so that the patterns of dysregulation early and later in life can differ (Baumeister et al., 2016; Trickett et al., 2010). Along these lines, we highlight that while the current study showed an attenuated or obliterated/reversed CAR in children with FND, studies with adults with FND show a normal CAR (Bakvis et al., 2009a; Maurer et al., 2015).

A discussion of the 'dysregulation' concept - it's a very vague idea that is favoured by BACME and Gladwell in relation to ME/CFS:

The concept of stress system dysregulation in children with FND has important implications for clinical practice and for the conceptualisation and treatment of FND and other functional disorders (Kozlowska et al., 2020). The stress system perspective is concerned with the continuous flow of homeostatic processes and rhythms, and with the quality of the relationship between these processes and rhythms. A healthy biological system is one whose subsystems function in a synchronised way, enabling and maintaining the efficient utilisation of energy, the capacity to respond to environmental demands and the processes of tissue regeneration and repair (McCraty and Childre, 2010).

An unhealthy biological system is associated with a loss of normal flows, rhythms and patterns of connection between systems. In consequence, regulation strategies – both bottom-up and top-down Kozlowska et al., 2020; Myers et al., 2021; Velani and Gledhill, 2021) – that facilitate regulation within the stress system should be considered be a core element of biopsychosocial interventions for children with FND. These strategies aim to facilitate healthy sleep, down-regulate the autonomic system and down-regulate inflammatory processes (e.g. via regular exercise; Scheffer and Latini, 2020), with an overarching aim of reinstating normal circadian rhythms, healthy synchrony between stress system components (including the HPA axis) and neuroprotective mechanisms.

Regulation within these systems may provide the necessary backdrop in which dysregulated neural networks – the aberrant connectivity changes that underpin FND – can more easily revert back to normal function. Interestingly, the process of integrating such interventions into paediatric (and adult) treatment programmes has already begun (Kozlowska et al., 2020; Myers et al., 2021; Sawchuk et al., 2020a, 2020b; Vassilopoulos et al., 2022; Velani and Gledhill, 2021).

 

[Eleanor]

For example, when these patients (vs healthy controls) attempt to utilise slow-paced breathing to down-regulate autonomic arousal, their autonomic measures show a paradoxical increase in arousal (a further decrease in heart rate variability) and not the expected increase

"Slow-paced breathing improves HRV and calms the nervous system" is one of those articles of faith for all the wellness devotees and mind-body proponents, so I wouldn't be at all surprised if it turned out that the reality is a little more complex.

(My own HRV decreases with slow-paced breathing - my guess is I'm one of the subset of Long Covid patients who have impaired oxygen uptake/ventilatory efficiency. FWIW, my morning cortisol was normal the only time it was tested.)