Neurometabolic Alterations in Children and Adolescents with Functional Neurological Disorder, 2023, Charney et al.

[SNT Gatchaman]

Neurometabolic Alterations in Children and Adolescents with Functional Neurological Disorder
Charney; Foster; Shukla; Zhao; Jiang; Kozlowska; Lin

Objectives
In vivo magnetic resonance spectroscopy (MRS) was used to investigate neurometabolic homeostasis in children with functional neurological disorder (FND) in three regions of interest: supplementary motor area (SMA), anterior default mode network (aDMN), and posterior default mode network (dDMN). Metabolites assessed included Nacetyl aspartate (NAA), a marker of neuron function; myo-inositol (mI), a glial-cell marker; choline (Cho), a membrane marker; glutamate plus glutamine (Glx), a marker of excitatory neurotransmission; γ-aminobutyric acid (GABA), a marker of inhibitor neurotransmission; and creatine (Cr), an energy marker. The relationship between excitatory (glutamate and glutamine) and inhibitory (GABA) neurotransmitter (E/I) balance was also examined.

Methods
MRS data were acquired for 32 children with mixed FND (25 girls, 7 boys, aged 10.00 to 16.08 years) and 41 healthy controls of similar age using both short echo point resolved spectroscopy (PRESS) and Mescher-Garwood point-resolved spectroscopy (MEGAPRESS) sequences in the three regions of interest.

Results
In the SMA, children with FND had lower NAA/Cr, mI/Cr (trend level), and GABA/Cr ratios. In the aDMN, no group differences in metabolite ratios were found. In the pDMN, children with FND had lower NAA/Cr and mI/Cr (trend level) ratios. While no group differences in E/I balance were found (FND vs. controls), E/I balance in the aDMN was lower in children with functional seizures—a subgroup within the FND group. Pearson correlations found that increased arousal (indexed by higher heart rate) was associated with lower mI/Cr in the SMA and pDMN.

Conclusions
Our findings of multiple differences in neurometabolites in children with FND suggest dysfunction on multiple levels of the biological system: the neuron (lower NAA), the glial cell (lower mI), and inhibitory neurotransmission (lower GABA), as well as dysfunction in energy regulation in the subgroup with functional seizures.

Link | PDF (NeuroImage: Clinical)

 

[SNT Gatchaman]

No published studies have used MRS to study FND in children. In the adult FND literature, however, three studies using MRS have been reported.

Limbic neurochemical changes in patients with functional motor symptoms (2023, Neurology)

Neurochemicals of limbic system and thalamofrontal cortical network: Are they different between patients with idiopathic generalized epilepsy and psychogenic nonepileptic seizure? (2020, Epilepsy & Behavior)

1HMRS in the Hippocampus of the Female Patients with Conversion Disorder (2021, Noro psikiyatri arsivi)

Considered together, MRS studies suggest that adult patients with FND show changes in neurometabolic homeostasis across multiple regions: emotion-processing regions located in the prefrontal cortex; thalamic subcortical regions involved in sensory and motor processing, and in regulating consciousness and alertness; and the hippocampus, involved in memory and learning. All of these functional domains are known to be affected in patients with FND.

While MRS has not been used to study FND in the pediatric population, other advanced imaging methods have been employed to uncover structural and functional differences in children with FND.

The aim of the current study is to examine neurometabolic homeostasis in children with mixed FND—that is, various combinations of symptom presentations—compared to healthy controls, by quantifying the following neurometabolites—NAA, Cr, Cho, mI, Glx, and GABA.

Because data acquisition in MRS is time-consuming and children (including adolescents) are often unable to tolerate long periods in the MRI scanner, we chose three regions of interest based on the pediatric literature available at the time 16,17 :

• SMA, a motor region that is part of the somatomotor network
• medial walls of the frontal lobes (ACC and medial PFC), which make up the aDMN
• posterior cingulate cortex (PCC) and precuneus, which make up the pDMN

aDMN and pDMN are anterior and posterior default mode network, respectively.

We hypothesized that children with FND would show changes in neurometabolic homeostasis in all three regions of interest.

 

[SNT Gatchaman]

Thirty-two children admitted for treatment of FND to the inpatient Mind-Body Program at The Children’s Hospital at Westmead (Australia), during the period January 2019 to July 2021 agreed to participate in the current study. All children had undergone a comprehensive neurology assessment and had been given a DSM-5 diagnosis of FND by a pediatric neurologist.

The final study groups for MRS acquisition comprised 32 children and adolescents (25 girls and 7 boys) with FND aged 10.00 to 16.08 years (mean = 13.33; SD = 1.48; median = 13.46) and 41 healthy controls (30 girls and 10 boys, aged 8.58 to 17.92 years [mean = 13.78; SD = 2.56; median = 14.33]). The groups were matched for sex (χ2 = 0.06; p = .80) and age (t(63.91) = −.53; p = 0.596).

The clinical presentations of the 32 children with FND were diverse. They presented with one or more functional neurological symptoms (range, 1–8; mean = 3.47; median = 3.00). Length of illness ranged from 1 week to 12 months (mean = 4.27 months; median = 4.00 months), with over two-thirds (23/32; 72%) having been ill for less than six months. Levels of functional disability at clinical assessment were high, with GAF scores ranging from 10 to 51 (mean = 32/100; median = 31/100) and days of school loss ranging from 0 to 20 weeks (mean = 5.33; median = 2.50) on presentation.

Relative to controls, patients with FND had significantly higher total scores on the DASS (subjective distress) and lower scores on the GAF.

Twenty-eight children had had clinical medical imaging—MRI (n = 20), CT (n = 2), and MRI and CT (n=6) as part of their neurology workup (prior to their participation in the study and acquisition of the research MRS). Two children with FND had incidental MRI findings on clinical imaging

 

[SNT Gatchaman]

Excitatory/inhibitory ratios

There were no significant differences between groups (FND vs. controls) for the E/I ratio in any of the three regions of interest. However, children experiencing functional seizures (n = 11) had lower E/I ratios in the aDMN compared to children with FND with no functional seizures (n = 14) (t(21.27) = −2.55; p = 0.018; mean = 3.90 vs. 5.42) and compared to controls (n=33) (t(41.74) = −2.62; p = 0.012; mean = 4.00 vs. 5.53). Children with functional seizures (n = 14) also had lower E/I ratios in the pDMN (trend level) compared to healthy controls (n = 40) (t(52.00) = −2.46; p = 0.017; mean = 4.72 vs. 5.32).

 

[SNT Gatchaman]

NAA is the largest peak identified by MRS. NAA—a precursor to enzyme synthesis, and involved in neuronal osmoregulation, and axon–glial signaling—is synthesized in the mitochondria of neurons and is present in the cell body, axons, and dendrites. It is considered a marker of neuronal health, viability, number of neurons, and functional capacity of neuronal mitochondria. Since children with FND are expected to achieve a full recovery with treatment, the decreased NAA in the SMA and pDMN may potentially reflect reversible neuronal or mitochondrial dysfunction. Alternately, it may be a byproduct of glial dysfunction due to altered glial metabolism or dysregulated neuronal–glial signaling.

Akin to their adult counterparts, children with FND show a loss of self-agency in relation to their FND symptoms: the symptoms are experienced as involuntary. Lower NAA/Cr ratios in the pDMN, coupled with decreased mI/Cr ratios (trend level), may potentially contribute to this loss of self-agency.

Glial cells are heterogeneously distributed throughout the brain. In contemporary neuroscience, glial cells are conceptualized as key homeostatic regulators of the central nervous system—guardians of neuronal excitability, neuroplasticity, and connectivity. In illness states, they can drive abnormal neuronal activity, illness-promoting neuroplasticity processes, and aberrant neural network function.

Glial cells may also serve as immunosensors of the stress response. They “display an amazing repertoire of functions that put them in the unique position to sense and respond rapidly to alterations in homeostasis and integrate the neural response to threat”. This role implicates them as key players in the neurobiology of stress-related disorders, including FND.

 

[SNT Gatchaman]

One can hypothesize that dysregulation within either of these two networks or within any of their components is likely to affect energy regulation and also regulation of other emotionprocessing functions. This issue is of particular interest in FND because multiple studies have shown that children with FND—and children with functional seizures, in particular—are characterized by a state of increased resting-state arousal.

We have threads for —

[18] Activation of Functional Brain Networks in Children With Psychogenic Non-epileptic Seizures (2020, Frontiers in Human Neuroscience)

[19] Autonomic, Endocrine, and Inflammation Profiles in Functional Neurological Disorder: A Systematic Review and Meta-Analysis (2021, The Journal of Neuropsychiatry and Clinical Neurosciences)

Moreover, children with functional seizures demonstrate difficulties in regulating their biological systems back to a healthy baseline state following exposure to a stressor. In the adult literature, an intriguing pilot study used brain temperature mapping to show elevations in brain temperature across multiple brain regions in women with functional seizures. The authors interpreted these findings as reflecting stress-induced neuroinflammation in the context of adverse childhood experiences.

Of course.

 

[SNT Gatchaman]

Within the FND group, children with FND with functional seizures had lower E/I ratios in the aDMN (vs. those with FND without functional seizures and vs. controls) and pDMN E/I (vs. controls, trend level). Because flow of information through the neural network requires energy, alterations in E/I balance in children with functional seizures may reflect difficulties in energy regulation and energy flow.

Any chance all this could all be metabolically (or immuno-metabolically) driven then?

Our findings of multiple differences in neurometabolites in children with FND compared to healthy children suggests dysfunction on multiple levels of the biological system—neurons, glial cells, and neurotransmitters/signaling. All presumably combine to contribute to symptoms experienced by our child and adolescent patients with FND across motor-sensory, emotion-processing, and cognitive-control domains. The potentially important role of glial cells in mediating neurometabolite changes—via glia cell signaling and intercellular signaling in neuron–glia networks—suggests a need for a broader research lens, one that conceptualizes glial cells as key players within neuron–glia networks.

Ooh, ooh ...

Our findings pertaining to the potential role of arousal and subjective distress in modulating neurometabolites changes, cohere with the idea that FND is a disorder that emerges at the brain-mind-body interface. Finally, our findings regarding E/I balance in children with functional seizures add to a growing literature implicating problems with energy regulation and energy flow as a mechanism underpinning functional seizures. While this study is the first to use MRS in children with FND, it builds upon prior work using EEG, fMRI, and diffusion tensor imaging to characterize and better understand the underlying neurophysiology of FND.

So close.

 

[Amw66]

The cognitive dissonance is truly stunning.

 

[Sid]

In the adult literature, an intriguing pilot study used brain temperature mapping to show elevations in brain temperature across multiple brain regions in women with functional seizures. The authors interpreted these findings as reflecting stress-induced neuroinflammation in the context of adverse childhood experiences.

I know I shouldn't be laughing because this is deadly serious for people who are told they have FND but this is actually insane and reads like a parody of some medieval text where everything is attributed to ghosts and demons.

 

[Sid]

COMMON ADVERSE CHILDHOOD EXPERIENCES (ACEs) REPORTED BY THE CHILD AND FAMILY (maltreatment-related events are denoted by an asterisk)
One or more ACEs (range 1–10, mean 6, SD 2.5) 32 100%
Bullying by peers 20 62.5%
Child physical illness 19 59.4%
Family conflict 15 46.9%
Maternal mental illness 13 40.6%
Loss via separation from a loved one or a close friend 12 37.5%
Loss via death of a loved one 10 31.3%
Maternal physical illness 8 25.0%
Paternal mental illness 9 28.1%
Paternal physical illness 6 18.8%
Exposure to domestic violence* 6 18.8%
Emotional abuse (e.g., rejection/abandonment by a parent)* 6 18.8%
Sexual abuse* 4 12.5%
Physical abuse* 1 3.1%
Neglect* 1 3.1%

Literally everyone on the planet has experienced one or more of these adverse events.

 

[Arnie Pye]

Literally everyone on the planet has experienced one or more of these adverse events.

I agree. And this is why FND is probably one of the fastest growing diagnoses in the world. This is the end result the insurance companies wanted. Everyone is mentally ill and payouts from insurance policies can be restricted as a result because apparently being mentally ill is a "choice" and people could get better if they really wanted to.

 

[rvallee]

The authors interpreted these findings as reflecting stress-induced neuroinflammation in the context of adverse childhood experiences.

Infections cannot cause neuroinflammation because neuroinflammation is not an accepted thing. But bad experiences in childhood can and it can lead to any and all illness and symptoms as long as it's all attributed to stress. Got it. Makes sense if you don't think about it.

Functional disorders don't have any biological anomalies. But if you find biological anomalies in patients labeled with functional disorders, they were always caused by some stress and fixed with thinking differently under the guiding hand of a smart doctor. Also got it. Also makes sense if you don't think about it.

Clearly, the water on the ground were caused the clouds above. Which is true, also if you don't think about it.

 

[rvallee]

I know I shouldn't be laughing because this is deadly serious for people who are told they have FND but this is actually insane and reads like a parody of some medieval text where everything is attributed to ghosts and demons.

I was thinking about this recently, how ghosts have basically vanished from popular cultures. Up to the 90's, movies about or featuring ghosts were common and often of a scary nature. Nowadays outside of fantasy movies, like Harry Potter and stuff, they basically don't exist anymore.

Which probably reflects why things that used to be blamed on ghosts and demons are now simply blamed on some imaginary process. Same thing, really. It's just a reflection of the culture, but they're still just fairy tales.

 

[Amw66]

Literally everyone on the planet has experienced one or more of these adverse events.

It's completely nuts.
There's no input for frequency , age these happened at etc.
Coyne did a pretty good take down of ACES .
Here it inputs into everything .