Welcome to PracticeUpdate! We hope you are enjoying access to a selection of our top-read and most recent articles. Please register today for a free account and gain full access to all of our expert-selected content.
Already Have An Account? Log in Now
Neurometabolic Alterations in Children and Adolescents With Functional Neurological Disorder
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersOBJECTIVES
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 N-acetyl 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.
Additional Info
Disclosure statements are available on the authors' profiles:
Neurometabolic alterations in children and adolescents with functional neurological disorder
Neuroimage Clin 2024 May 01;41(1)103557, M Charney, S Foster, V Shukla, W Zhao, SH Jiang, K Kozlowska, A LinFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Children and adolescents with functional neurological disorder (FND) are prevalent in pediatric clinics1; yet, much remains to be explored about the neurobiology of this condition. Prior investigations into structural and functional brain alterations in children with FND have revealed alterations in several brain areas, including the supplementary motor area (SMA) and regions of the default mode network (DMN).2,3 The study recently published by Charney and colleagues in NeuroImage: Clinical focused on these previously implicated brain regions to investigate neurometabolic differences in children with mixed FND (n = 32; 25 girls; age, 10–16 years) compared with age- and sex-matched healthy controls (n = 41). The authors used magnetic resonance spectroscopy, a noninvasive MRI technique that can quantify neurometabolites. Creatinine values were used as a reference. The authors observed decreases in N-acetyl aspartate levels (a marker of neuron function) and trending decreases in myo-inositol levels (mI; a marker of glial cell function) in the SMA and posterior DMN as well as decreases in γ-aminobutyric acid levels (GABA; a marker of inhibitory neurotransmission) in the SMA of children with FND compared with those of healthy controls. Differences in mI and GABA levels were not significant when subjective distress scores were included as a covariate. Additionally, a higher resting heart rate, reflecting increased arousal, was associated with lower mI levels in both the SMA and posterior DMN. The authors also observed a lower ratio between excitatory (glutamate and glutamine) and inhibitory (GABA) neurometabolites (E/I ratio) in the anterior DMN of children with functional seizures than in that of children with other FND presentations.
Together, these findings implicate alterations in neuronal and glial cell function, and in neurotransmission, as potential contributing factors for pediatric FND. In young people with functional seizures, a decreased E/I ratio highlights the potential role of aberrant energy regulation as an underlying mechanism that needs to be further explored. Additionally, the findings of subjective distress and arousal influencing neurometabolism are consistent with accounts of FND as a brain–mind–body interface disorder,4 suggesting that a more complete understanding of FND and related conditions may come from a focus on signals not only from the brain but also on interacting signals from the body and surrounding environment. Although this study is limited by a modest sample size and a focus on only three brain regions of interest, it, nonetheless, is the first to characterize neurometabolic differences in children with FND, providing a foundation for future investigations and new potential treatment options. Future larger-scale efforts investigating differences across the whole brain will help shed additional light on the mechanistic role of neurometabolic alterations in pediatric patients with FND.
References
Functional neurological disorders (FND) are characterized by the presence of neurological symptoms that cannot be explained by typical neurological diseases or other medical conditions, but are authentic, causing significant discomfort and potential disability to the patient.1 In the last decades, consensus has been reached that FND should be understood in the context of a bio-psycho-social framework, with a consequent increase in the number of neurobiological studies on FND.
The current study examined neurometabolic homeostasis in pediatric patients with different FNDs (ie, motor FND, sensory FND, and psychogenic nonepileptic seizures [PNES]) with respect to healthy controls. Children with FND showed lower NAA/Cr, mI/Cr, and GABA/Cr ratios in the SMA and lower NAA/Cr and mI/Cr ratios in the posterior default mode network (posterior cingulate cortex and precuneus). Excitatory/Inhibitory (Glx/GABA) balance in the anterior default mode network (anterior cingulate cortex/medial prefrontal cortex) was lower in children with PNES than in healthy controls. Overall, the results suggest a dysfunction at the neuronal level (lower NAA levels), at the glial cell level (lower mI levels), and at the inhibitory neurotransmission level (lower GABA levels) as well as a dysfunction in energy regulation in the PNES subgroup. Moreover, increased arousal was associated with a lower mI/Cr in the supplementary motor area and posterior default mode network. Notably, pediatric patients with FND had significantly higher rates of depression, anxiety, stress, and adverse childhood experiences in their lifespan with respect to healthy controls and reported that stressing events (physical, psychological, or mixed) typically triggered their clinical presentations. Similarly, in adult patients with FND, adverse life events (eg, neglect, maltreatment, physical abuse, and sexual abuse) were significantly more frequent compared with healthy controls,2 and recalling these traumatic events during a structured clinical interview resulted was associated with the manifestation of the functional symptoms.3
Since the publication of the DMS-5, the presence of precipitating psychological stressors is not strictly required for the FND diagnosis. Nonetheless, there is an ongoing debate on how much they contribute to the origin, exacerbation, severity, or maintenance of FND.4,5
Recent research on FND has expanded beyond traditional environmental and psychological factors to include the attachment theory,6-10 according to which childhood emotional relationships shape how individuals adapt to new experiences and form mental representations of self and others. A predominant attachment style provides a lasting template for future relationships and affects emotional regulation skills. An MRI study examining the neurobiology of attachment and stress management in patients with FND revealed that women with FMD and a dismissing attachment style showed a reduced cortical thickness in the left parahippocampal gyrus,11 which connects the memory system of the medial temporal lobe and the cortical nodes of the default mode network. Hence, Pick et al12 suggested that, in patients with FND, an enhanced preconscious (implicit) processing of emotionally salient stimuli, associated with increased limbic reactivity, may trigger the initiation of basic affective/defensive responses. These affect-related brain areas may concomitantly negatively influence the circuitry involved in motor control as well as awareness and emotional regulation.
Moreover, with respect to neurochemical alterations in the limbic system of patients with FND, our group previously found that patients with motor FND showed a higher Glx/Cr in the anterior cingulate cortex/medial prefrontal cortex with respect to healthy controls, which was correlated with alexithymia, anxiety, and severity of motor FND symptoms.13 Moreover, we found that glutamate levels were lower in the CSF and peripheral blood14,15 of patients with motor FND, again correlating with higher alexithymia levels. In a previous study,16 we investigated the somatic and psychological state of pediatric patients with FND; significant discrepancies emerged between the self-report and parent-report questionnaires about anxious and depressive feelings, which might suggest that children and adolescents with FND have difficulties in recognizing some internal emotional states, that are instead more easily recognized by their parents (while the relevance of somatic symptoms was also acknowledged by the children themselves). This profile fits with the alexithymic traits that characterize adults with FND and is in line with a recent systematic review showing that the rate of alexithymia appears to be significantly higher among children with medically unexplained symptoms (including pain, tension-type headache, functional abdominal pain, headache, and chronic fatigue syndrome) with respect to healthy controls.17
By showing neurometabolic alterations in the supplementary motor area, associated with levels of stress and hyperarousal, this study gives further evidence suggesting the link between alterations in emotional regulation and motor control in patients with FND.18
In conclusion, exploring personality and psychopathological traits, attachment styles, and the presence of traumatic events and correlating them with novel neurobiological findings seem to be crucial to trying to understand the pathophysiology of FND.
References