Category: Neurology

Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis

Abstract:

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.

Source: Yi-Dan Zhang, Li-Na Wang. Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis. Front. Endocrinol., 09 April 2024, Sec. Neuroendocrine Science, Volume 15 – 2024 | https://doi.org/10.3389/fendo.2024.1373748 https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1373748/full

Imbalanced Brain Neurochemicals in long COVID and ME/CFS: A Preliminary Study using MRI

Abstract:

Purpose: Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients experience multiple complex symptoms, potentially linked to imbalances in brain neurochemicals. This study aims to measure brain neurochemical levels in long COVID and ME/CFS patients as well as healthy controls to investigate associations with severity measures.

Methods: Magnetic resonance spectroscopy (MRS) data was acquired with a 3T Prisma MRI scanner. We measured absolute levels of brain neurochemicals in the posterior cingulate cortex in long COVID (n=17), ME/CFS (n=17), and healthy controls (n=10) using Osprey software. The statistical analyses were performed using SPSS version 29. Age and sex were included as nuisance covariates.

Results: Glutamate levels were significantly higher in long COVID (p=0.02) and ME/CFS (p=0.017) than in healthy controls. No significant difference was found between the two patient cohorts. Additionally, N-acetyl-aspartate levels were significantly higher in long COVID patients (p=0.012). Importantly, brain neurochemical levels were associated with self-reported severity measures in long COVID and ME/CFS.

Conclusion: Our study identified significantly elevated Glutamate and N-acetyl-aspartate levels in long COVID and ME/CFS patients compared with healthy controls. No significant differences in brain neurochemicals were observed between the two patient cohorts, suggesting a potential overlap in their underlying pathology. These findings suggest that imbalanced neurochemicals contribute to the complex symptoms experienced by long COVID and ME/CFS patients.

Source: Thapaliya K, Marshall-Gradisnik S, Eaton-Fitch N, Eftekhari Z, Inderyas M, Barnden L. Imbalanced Brain Neurochemicals in long COVID and ME/CFS: A Preliminary Study using MRI. Am J Med. 2024 Apr 6:S0002-9343(24)00216-X. doi: 10.1016/j.amjmed.2024.04.007. Epub ahead of print. PMID: 38588934. https://www.sciencedirect.com/science/article/pii/S000293432400216X (Full text)

Machine learning algorithms for detection of visuomotor neural control differences in individuals with PASC and ME

Abstract:

The COVID-19 pandemic has affected millions worldwide, giving rise to long-term symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) infection, colloquially referred to as long COVID. With an increasing number of people experiencing these symptoms, early intervention is crucial. In this study, we introduce a novel method to detect the likelihood of PASC or Myalgic Encephalomyelitis (ME) using a wearable four-channel headband that collects Electroencephalogram (EEG) data. The raw EEG signals are processed using Continuous Wavelet Transform (CWT) to form a spectrogram-like matrix, which serves as input for various machine learning and deep learning models. We employ models such as CONVLSTM (Convolutional Long Short-Term Memory), CNN-LSTM, and Bi-LSTM (Bidirectional Long short-term memory). Additionally, we test the dataset on traditional machine learning models for comparative analysis.

Our results show that the best-performing model, CNN-LSTM, achieved an accuracy of 83%. In addition to the original spectrogram data, we generated synthetic spectrograms using Wasserstein Generative Adversarial Networks (WGANs) to augment our dataset. These synthetic spectrograms contributed to the training phase, addressing challenges such as limited data volume and patient privacy. Impressively, the model trained on synthetic data achieved an average accuracy of 93%, significantly outperforming the original model.

These results demonstrate the feasibility and effectiveness of our proposed method in detecting the effects of PASC and ME, paving the way for early identification and management of the condition. The proposed approach holds significant potential for various practical applications, particularly in the clinical domain. It can be utilized for evaluating the current condition of individuals with PASC or ME, and monitoring the recovery process of those with PASC, or the efficacy of any interventions in the PASC and ME populations. By implementing this technique, healthcare professionals can facilitate more effective management of chronic PASC or ME effects, ensuring timely intervention and improving the quality of life for those experiencing these conditions.

Source: Harit Ahuja, Smriti Badhwar, Heather Edgell, Lauren E. Sergio, Marin Litoiu. Machine learning algorithms for detection of visuomotor neural control differences in individuals with PASC and ME. Front. Hum. Neurosci. Sec. Brain-Computer Interfaces, Volume 18 – 2024 | doi: 10.3389/fnhum.2024.1359162 https://www.frontiersin.org/articles/10.3389/fnhum.2024.1359162/full (Full text)

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Abstract:

Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood.

These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration.

Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

Source: Cohen J, Mathew A, Dourvetakis KD, Sanchez-Guerrero E, Pangeni RP, Gurusamy N, Aenlle KK, Ravindran G, Twahir A, Isler D, Sosa-Garcia SR, Llizo A, Bested AC, Theoharides TC, Klimas NG, Kempuraj D. Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders. Cells. 2024 Mar 14;13(6):511. doi: 10.3390/cells13060511. PMID: 38534355; PMCID: PMC10969521. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10969521/ (Full text)

A Case Report of Chronic Epipharyngitis With Chronic Fatigue Treated With Epipharyngeal Abrasive Therapy (EAT)

Abstract:

A case of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with chronic epipharyngitis was treated with epipharyngeal abrasive therapy (EAT). The symptoms of ME/CFS improved along with the improvement of chronic epipharyngitis. The patient was followed up with endocrine and autonomic function tests.

Endocrine function tests included salivary cortisol and salivary α-amylase activity. Salivary α-amylase activity was stimulated by EAT. EAT improved the diurnal variability of salivary cortisol secretion. Autonomic function tests included heart rate variability analysis by orthostatic stress test. EAT normalized parasympathetic and sympathetic reflexes over time and regulated autonomic balance.

Based on the improvement of symptoms and test results, EAT was considered effective for ME/CFS. A literature review was conducted on the mechanism of the therapeutic effect of EAT on ME/CFS.

Source: Hirobumi I. A Case Report of Chronic Epipharyngitis With Chronic Fatigue Treated With Epipharyngeal Abrasive Therapy (EAT). Cureus. 2024 Feb 23;16(2):e54742. doi: 10.7759/cureus.54742. PMID: 38405656; PMCID: PMC10884883. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10884883/ (Full text)

People with Long Covid and ME/CFS Exhibit Similarly Impaired Dexterity and Bimanual Coordination: A Case-Case-Control Study

Abstract:

Purpose: Dexterity and bimanual coordination had not previously been compared between people with long COVID and people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Therefore, this study determined dexterity and bimanual coordination in people with long COVID (∼16 month illness duration; n=21) and ME/CFS (∼16 year illness duration; n=20), versus age-matched healthy controls (n=20).

Methods: Dexterity, and bimanual coordination was determined using the Purdue pegboard test.

Results: The main findings of the present investigation were that people with ME/CFS and people with long COVID were generally comparable for Purdue pegboard tests (p>0.556 and d<0.36 for pairwise comparisons). It is worth noting however, that both these patient groups performed poorer in the Perdue pegboard test than healthy controls (p<0.169 and d>0.40 for pairwise comparisons).

Conclusions: These data suggest that both people with long COVID and people with ME/CFS have similarly impaired dexterity, and bimanual coordination. Therefore, there is an urgent need for interventions to target dexterity and bimanual coordination in people with ME/CFS, and given the current pandemic, people with long COVID.

Source: Sanal-Hayes NEM, Hayes LD, Mclaughlin M, Berry ECJ, Sculthorpe NF. People with Long Covid and ME/CFS Exhibit Similarly Impaired Dexterity and Bimanual Coordination: A Case-Case-Control Study. Am J Med. 2024 Feb 23:S0002-9343(24)00091-3. doi: 10.1016/j.amjmed.2024.02.003. Epub ahead of print. PMID: 38403179. https://www.amjmed.com/article/S0002-9343(24)00091-3/fulltext (Full text)

NIH study offers new clues into the causes of post-infectious ME/CFS

Press Release:

In a detailed clinical study, researchers at the National Institutes of Health have found differences in the brains and immune systems of people with post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS). They also found distinct differences between men and women with the disease. The findings were published in Nature Communications.

“People with ME/CFS have very real and disabling symptoms, but uncovering their biological basis has been extremely difficult,” said Walter Koroshetz, M.D., director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS). “This in-depth study of a small group of people found a number of factors that likely contribute to their ME/CFS. Now researchers can test whether these findings apply to a larger patient group and move towards identifying treatments that target core drivers of the disease.”

A team of multidisciplinary researchers discovered how feelings of fatigue are processed in the brains of people with ME/CFS. Results from functional magnetic resonance imaging (fMRI) brain scans showed that people with ME/CFS had lower activity in a brain region called the temporal-parietal junction (TPJ), which may cause fatigue by disrupting the way the brain decides how to exert effort.

They also analyzed spinal fluid collected from participants and found abnormally low levels of catecholamines and other molecules that help regulate the nervous system in people with ME/CFS compared to healthy controls. Reduced levels of certain catecholamines were associated with worse motor performance, effort-related behaviors, and cognitive symptoms. These findings, for the first time, suggest a link between specific abnormalities or imbalances in the brain and ME/CFS.

“We think that the immune activation is affecting the brain in various ways, causing biochemical changes and downstream effects like motor, autonomic, and cardiorespiratory dysfunction,” said Avindra Nath, M.D., clinical director at NINDS and senior author of the study.

Immune testing revealed that the ME/CFS group had higher levels of naive B cells and lower levels of switched memory B cells—cells that help the immune system fight off pathogens—in blood compared to healthy controls. Naive B cells are always present in the body and activate when they encounter any given antigen, a foreign substance that triggers the immune system. Memory B cells respond to a specific antigen and help maintain adaptive or acquired immunity. More studies are needed to determine how these immune markers relate to brain dysfunction and fatigue in ME/CFS.

To study fatigue, Dr. Nath and his team asked participants to make risk-based decisions about exerting physical effort. This allowed them to assess the cognitive aspects of fatigue, or how an individual decides how much effort to exert when given a choice. People with ME/CFS had difficulties with the effort choice task and with sustaining effort. The motor cortex, a brain region in charge of telling the body to move, also remained abnormally active during fatiguing tasks. There were no signs of muscle fatigue. This suggests that fatigue in ME/CFS could be caused by a dysfunction of brain regions that drive the motor cortex, such as the TPJ.

“We may have identified a physiological focal point for fatigue in this population,” said Brian Walitt, M.D., M.P.H., associate research physician at NINDS and first author of the study. “Rather than physical exhaustion or a lack of motivation, fatigue may arise from a mismatch between what someone thinks they can achieve and what their bodies perform.”

Deeper analyses revealed differences between men and women in gene expression patterns, immune cell populations, and metabolic markers. Males had altered T cell activation, as well as markers of innate immunity, while females had abnormal B cell and white blood cell growth patterns. Men and women also had distinct markers of inflammation.

“Men and women were quite divergent in their data, and that tells you that ME/CFS is not one-size-fits-all,” said Dr. Nath. “Considering male and female immune differences in ME/CFS, the results may open up new avenues of research that could provide insight into other infection-associated chronic diseases.”

The study, which was conducted at the NIH Clinical Center, took a comprehensive look at ME/CFS that developed after a viral or bacterial infection. The team used state-of-the-art techniques to examine 17 people with PI-ME/CFS who had been sick for less than five years and 21 healthy controls. Participants were screened and medically evaluated for ME/CFS over several days and underwent extensive tests, including clinical exams, fMRI brain imaging, physical and cognitive performance tests, autonomic function tests, skin and muscle biopsies, and advanced analyses of blood and spinal fluid. Participants also spent time in metabolic chambers where, under controlled conditions, their diet, energy consumption, metabolism, sleep patterns, and gut microbiome were evaluated. During a second visit, they completed a cardiopulmonary exercise test to measure the body’s response to exercise.

Many studies have identified immune, microbiome, and other abnormalities in ME/CFS, but the results tend to be inconsistent and exactly how these markers relate to or cause fatigue and other symptoms is unknown. By using a rigorous phenotyping approach to pull out meaningful differences, this study helps validate prior results and may identify new ways to target the brain or immune system therapeutically.

The highly collaborative project involved 75 investigators across 15 institutes and centers in the NIH Intramural Research Program, and at national and international institutions. Dr. Nath and his colleagues plan to publish additional findings from the data that was collected during this study.

The study was supported in part by the Intramural Research Program at the NIH.

Article:

Walitt, B., et al. “Deep phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.” Nature Communications. February 21, 2024. DOI: 10.1038/s41467-024-45107-3

NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease

Abstract:

Importance: While the understanding of inflammation in the pathogenesis of many neurological diseases is now accepted, this special commentary addresses the need to study chronic inflammation in the propagation of cognitive Fog, Asthenia, and Depression Related to Inflammation which we name Brain FADE syndrome. Patients with Brain FADE syndrome fall in the void between neurology and psychiatry because the depression, fatigue, and fog seen in these patients are not idiopathic, but instead due to organic, inflammation involved in neurological disease initiation.

Observations: A review of randomized clinical trials in stroke, multiple sclerosis, Parkinson’s disease, COVID, traumatic brain injury, and Alzheimer’s disease reveal a paucity of studies with any component of Brain FADE syndrome as a primary endpoint. Furthermore, despite the relatively well-accepted notion that inflammation is a critical driving factor in these disease pathologies, none have connected chronic inflammation to depression, fatigue, or fog despite over half of the patients suffering from them.

Conclusions and relevance: Brain FADE Syndrome is important and prevalent in the neurological diseases we examined. Classical “psychiatric medications” are insufficient to address Brain FADE Syndrome and a novel approach that utilizes sequential targeting of innate and adaptive immune responses should be studied.

Source: Khalid A. Hanafy, Tudor G. Jovin. Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease. Front. Immunol., 17 January 2024, Sec. Inflammation, Volume 15 – 2024 | https://doi.org/10.3389/fimmu.2024.1332776 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1332776/full (Full text)

Correspondence: Inaccurate reference leads to tripling of reported FND prevalence

Highlights:

  • Perez et al asserted that FND is the “2nd most common” diagnosis in outpatient neurology.
  • Stone et al (2010), cited by Perez et al, does not support the “2nd most common” claim.
  • In Stone et al, a broad “functional/psychological” category was the second most common
  • •

    FND is not synonymous with the “functional/psychological” category in Stone et al.

To the editor:

An article in NeuroImage: Clinical, “Neuroimaging in functional neurological disorder: state of the field and research agenda” (Perez et al., 2021), cited a prominent paper (Stone et al., 2010) as evidence for the assertion that functional neurological disorder (FND) is the “2nd most common outpatient neurologic diagnosis.” Although studies have yielded varying FND prevalence rates, the claim that it is the second-most common diagnosis at outpatient neurology clinics represents an erroneous interpretation of the findings of the referenced 2010 paper.

FND is the current name for what was formerly called conversion disorder, the diagnosis previously given to patients believed to have psychogenic motor and gait dysfunctions, sensory deficits, and non-epileptic seizures. According to the 2013 edition of the Diagnostic and Statistical Manual of Mental Disorders and as noted in Perez et al, FND is not a diagnosis of exclusion but requires the presence of specific “rule-in” clinical signs believed to be incompatible with known neurological disease. Some of these clinical signs have long been used by neurologists and other clinicians to help them identify cases of conversion disorder.

Stone et al.,’s (2010) paper was one of several arising from the Scottish Neurological Symptoms Study (SNSS). The study reviewed records from multiple outpatient neurology clinics and reported that 209 of 3781 attendees, or less than 6 %, received diagnoses compatible with conversion disorder–in other words, what would now be called FND. In terms of ranking, this group of patients—labeled in the SNSS as having “functional” symptoms or diagnoses–was far down the list. The study found higher rates of many other conditions, including headache (19 %), epilepsy (14 %), peripheral nerve disorders (11 %), miscellaneous neurological disorders (10 %), multiple sclerosis/demyelination (7 %), spinal disorders (6 %) and Parkinson’s disease/movement disorders (6 %).

Earlier this year, a paper in the European Journal of Neurology (Mason et al., 2023) cited a different SNSS paper (Stone et al., 2009) to support the assertion that FND prevalence at outpatient neurology clinics was 5.4 %—far lower than the percentage needed to be the “2nd most common” diagnosis. Moreover, the authors of another paper (Foley et al., 2022) have recently issued a correction for the same misstatement of FND prevalence from the SNSS findings as the one identified in Perez et al.

The assertion that the SNSS found FND to be the “2nd most common” diagnosis at outpatient neurology clinics is based on a parallel and commonly repeated claim that the study found the prevalence in these settings to be 16 % (e.g. Ludwig et al., 2018). That rate is almost three times the 5.4 % prevalence recently highlighted in Mason et al. The extra patients included in this greatly expanded FND category were another 10 % collectively identified in the SNSS as having “psychological” symptoms or diagnoses. These “psychological” patients fell into a range of clinical sub-categories, among them hyperventilation, anxiety and depression, atypical facial/temporomandibular joint pain, post-head injury symptoms, fibromyalgia, repetitive strain injury, and alcohol excess. The SNSS paper cited in Perez et al reported that a combined grouping of the patients with “functional and psychological” symptoms or diagnoses had a prevalence of 16 % but did not provide any evidence that the 10 % included under the “psychological” label met, or could have met, the explicit FND requirement for rule-in clinical signs.

FND is not synonymous with the broader “functional and psychological” category in the SNSS and should not be presented as if it were. The post-hoc reinterpretation of previously reported data in a way that conflates FND with other complex conditions—almost tripling its apparent prevalence in the process–is an example of the phenomenon known as diagnostic creep. In any event, the SNSS results are a matter of record. Whatever future studies might determine about FND rates, the published findings cited by Perez et al and addressed in this letter do not support either the claim that it is the “2nd most common” diagnosis in outpatient neurology clinics or the related claim that its prevalence at these venues is 16 %.

Sincerely–

David Tuller (corresponding author)

Center for Global Public Health

School of Public Health

University of California, Berkeley

Berkeley, CA, USA

David Davies-Payne

Department of Radiology

Starship Children’s Hospital

Auckland, New Zealand

Jonathan Edwards

Department of Medicine

University College London

London, England, UK

Keith Geraghty

Centre for Primary Care and Health Services Research

Faculty of Biology, Medicine and Health

University of Manchester

Manchester, England, UK

Calliope Hollingue

Center for Autism and Related Disorders/Kennedy Krieger Institute

Department of Mental Health/Johns Hopkins Bloomberg School of Public Health

Johns Hopkins University

Baltimore, MD, USA

Mady Hornig

Department of Epidemiology

Columbia University Mailman School of Public Health

New York, NY, USA

Brian Hughes

School of Psychology

University of Galway

Galway, Ireland

Asad Khan

North West Lung Centre

Manchester University Hospitals

Manchester, England, UK

David Putrino

Department of Rehabilitation Medicine

Icahn School of Medicine at Mt Sinai

New York, NY, USA

John Swartzberg

Division of Infectious Diseases and Vaccinology

School of Public Health

University of California, Berkeley

Berkeley, CA, USA

Source: Correspondence: Inaccurate reference leads to tripling of reported FND prevalence. Neuroimage Clin. 2024 Feb 7;41:103537. doi: 10.1016/j.nicl.2023.103537. Epub ahead of print. PMID: 38330816. https://www.sciencedirect.com/science/article/pii/S2213158223002280 (Full text)

The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability

Highlights:

  • Though a common symptom, fatigue is difficult to define and investigate, and occurs in a wide variety of disorders, with differing pathological causes.
  • This review aims to guide clinicians in how to approach fatigue and to suggest that neurophysiological tests may allow an understanding of its origin and severity.
  • The effectiveness of neurophysiological tests as cost-effective objective biomarkers for the assessment of fatigue has been summarised.

Abstract

Though a common symptom, fatigue is difficult to define and investigate, occurs in a wide variety of neurological and systemic disorders, with differing pathological causes. It is also often accompanied by a psychological component. As a symptom of long-term COVID-19 it has gained more attention.

In this review, we begin by differentiating fatigue, a perception, from fatigability, quantifiable through biomarkers. Central and peripheral nervous system and muscle disorders associated with these are summarised. We provide a comprehensive and objective framework to help identify potential causes of fatigue and fatigability in a given disease condition. It also considers the effectiveness of neurophysiological tests as objective biomarkers for its assessment. Among these, twitch interpolation, motor cortex stimulation, electroencephalography and magnetencephalography, and readiness potentials will be described for the assessment of central fatigability, and surface and needle electromyography (EMG), single fibre EMG and nerve conduction studies for the assessment of peripheral fatigability.

The purpose of this review is to guide clinicians in how to approach fatigue, and fatigability, and to suggest that neurophysiological tests may allow an understanding of their origin and interactions. In this way, their differing types and origins, and hence their possible differing treatments, may also be defined more clearly.

Source: Tankisi H, Versace V, Kuppuswamy A, Cole J. The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability. Clin Neurophysiol Pract. 2023 Dec 18;9:39-50. doi: 10.1016/j.cnp.2023.12.004. PMID: 38274859; PMCID: PMC10808861. https://www.sciencedirect.com/science/article/pii/S2467981X23000367 (Full text)