A Systems Neuroscience Approach to Diagnosis and Rehabilitation of Post COVID Neurological Syndrome Based on the Systems Neuroscience Test Battery (SNTB) Study Protocol

Abstract

The proposed study reports the design and development of a rapid screening tool, the Systems Neuroscience Test Battery (SNTB), for diagnosing and evaluating the neurological manifestations of Post-COVID-19 Neurological Syndrome (PCNS) within the broader context of Post-Acute Sequelae to COVID-19 (PASC). The SNTB is designed to incorporate a behaviorally relevant Telehealth component that enhances consumer confidence in symptom discrimination, management of PCNS, and guides rehabilitation programs while allowing for continuous evaluation of intervention effectiveness.

The study employs a longitudinal design, with telehealth and routine blood assessments conducted at three-month intervals, including at least two follow-ups post-recruitment. These assessments will involve Consumer-Reported Symptoms, Clinical History, Neuropsychological Data, and Timed Psychophysics, aimed at rapid screening of PCNS-related symptoms including ‘brain fog” and its affect on visually driven attention, cognition and visually driven motor behaviors. These assessments are intended to validate the characteristics of ‘brain fog’ and identify predictive behavioral biomarkers for the development of PCNS.

The target population includes adults aged 18–65 who have experienced persistent neurological symptoms for at least three months following a confirmed COVID-19 infection. Exclusion criteria include individuals unable to undergo radiological examinations, such as pregnant women or those with contraindications to MRI, ensuring the robustness of the sample and reducing potential selection bias.

The SNTB tool will facilitate the online identification of predictive biomarkers for PCNS and aid in the discovery of effective molecular biomarker combinations for medical intervention and rehabilitation. Complementary to the Telehealth Assessment, hospital facilities will be utilized for radiological and blood-based molecular assessments, ensuring concurrent profiling of structural and functional changes during ‘brain fog’ and recovery from PCNS symptoms.

Keywords

PASC post acute sequelae of COVID-19 post acute COVID-19 syndrome post-acute sequelae of COVID-19 post-Acute sequelae of SARS-CoV-2 infection post- COVID conditions PCNS

Introduction

The global burden of brain disorders is staggering. As highlighted in the 2021 Lancet Global Burden of Disease (GBD) study one in three people worldwide was affected by a neurological disorder in 2021 (Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021, 2024). The COVID-19 pandemic (2020–2022) has also exacerbated the global burden of neurological disorders by introducing a new and poorly understood condition: Post COVID Neurological Syndrome (PCNS) (Wijeratne & Crewther, 2021). With millions of people worldwide experiencing persistent neurological and psychiatric symptoms following recovery from SARS-CoV-2 infection, there is an urgent need for tools and strategies to understand, diagnose, and treat these post-viral neurological symptoms effectively (Asadi-Pooya, Nemati, et al., 2022; Koc et al., 2022; Leng et al., 2023; Maes et al., 2022; Tsuzuki et al., 2022). The GBD 2021 staggering statistic underscores the critical need for new innovative approaches to address neurological disorders that pose significant medical challenges not only due to the prevalence but also because of the complex and often elusive nature of the symptoms(“Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021,” 2024). In this context, the rise of tele-neurology and tele-neurorehabilitation in combination with follow up with more individualized specific investigations offers promising avenues to improve access to care and address issues of equity, particularly for those in underserved or remote areas(Rezania et al., 2021)

PCNS is a new and poorly understood neurological condition that characterizes the persistent neurological symptoms experienced by many people worldwide following recovery from SARS-CoV-2 respiratory infection and occasionally after Covid-19 vaccination (Quinn et al., 2023; Wijeratne & Crewther, 2020; Wijeratne, Gillard Crewther, et al., 2020; Wijeratne et al., 2021; Wijeratne & Wijeratne, 2021; Xie et al., 2023) . In Australia alone, PCNS is estimated to affect 5–10% of the population with symptoms such as “brain fog” and “persistent fatigue,” which patients have described as an abrupt aging of 10–20 years (Byambasuren et al., 2023; Clark, 2022; Schuliga et al., 2021; Wijeratne & Crewther, 2021; Wijeratne, Sales, Crewther, et al., 2020). PCNS symptoms have been linked to maladapted neuroinﬂammation-affected mitochondrial energy systems, though not investigated in detail, remaining poorly understood from a biological and neuropsychophysiological standpoint. This need for rigorous research also highlights the basic medical and psychological need for tools and strategies to understand, diagnose, and effectively treat these post-viral neurological symptoms. Indeed, the fatigue like symptoms of PCNS are often seen as similar to those of Chronic Fatigue i.e., myalgic encephalomyelitis, further implicating the need for molecular and neuroscientiﬁc research to develop tools and strategies to rapidly improve understanding, accurate diagnosis, and strategic management of these and other post-viral neurological symptoms especially those not directly affected by age (Wijeratne & Crewther, 2020; Wijeratne et al., 2021).

Hence this manuscript aims to document the experimental program designed to utilize our Systems Neuroscience Toolbox (SNTB) to explore the biological aetiology and source of ‘brain fog’ symptoms that encompass many of the consumer reported characteristics of PCNS. Our multidisciplinary professional and scientific team including neuroscientists and biostatisticians brings together experts in clinical and experimental medicine, neurology and neuropsychology in the fields of cognitive, molecular and behavioral neuroscience to objectively and rigorously characterize the physiological basis of perceived “brain fog and fatigue” associated with PCNS. By refining and validating a battery of clinical, neuropsychological, blood based molecular, radiological, static and dynamic assessment of vision, visually driven attention and actions, we seek to use machine learning to develop an analysis algorithm that can evaluate and enhance decision making based on our comprehensive toolkit for diagnosing and directing PCNS rehabilitation (Asadi-Pooya et al., 2021; Asadi-Pooya, Akbari, et al., 2022; Bai et al., 2022; Cardinali et al., 2022; Chatys-Bogacka et al., 2022; Chaves-Filho et al., 2023; Chudzik et al., 2022; Hugon, 2022; Hugon et al., 2022; Humphreys et al., 2021; Jain et al., 2024; Jennings et al., 2022; Kao & Frankland, 2022; Kavanagh, 2022; Kingstone et al., 2020; Leng et al., 2023; Low et al., 2017; Naeije & Caravita, 2021; Reinfeld, 2023; Reiss et al., 2023; Stefano, 2021; Stefano et al., 2021; Stefano et al., 2022; Watanabe et al., 2022; Wijesundera et al., 2022; Wose Kinge et al., 2022) that can also be used to objectively evaluate the effectiveness of the treatment strategies.

Tele-neurology and tele-neurorehabilitation play a crucial and initial role in our approach, offering scalable solutions to reach diverse and vulnerable populations by bridging distance and social communication gaps in medical and healthcare access(Kingstone et al., 2020; Li et al., 2024). In Australia such distance enabling social technologies will enable remote clinical and neuropsychological assessment and treatment, ensuring that patients with PCNS receive the specialized expert care they need regardless of geographic, timing or socio-economic barriers(Messler et al., 2022). Our research will not only contribute to a better biological understanding of the aetiology of PCNS but also set a precedent for leveraging telemedicine in the broader context of management of neurological disorders.

By integrating advanced computer based neuropsychological and visually driven attention and cognitive diagnostic tools with telehealth interactions, with GP authorized blood based assessment and house prescribed radiology where available, we aim to pave the way for more equitable and effective personalized care for individuals suffering from PCNS and other neurological disorders (Low et al., 2017; Wijeratne & Wijeratne, 2021; Wijeratne, Wijeratne, et al., 2020). Our Systems Neuroscience Toolbox (SNTB) represents a significant step forward in the quest to alleviate the global burden of brain disorders, offering hope and improved quality of life for millions worldwide (Alharthi et al., 2022; de Miranda et al., 2022; Feng et al., 2023; Huang et al., 2022; Lv et al., 2022; Sharma & Sarode, 2022; Shen et al., 2023; Siska et al., 2021; Thakur et al., 2023; Yang et al., 2021; Zou et al., 2021).

Proposed Systems Neuroscience Toolbox

The Systems Neuroscience Toolbox is designed to provide targeted measures that facilitate the correlation of self-reported symptoms with objective speed of processing assessments. SNTB includes tools for evaluating the speed of activation of visual attention, visually driven cognition, visuomotor behaviors, and glucose utilization via Positron Emission Technology (PET) imaging in those experiencing PCNS (Amiruddin et al., 2024). A focus on the visual system and information processing stems from understanding of the vast volume of brain vision occupies to drive the 90% of human behaviour and its relation to brain effort, cortical metabolism. The retina projects to multiple sites including thalamus, superior colliculus and pulvinar in the mid brain, and geniculo-cortical pathways that together drive visual attention visuomotor activity, perception, working memory, higher cognition (Corbetta & Shulman, 2002) and emotional processing. The retina also projects to hypothalamus and drives circadian rhythms and sleep and mood behaviours that include modulation of stress and anxiety. As the site of circadian, neuroendocrine and autonomic nervous system responses to stress hormones, via the Hypothalamus Pituitary Adrenal Axis and Sympathetic-Adrenal Medullary (SAM) pathway). The rapid simple multifocal Visually Evoked Potential (mfVEP) also allows measurement of latency and speed of conduction and neural recovery of the visual pathway and assessment of speed of processing and cognitive recovery. Spatially sensitive FMRI will be used for brain localization of function and Magnetoencephalography (MEG) and its temporo-spatial sensitivity will be included where possible to assess brain neuroanatomy and regional connectivity (Heitmann et al., 2023)

AI and machine learning techniques are currently in use in pathway analysis of blood based human proteomics but will now be extended to integrate and correlate analysis of clinical, psychophysiological, radiological, and molecular data. This staged approach aims to precisely deﬁne PCNS and “brain fog” while identifying physiologically and endocrinologically safe therapeutic agents for a proposed clinical trial in 2026 (Ahmad et al., 2023). Expertise in use of Toolbox techniques developed over the last 25 years also addresses the responsibility to increase and disseminate biological and psychoneuroimmunology knowledge of the of this post-viral disorder while advocating for better medical management universally through medical communities and offering a telehealth point of contact across Australia. The desire of patients to be taken seriously and new knowledge made available to other medicos was front and centre highlighted during our initial Consumer Group Forum on October 29, 2023, Melbourne, Australia.

Reports of “brain fog” and fatigue following recovery from SARS-CoV-2 infection, without evidence of lung or heart abnormalities, have been common since early 2020 (Akbarialiabad et al., 2021; Baig, 2021; Clough et al., 2021; Johansson et al., 2021; Kingstone et al., 2020; Raveendran et al., 2021; Schmidt, 2021; Stefano, 2021; Thurnher et al., 2021; Yong, 2021). Such symptoms suggest lasting pro-inflammatory effects that are separate from lung capacity and potential hypoxia and are more often associated with persistent impaired mitochondrial energy functions both peripherally and centrally (Karimi et al., 2020; Wijeratne & Crewther, 2020, 2021; Wijeratne, Gillard Crewther, et al., 2020; Wijeratne et al., 2021; Wijeratne, Sales, Karimi, et al., 2020; Wijeratne, Sales, Crewther, et al., 2020; Wijeratne & Wijeratne, 2021; Wijeratne, Wijeratne, et al., 2020). Thus our research aims to understand “brain fog” and mental fatigue from a systems neuroscience perspective and also aims to apply this knowledge to create an educational platform, the PCNS website, for use by both the community and healthcare systems. The ultimate goal of our research is to apply the Systems Neuroscience Toolbox as a monitoring system in a clinical trial targeting mitochondrial energy enhancement.

We will also utilize routine blood analyses for a quick assessment of peripheral inflammation, along with in-depth profiling of proteomics, phosphoproteomics, and metabolic function within peripheral blood mononuclear cell (PBMC) fractions (Cao et al., 2022; Díaz-Resendiz et al., 2022; Dirajlal-Fargo et al., 2024; Huecksteadt et al., 2024; Kakugawa et al., 2024; Khanaliha et al., 2024; Salihoğlu et al., 2023; Wijeratne & Crewther, 2021) PBMCs, which include lymphocytes, monocytes, dendritic cells, and low-density neutrophils, play a significant role in both the innate and adaptive immune systems. Dysfunctions in these cells have been linked to the symptomatology of Post-COVID Neurological Syndrome (PCNS) (Wijeratne & Crewther, 2020; Wijeratne, Gillard Crewther, et al., 2020; Wijeratne et al., 2021; Wijeratne & Wijeratne, 2021). Research has also shown that changes in global protein abundance and phosphorylation profiles are associated with PBMC dysfunction in acute COVID-19 cases (Cao et al., 2022; Díaz-Resendiz et al., 2022; Dirajlal-Fargo et al., 2024; Huecksteadt et al., 2024; Kakugawa et al., 2024; Khanaliha et al., 2024; Salihoğlu et al., 2023). Furthermore, in PCNS, alterations in inflammatory pathways and associations between oxidative phosphorylation proteins and neurological symptoms like ‘brain fog’ have been identified (Molnar et al., 2024; Pizzamiglio et al., 2023). Thus to explore these mechanisms further, we will employ label-free proteomics and phosphoproteomics to investigate immune cell function changes over time in individuals with PCNS and hopefully during recovery as we have done following stroke Nygen et al. (2020) and in ocular tissue (Riddell and Crewther, 2017). This will be combined with Seahorse respirometry and TCA cycle metabolomics to provide a detailed understanding of the biological signaling cascades involved (Hirschberger et al., 2022; Huynh et al., 2023; Liu et al., 2021; Wang et al., 2021). The insights gained from these analyses will help identify the most effective monitoring techniques and targeted interventions for addressing “brain fog” in future clinical trials (Hirschberger et al., 2022; Huynh et al., 2023; Liu et al., 2021; Wang et al., 2021).

A significant aspect of our project is the use of telemedicine for remote assessments and interventions. This approach will ensure that individuals affected by PCNS, especially those unable to attend a research institute, have equitable access to care. By integrating telehealth solutions, we can maximize the reach and impact of our research, improving the quality of life for a broader population. Our team of experienced researchers will lead this effort, ensuring that both remote and in-person interactions are used effectively to meet our research objectives.

Our overarching aim is to utilize the Systems Neuroscience Toolbox to comprehensively characterize the subjective, clinical, behavioral, and molecular underpinnings of PCNS, with a particular focus on “brain fog.” This comprehensive characterization will allow us to develop practical clinical and biomarker screening tools and provide evidence-based guidance for potential pharmacological or behavioral interventions.

Study Design

Our study is structured around four major data collection streams:

Telehealth assessed consumer-reported symptoms and clinical screening using well validated screening tools like the DASS-21

Psychophysiology via telehealth and face-to-face assessments

Brain imaging, FMRI, MEG and mfVEP

Molecular tests

Each stream incorporates well-validated techniques, drawing on our team's extensive research experience (Brown et al., 2017; Brown & Crewther, 2017; Brown et al., 2020; Ebaid & Crewther, 2018, 2019, 2020a, 2020b; Ebaid et al., 2017a, 2017b; Low et al., 2017; Nguyen et al., 2020; Peters, Bavin, Brown, et al., 2020; Peters, Bavin, & Crewther, 2020; Peters et al., 2021; Peters et al., 2019; Pickering et al., 2023; Wijesundera et al., 2020, 2022). This study employs a collaborative, multicenter approach, including Western Health and regional areas of western and northern Victoria, to ensure a diverse participant pool. The use of telemedicine for remote data collection and analysis is central to this design. In cases where participants can attend a nominated clinic, face-to-face testing and blood sample collection will be conducted. Participants will complete consumer-reported history and symptom questionnaires remotely via telemedicine platforms such as REDCap, which facilitates secure remote participation.

1&2-Telehealth -Clinical Screening and Timed Psychophysics: Towards Defining ‘Brain fog’ as a Behavioral Phenotype

We aim to utilize our well-established and validated test battery to assess age-appropriate brain function and differentiate viral-induced “brain fog” as a distinct behavioral phenotype. The evidence surrounding “brain fog” and “fatigue” as distinct neurological symptoms remains notably sparse and underdeveloped. These symptoms are often reported subjectively, lacking clear, objective biomarkers or standardized diagnostic criteria, which complicates their recognition and study within the broader spectrum of neurological conditions. In the context of PCNS, the challenge lies in distinguishing these symptoms from other potential causes and correlating them with underlying neurological changes specific to PCNS. This underscores the importance of rigorous, multi-modal assessment approaches, like the Systems Neuroscience Test Battery (SNTB), to validate and objectively characterize these symptoms, thereby advancing our understanding and management of PCNS. As indicated this will be achieved through clinical screening, eye movement and gaze pattern analysis, and custom psychophysical tasks. These tasks will quantify temporal and spatial accuracy in attention shifting and the neural speed of accessing language lexicons and motor vocalization. By objectively evaluating changes in processing speed and cognitive performance (reaction times and accuracy), we will gain further specific insights into normal and impaired brain function. These findings will be correlated with brain imaging and molecular data, collected both during COVID-19 episodes and “brain fog” incidents, as well as longitudinally during recovery.

Hospital Based Radiological Assessments

Radiological assessments will profile structural and functional changes in the brain during and after episodes of “brain fog” and PCNS symptom recovery. These assessments will utilize methodologies such as PET (Positron Emission Tomography) to measure cortical glucose activation, 3 T MRI for structural imaging, and Swinburne's MEG (Magnetoencephalography) to map brain activation during cognitive tasks. If funding allows, advanced imaging with a 7 T MRI scanner at UniMelb will be used for enhanced sensitivity to structural changes at the sub-voxel level.

The use of multiple advanced imaging techniques, will provide unparalleled insights into the structural and functional changes occurring in the brains of PCNS patients over time. These longitudinal imaging modalities will allow observation of the neural correlates of symptoms like “brain fog,” giving us a much clearer and more detailed picture of how PCNS affects activation during brain function at a physiological level across the recovery trajectory. The potential inclusion of multi-point 7 T MRI, with its enhanced sensitivity, should further our understanding by revealing subtle changes in activation and connectivity of various brain structures across the recovery trajectory that might be missed by less sensitive techniques and single point assessments. These insights are invaluable for identifying potential biomarkers of PCNS, which could be used to develop diagnostic tools and monitor the effectiveness of therapeutic interventions

Gp Initiated Molecular Assessments

Blood based assessments will focus on profiling interactions between immune, metabolic/mitochondrial, and ER stress pathways in Post-Acute Sequelae of COVID (PASC). This will involve routine pathology tests (e.g., WBC differential, lipid profiles) and the isolation of PBMCs for protein abundance and signaling assessment using label-free proteomics and phosphoproteomics. Metabolic function, particularly mitochondrial function, will also be explored using Seahorse respirometry and targeted TCA cycle metabolite profiling.

Our hypothesis is that mitochondrial activity in leukocytes will be reduced during long-haul COVID, correlating with radiological findings of glucose uptake via PET scanning during cognitive tasks that induce mental fatigue. By understanding the biological and clinical features that define PCNS and focusing on “brain fog,” we aim to identify actionable targets for intervention. This will include exploring drug repurposing opportunities through databases like DrugKiNET and the Connectivity Map (CMap) to identify existing drugs with potential efficacy in treating inflammation associated PCNS.

More sophisticated molecular assessments, including proteomics, phosphoproteomics, and Seahorse respirometry, offer the potential to delve into the cellular and metabolic dysfunctions associated with PCNS. By examining changes in protein expression and mitochondrial function across the recovery trajectory, identification of specific pathways that are disrupted in PCNS should be possible.

Such molecular-level understanding is crucial for the development of targeted therapies. For instance, if mitochondrial dysfunction can be identified as a key driver of PCNS symptoms, interventions aimed at enhancing mitochondrial function could be prioritized in clinical trials. Similarly, understanding how immune cell function is altered in PCNS could lead to the development of immunomodulatory treatments. These insights will be invaluable for identification of potential biomarkers of PCNS, that could be used to develop diagnostic tools and also to monitor the effectiveness of therapeutic interventions.

Bioinformatics and Future Directions

The integration of bioinformatic analyses into our study will facilitate synthesis and correlation of vast amounts of data that are unlikely to be apparent through traditional analytical methods. Bioinformatic differential protein and pathway analyses will be integrated with data from across the research program. Utilizing resources like the Broad Institute's drug repurposing hub, we aim to guide our analysis and identify therapeutic targets. Furthermore addition of machine learning and other advanced data analysis techniques, will aid development of predictive models that can identify which patient types are most at risk of developing severe PCNS and which interventions are likely to be most effective for different patient subgroups. This personalized approach to treatment is one of the key advantages of the systems neurology approach.

Availability of Diagnostic Technologies in the Research Area

The geographical area targeted for our research includes a diverse mix of urban centers and remote, medically underserved regions. Despite the challenges associated with conducting research in these varied locations, the availability of advanced diagnostic technologies such as PET, 3 T MRI, and Swinburne's Magnetoencephalography (MEG) is well-established in the urban hubs. For example, Melbourne, where our central research activities will be based, is equipped with state-of-the-art facilities, including a 7 T MRI scanner at the University of Melbourne. This infrastructure supports the rigorous methodologies required for our investigations.

In contrast, remote areas may have limited access to such high-end diagnostic tools. To address this disparity and uphold the inclusive nature of our research, we plan to use a stratified approach. Patients in remote areas will undergo initial assessments using more accessible tools such as telehealth-based cognitive evaluations and portable neuroimaging devices. When necessary, patients from these regions will be transported to urban centers for further testing using advanced technologies, ensuring that the same level of diagnostic accuracy is applied across all study participants. This approach not only justifies our claim of inclusivity but also ensures coherence between our stated objectives and the methodologies employed.

Differences and Integration of the SNTB with Existing Tools

The proposed SNTB (Systems Neurological Testing Battery) will significantly differ from pre-existing tools by integrating a comprehensive, multi-modal assessment approach that combines conventional neurological testing and advanced molecular and neuroimaging techniques. Unlike traditional clinical approaches tools that often focus on a singular aspect of neurological function, the machine learning analysis system developed to integrate the tools of the SNTB is designed to provide a holistic overview by incorporating data from PET, MRI, MEG, and other diagnostic technologies. This integrated approach allows for a more nuanced understanding of the neurological syndromes under investigation, particularly in post-COVID-19 conditions where multiple systems may be concurrently affected.

The SNTB will also be adaptable, allowing for the inclusion of emerging technologies and methodologies as they become available. This adaptability ensures that our research remains at the cutting edge of neurological assessment, but most importantly our integrated approach means the vascular system patients will be concurrently assessed quantitatively molecularly, bioenergetically, and psychoneuroimmunologically providing insights that are both comprehensive and clinically relevant. By integrating various diagnostic modalities, the SNTB will offer a more complete and detailed analysis of patient conditions, ultimately contributing to more personalized and effective treatment strategies.

Sources of Funding and Cost Considerations

The investigations proposed in this research will be funded through a combination of institutional grants and external funding sources dedicated to advancing neurological research. Specifically, funding has been secured from Australian national health research funding schemes and internal funding from the University resources and health service resources. These funds cover the costs associated with the use of high-end diagnostic technologies, patient transportation, and data analysis, ensuring that patients do not bear the financial burden of these investigations.

Conclusion

The proposed study aims to fill critical gaps in our understanding of Post-COVID Neurological Syndrome (PCNS), a condition affecting many individuals long after their initial recovery from COVID-19. PCNS presents a complex array of symptoms, including “brain fog,” fatigue, and cognitive impairment, which traditional diagnostic and treatment methods have struggled to address comprehensively. By leveraging the Systems Neuroscience Toolbox (SNTB), we offer a novel, integrative approach that considers the multifaceted nature of PCNS.

The SNTB framework combines telemedicine, advanced imaging, molecular assessments, and bioinformatics to provide a holistic view of PCNS. This systems-level approach recognizes that PCNS likely involves intricate interactions between inflammation, immune response, and neural function, rather than being merely a residual effect of the initial infection. By examining these complex dynamics, we aim to uncover the underlying mechanisms of PCNS and develop more effective interventions.

The potential impact of the SNTB extends beyond PCNS, offering valuable tools and methodologies that could be applied to other neurological disorders with similar symptoms, such as chronic fatigue syndrome and neurodegenerative diseases. The insights gained from this study could lead to the identification of reliable biomarkers and the development of targeted therapies, improving outcomes for a broad range of patients.

In summary, the Systems Neuroscience Toolbox represents a transformative approach to the study and treatment of Post-COVID Neurological Syndrome. By integrating cutting-edge technologies and a systems-level perspective, this study has the potential to advance the field of neurology significantly. The results will not only enhance our understanding of PCNS but also provide a model for addressing other complex neurological disorders, ultimately leading to earlier diagnosis and more effective treatments for patients worldwide.

Footnotes

ORCID iD

Tissa Wijeratne

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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