Investigating the neural underpinnings of Chronic Fatigue: A multi-modal approach, 2021, Rayhan (PhD thesis)

Source: Howard University
Date: April 16, 2021
URL:
https://www.proquest.com/openview/c0a823ec519e5e6acdd89c29ff4a4b2a/1


Investigating the neural underpinnings of Chronic Fatigue:
A multi-modal approach
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Rakib U. Rayhan
- Department of Physiology and Biophysics, Howard University,
Washington DC, USA


Abstract

Unrelenting pathological fatigue is a common symptom across a wide range
of diseases. Despite its near ubiquitous reporting, little is known
about the neurobiology of fatigue. Absence of a clinical consensus
definition, meaningful treatment options, and reliable methods that
allow for the detection and study of fatigue further hamper our
understanding. In the study of clinically relevant fatigue, its
presentation is often secondary to a diagnosed illness such as Multiple
Sclerosis (MS) or cancer.
However, there are two illnesses where
unrelenting fatigue is the primary feature: Gulf War Illness (GWI) and
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Diagnoses
are based on case definition criteria that solely relies on subjective
symptoms and their duration. Lack of identified pathophysiological
mechanisms, use of subjective criteria for diagnoses, and symptom
overlap with psychiatric illnesses make ME/CFS and GWI debatable
syndromes within the field of medicine. Despite the controversy, both
share a very notable symptom that may further our understanding of
fatigue. This cardinal complaint is known as post-exertional malaise
(PEM) and is defined as an increase in the severity of fatigue and other
symptoms from baseline following a physically demanding activity. Unlike
other reported symptoms, PEM is associated with a distinct event that
leads to a before and after clinical state. The causal nature of PEM
presents an opportunity to study fatigue and worsening symptomatology in
a controlled research setting. Previous attempts have been made to
recapitulate PEM, but did not provide reproducible findings. To address
those limitations, we developed a novel protocol that subsequently
modeled PEM using a multi-day paradigm where an fMRI brain scan was
taken before and after two fatiguing exercise stressors. Data presented
provides sufficient proof-of-principle that the protocol successfully
modeled PEM. Initial studies were completed in GWI subjects and showed
disrupted cortical activity within Working Memory (WM) and Default Mode
Network (DMN) cognitive domains. Follow-up studies in a larger cohort of
ME/CFS subjects reproduced similar post-stressor alterations within the
DMN and its underlying functional nodes. As a corollary, modalities
assessing gray and white matter provided further evidence that central
nervous dysfunction may underlie the chronic symptoms of these
disorders. From a broader perspective, modeling PEM using the developed
protocol may hold utility in studying chronic fatigue in other
pathological states and for the first time provide accurate detection of
this almost universal symptom in a clinical setting.

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