Investigation into the Pathophysiology & the Objective Neurophysiological Measurement of Cancer-Related Fatigue (ME/CFS control group),2020, O'Higgins

[Dolphin]

This study used ME/CFS patients as a control group. I haven't read it yet.

Free full text: <http://www.tara.tcd.ie/handle/2262/92573>

O'HIGGINS, CIARA MARIE, Investigation into the Pathophysiology and the Objective Neurophysiological Measurement of Cancer-Related Fatigue in a Pre-Treatment Cancer Cohort, Trinity College Dublin.School of Medicine, 2020

Abstract

Cancer-related fatigue (CRF) is one of the most common, debilitating, highly prevalent and unrelenting symptom experienced by patients through all stages of the cancer trajectory and often into survivorship (Berger et al., 2015a; Barsevick et al., 2010). Two factors, central and peripheral, can contribute to fatigue in CRF sufferers. Central fatigue involves difficulty in initiating or sustaining voluntary activities (Davis and Walsh, 2010; Gandevia, 2001), due to challenges with self-motivation, perceived demand and internal biochemical cues, without demonstrable cognitive failure or motor weakness (Davis and Walsh, 2010; Finsterer and Mahjoub, 2014). Peripheral fatigue is caused by failure of either muscle excitation-contraction mechanisms or metabolic changes within the muscle which generally manifest at the affected muscle site and can be described as a progressive loss of power or any exercise induced reduction in the ability to exert muscle force or power. (Davis and Walsh, 2010; Edwards, 1981; Gandevia, 2001; Prinsen et al.).

Despite the high prevalence rates, CRF is under-diagnosed and under-treated and perhaps due to its perceived multifactorial nature no universal definition or standard objective measure exists. Current CRF evaluation is based on subjective questionnaires, some of which focus on examining fatigue severity while others address its affective, functional and/or cognitive impact. However, subjective evaluation does not provide insight into the possible underlying aetiologies (cause of CRF) and/or pathophysiology (functional changes as a result of CRF) which remains undetermined and obscured. Therefore, to increase our knowledge and understanding of CRF, a standardised means to objectively assess CRF and its manifestations must be developed.

The primary focus of this research was to build on the literature, design and test an objective measurement method employing neurophysiology, electroencephalography (EEG) and electromyography (EMG), which may enhance assessment and help clarify any possible underlying mechanisms of CRF and to address the gaps in the current knowledge about relative contribution of central and peripheral mechanisms, if any. This was to be achieved by examining independent and combined EEG and EMG signal changes for CRF sufferers and healthy controls during a fatigue inducing motor task in a clinical outpatient setting. In addition, the clinical applicability of the objective method in an outpatient clinic was evaluated. The method was assessed in a pre-treatment cancer cohort, which had not been previously examined.

In this research, which was carried out over a series of studies, all participants performed a fatigue-inducing task consisting of a sustained isometric contraction at 30% of their maximal force until failure due to fatigue. A hand-held dynamometer was employed in the studies and EEG and EMG were simultaneously recorded during the fatigue-inducing task. The main findings demonstrated that at diagnosis CRF was evident, prior to any fatigue inducing cancer treatment and may suggest a more centrally mediated disorder (i.e. fatigue that originates at the central nervous system (CNS) which decreases the neural drive to the muscle). A metric to objectively evaluate correlates of CRF was developed and its applicability to a routine clinical setting was confirmed.

The studies undertaken also provided comparisons between CRF and chronic fatigue syndrome (CFS), sufferers who share overlapping symptoms, onset, and a decreased quality of life. It was hypothesised that these two patient cohorts would show similar results. However, this was not observed, with CFS sufferers recording higher levels of fatigue. A possible explanation for the CFS results was perhaps due to the diagnostic process, whose symptoms must be evident and recorded for six months minimum prior to a diagnosis being confirmed.

Another element recognised as relevant to the studies undertaken was that results recorded may be impacted by participants’ lack of sustained attention to the task or mind wandering. Cancer patients often describe attentional problems, finding it interferes with their cognitive and motor performance, which in turn may affect their ability to complete the task required within this research. Thus, an important question arose as to whether failure during the task was caused by fatigue or inattention. A retrospective analysis of the EEG data obtained during the fatigue inducing motor task in the CRF showed no difference in what may be considered “mind wandering” when compared to healthy controls. However, as this was a retrospective study, no direct inference could be made as to whether the individuals did experience mind wandering or if there was comparability between the two groups. Nevertheless, by considering the impact of sustained attention and mind wandering this work highlights another element to be considered in research and what cognitive changes may occur with CRF.

In conclusion, an objective method employing EEG and EMG was developed and tested which added to existing measurement knowledge of CRF. This was achieved by examining EEG and EMG signal changes for CRF sufferers and healthy controls during a fatigue inducing motor task in a clinical setting with clinical applicability and participant acceptability recorded. Results of this research demonstrated that CRF and CFS had higher subjective fatigue and both CRF and CFS groups exhibited a reduced ability to perform the motor task and perceived physical exhaustion sooner (Lower MVC and endurance time) than healthy controls.

The further development of objective methods of CRF assessment may provide clinicians with objective data which in turn could aid in designing more personalised therapeutic intervention of CRF symptoms and enhance the clinical outcomes of treatment.

 

[Snow Leopard]

Hypotheses of fatigue are discussed, though managed to overlook the endothelial dysfunction hypothesis - an aspect that could be shared between CRF and CFS. The usual (questionable) demarcation between central and peripheral fatigue that ignores any couplings between metabolism and regulation of motor nerve sensitivity.


Also the common myth of slow twitch vs fast twitch muscle fibres - when twitch speed of muscle fibres actually has a Gaussian distribution, so "slow" and "fast" twitch fibres are just the tail ends of the distribution.

The discussion of contractile properties seemed to claim that the "central activation failure" is due to lack of central drive, when the study cited for CFS found the opposite - increased EEG activity in the theta band and increased motor activity-related cortical potential suggesting increased concentration/voluntary motor effort.
(example of increased theta power: https://www.tandfonline.com/doi/abs/10.1080/00222895.2019.1635983?journalCode=vjmb20)

Cited CFS study: https://pubmed.ncbi.nlm.nih.gov/15351380/ (Siemionow et al. 2004)

The MRCP NP data in the current study are the first to show that cortical signals representing voluntary effort for voluntary motor performance are greater in CFS. Based on the force data that the muscles were more severely fatigued in the CFS than control subjects (force was below target even with maximal effort, Fig. 2), it is reasonable to expect a higher level of voluntary-command signal for the ongoing motor task. This higher level of cortical signal related to controlling the motor task might have reflected a greater effort to recruit additional motor units to compensate for losses of force-generating capability of the muscles or to disinhibit the motor neurons whose activities might have been suppressed by inhibitory inputs from groups III and IV aferents that are particularly active during muscle fatigue (Garland et al., 1988, 1991; Hayward et al., 1988, 1991). Based on the results of this study, however, it is not clear whether increased MRCP NP amplitude indicates impairments in the peripheral neuromuscular system or CNS.

Nonetheless, the studies in the thesis provide some interesting data on both EMG and EEG differences during sustained contractions at 30% of MVC, with 10 seconds of rest in-between, until force dropped below 27% of MVC. Do note that they were not age/sex matched. Both CRF and CFS groups had greater statistical differences in normalised EMG amplitudes compared to healthy controls, despite lower absolute force outputs.

 

[rvallee]

Central fatigue involves difficulty in initiating or sustaining voluntary activities (Davis and Walsh, 2010; Gandevia, 2001), due to challenges with self-motivation, perceived demand and internal biochemical cues, without demonstrable cognitive failure or motor weakness (Davis and Walsh, 2010; Finsterer and Mahjoub, 2014). Peripheral fatigue is caused by failure of either muscle excitation-contraction mechanisms or metabolic changes within the muscle which generally manifest at the affected muscle site and can be described as a progressive loss of power or any exercise induced reduction in the ability to exert muscle force or power. (Davis and Walsh, 2010; Edwards, 1981; Gandevia, 2001; Prinsen et al.).

This is the failure right here. It mixes motivation with fatigue and various manifestations of what could be fatigue but is unclear are the same thing. Words have meaning. Use those words with their proper meaning. This is something we learn in kindergarten and even before. If you call a cookie a brush and expect people to give you cookies as you insist on calling it a brush your mommy and/or teacher is going to take you aside and explain to you why it's important to use the proper words for their intended meaning and nothing else (poetic license aside anyway).

Basically in medicine fatigue is a word used to describe any of a number of things, from motivation to sleepiness to stamina and many other different and unrelated things. This is why we've seen nothing but failure. You cannot do formal science with this much confusion over basic vocabulary. When the same word can mean about a half-dozen different things there will be nothing but confusion. Especially as those alternative meanings have their word in both common and clinical use. Sleepiness is sleepiness whether you are a child or a sleep specialist. Everyone understands what it means. To use fatigue to mean the same thing is just complete nonsense. Yes, everyone gets tired. No, you're not clever for bringing this unrelated thing to a discussion over a different thing.

Until medicine sorts out this deliberate mess I don't think any progress can be made. The foundation of science is to be able to tell things apart from other things. This is how it all begins. When you fail at the very first step you will do nothing but wander aimlessly. Because while you wander into the vast wilderlands of imaginationland people are not doing well at all as a result.

Do better. Please. For the literal sake of millions do a lot better than this.

 

[Sean]

The discussion of contractile properties seemed to claim that the "central activation failure" is due to lack of central drive, when the study cited for CFS found the opposite - increased EEG activity in the theta band and increased motor activity-related cortical potential suggesting increased concentration/voluntary motor effort.
(example of increased theta power: https://www.tandfonline.com/doi/abs/10.1080/00222895.2019.1635983?journalCode=vjmb20)

Cited CFS study: https://pubmed.ncbi.nlm.nih.gov/15351380/ (Siemionow et al. 2004)

Interesting.

 

[Trish]

I have only read the abstract, but it sounds to me as if it might be a useful way of objectively measuring muscle fatiguability in ME, even if it doesn't explain the mechanisms of that fatiguability.

That seems a useful step forward to me. I'd rather squeeze a hand held dynamometer and have my EEG and EMG measured while doing it than fill in the Chalder Fatigue Questionnaire!

 

[Snow Leopard]

I have only read the abstract, but it sounds to me as if it might be a useful way of objectively measuring muscle fatiguability in ME, even if it doesn't explain the mechanisms of that fatiguability.

That is not what was shown though. This is not a specific biomarker. It is difficult to control for effort (and difficult to directly examine the coupling between peripheral and central fatigue), so it is easy for researchers, including the authors of this thesis to simply conclude that the issue is of "centrally mediated disorder" and not delve any deeper.

Oh and statements like:

Many treatments and therapies have been examined and suggested and recent reviews conclude that cognitive behavioural therapy and exercise therapy have a proven benefit.

for good measure.

 

[Trish]

Thanks @Snow Leopard. I do understand it's not specific enough to be a biomarker. I was thinking more of it's possible use a before and after outcome measure for treatment trials, to be used alongside other objective measures and instead of fatigue questionnaires like CFQ. Less exhausting than the 6 minute walk or the step test or CPET perhaps.

 

[Snow Leopard]

Thanks @Snow Leopard. I do understand it's not specific enough to be a biomarker. I was thinking more of it's possible use a before and after outcome measure for treatment trials, to be used alongside other objective measures and instead of fatigue questionnaires like CFQ. Less exhausting than the 6 minute walk or the step test or CPET perhaps.

I was thinking which would I rather do, and the answer is none of them, but I guess I'd rather do the 6MWT, followed by this test, followed by the step test followed by the CPET in last place if forced to make a choice.

The protocol:

Once the participant was ready to commence the motor fatigue task, a demonstration of the task and a short trial was performed to familiarise the participant with the task. Any uncertainties were addressed until full comprehension was confirmed by the participant. In commencing the test, each participant was asked to perform three MVCs using the dynamometer, with a 10 second rest period in-between to allow for recovery. The highest of these three forces was entered into the LabChart programme and used to calculate 30% of the participants own MVC. This 30% target value was presented as a yellow horizontal line on the task screen located in front of the participant. The participant was then instructed to perform a sustained voluntary contraction at the 30% target value for as long as possible using the hand held dynamometer, until selfperceived exhaustion. Occasionally, the participants were verbally encouraged to continue, to prevent an early termination of the task due to motivational reasons. The experiment stopped once the target force fell below 27% (10% of 30% MVC) of the participant’s MVC for more than three seconds. This was communicated to the participant by a loud beep. After this beep, there was a three minute resting period where the participant was asked to remain in the same position without squeezing the dynamometer. After the three minute rest period, another beep signalled the end of the experiment. A questionnaire (Appendix B) was provided to CRF participants to request feedback regarding the acceptability and feasibility of the task and the study set up.

Also, on second reading, I note the curious omission of the participant reported acceptability in the second (CRF/CFS) study. I don't know why the thesis was accepted without this being reported.

 

[spinoza577]

That is not what was shown though. This is not a specific biomarker. It is difficult to control for effort (and difficult to directly examine the coupling between peripheral and central fatigue), so it is easy for researchers, including the authors of this thesis to simply conclude that the issue is of "centrally mediated disorder" and not delve any deeper.

But it´s doubled easy. Even if there is a centrally mediated disorder indeed, well hinted or maybe even confirmed (if possible) by any improved method your are requesting, it does not say that this centrally mediated disorder is driven by any proportion that can be influenced psychologically.

They failed already on a logical level, regardless of how this empirical investigation has come out.

Nerves should be able to fail on a very technical level, maybe even for simple reasons. Such principal possibility is not difficult to see. Their twitching doesn´t provide what they then convey.

Oh and statements like:

Their negative finding, and any negative finding, does not add evidence to these "suggested proves".

 

[alex3619]

The usual (questionable) demarcation between central and peripheral fatigue that ignores any couplings between metabolism and regulation of motor nerve sensitivity.

My current hypothetical stand is the distinction may be arbitrary. It may just be putting a different label to the same underlying physiology.

 

[alex3619]

followed by the CPET in last place if forced to make a choice

I am hoping that the nanoneedle, or other blood test, might decrease the need for exercise tests. Force our blood cells to exert and see their failure ... that is enough.