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Fatigue as a Window to the BrainReview - Fatigue as a Window to the Brain
by John DeLuca (Editor)
MIT Press, 2005
Review by Roy Sugarman, Ph.D.
Oct 3rd 2006 (Volume 10, Issue 40)

Some symptoms are so ubiquitous that their inclusion in any diagnosis is too non-specific to be of value, and fatigue is one of those symptoms. A symptom which may equally present in multiple sclerosis, depression, brain injury, or just about anywhere else is difficult to investigate, and given its subjective nature, difficult to quantify objectively. Its effects are equally damning for many physical functions, and cognition is just another one of them complicating the view of the clinician and researcher alike. Not only is fatigue so common, but it is unlikely that the quality or quantity of fatigue is directly related to how severe the underlying condition might be, or how this relates to cognition.

The term "as a window to the brain" indicates that the editor will set his chosen authors to work using fatigue as a way of gaining insight into the processes of the brain. The foreword informs us that whatever fatigue in a specific condition might be, it is predominantly of central origin; hence the most promising approaches to its alleviation are neurobiological if they are anything. By this, it is saying that we are to move away from trying to correlate lesions in the brain with fatigue: rather, we are to set about studying the impairment itself. It is therefore hoped that the book will drive research along to finding the underlying causes, or at least, inform us more fully as to how the brain works.

To this end the book is then divided into 6 parts, the first on the nature of fatigue. Sensibly, there is a starting point in examining the history of research into fatigue, or at least interest in the phenomenon, and its epidemiology. A second chapter serves as an introduction to assessing fatigue, and the third part of this first section is devoted to a chapter on the phenomenon of cognitive fatigue, together with its measurement. Torres-Harding and Jason take on the first part, covering an array of illnesses, including the once present in DSM terms 'neurasthenia' which enjoyed a long time as a popular diagnosis in Russia while disappearing from the DSM III. As with most aspects of humanity where psychiatry will attempt to play a role, while often being shunned, the chapter presents an argument for a biopsychosocial approach, where many sufferers of CFS for instance would deny the need for psychiatry at all. Christodoulou attempts to show how fatigue, like pain, can be a both subjective and objectively measured phenomenon, reviewing the techniques. John DeLuca himself comes into Chapter 3 to tackle the empirical research of inducing mental fatigue via several interventions to simulate and examine the effects on the neural substrate of prolonged activity. This last is not an easy task, as experts such as Lezak make commonsense evaluations of how to approach assessment of cognition where fatigue is an issue, without any real clinical evidence to support her assertions. There is also of course little understanding of the elusive nature of an objective measure of fatigue that would enlighten as to the mechanisms of fatigue. It is clear that the field is still in its infancy, but a start has been made as the pages of references at the end of this chapter suggest.

On to part two, which section approaches the many conditions in which fatigue might emerge as a criterion or sequel. Krupp and the aforementioned Christodoulou with Schombert added on, look at Multiple Sclerosis, which rightfully occupies pole position in such a section. Clinical aspects are evaluated in terms of pathophysiology, immune system dysregulation, CNS mechanisms and impaired nerve conduction as well as neuroendocrine and neurotransmitter dysregulation. The relationship with the ANS is however not straightforward, together with the co-factors of simply reduced energy, and others such as pain, sleep problems, mood disorders, medication and so on. Fatigue after stroke is handled by Stulemeijer, Fasotti and Bleijenberg in the next chapter, a neglected condition in this regard and like pain after stroke, it can be disabling and hard to treat, from either focal or widespread lesions. Fatigue after brain injury is next, with Elovic, Dobrovic and Fellus in the writer's chair, with perhaps almost 50% reporting this as a burden and obstacle to rehabilitation and return to normal psychosocial existence. Again a quote from Lezak is brushed aside, this time in terms of the necessity for a definition of fatigue in these authors' eyes. Fatigue here is not full remedied by sleep or rest, and is multifactorial and multidimensional in its origins and effects. A putative attempt is made here to rationalize all of this, and again psychiatric and endocrine input is mooted, as with other agencies of fatigue in the biochemistry of the brain and body. About a page is devoted to a discussion of the cognitive effects, in a linear way, as certainly using cognitive skills is depleted by limited energy, and in its turn depleting of energy resources, leading to further interference.

Given another chapter is devoted to treatment of fatigue, the authors don't go much further, a cop-out as there is only a single chapter in Section Five covering everything. Fellus emerges again in the next chapter, with Rashidzada as partner this time, to discuss fatigue in other conditions. As with pain, a distinction is made between central and peripheral fatigue, which makes sense. A great insertion here is to look at early or mild dementia, Alzheimer's, Parkinson's, post-Lyme encephalopathy, and a bit of a discussion on the basal ganglia too. A most interesting, small chapter.

Part three is likely to be the most contentious section, with its focus on psychiatric conditions. This includes CFS, which may anger some, with its focus on perception of effort, both mental and physical. As noted earlier, fatigue has become a non-disease in DSM terms, which many regard as a pity, given high levels of it in both normal and ill populations, returning to the days prior to 1870 when fatigue was ignored. When neurasthenia became favored after that, with no less than von Krafft-Ebing coming to the platform on it, together with Kraepelin, Freud and Janet joining the club later on, a hundred years of opinion followed. And so DSM II may have been described as 'brainless', its third version would be described as 'mindless' in dumping neurasthenia, the most diagnosed condition in Russia, and finally our present version decried as 'witless' by some wags, so the authors end with a small addendum on treatment. Its enough to send one to the barricades, if it were to end there, but Johnson and DeLuca take over with CFS and the brain, drawing on the definitions of Holmes et al in 1988 and Fukuda et al in 1994. The authors keep to both sides of the psychiatric-organic street in this chapter, referring to neuropsychological performance as not illuminating on the subjective complaints, which appear unrelated to depression or fatigue levels. Neuroimaging studies show varying degrees of punctate high signal intensity of the white matter, in some studies cerebral, in others subcortical and periventricular, or in fact nothing. In terms of functional neuroimaging, lateral frontal cortex, lateral temporal cortex and basal ganglia were promising origin sites, with perhaps the medical temporal lobes involved as well. Brainstem hypoperfusion is noted in other studies, with thalamus, basal ganglia and frontal areas involved in still more studies as well. More specifically, the right thalamus, pallidum and putamen may be involved. Together with other studies, the review speculates that the perception of effort might be skewed in such cases, but the heterogeneity of the CFS group is too wide to allow for localization to be exact. The HPA axis comes under scrutiny in a similar way. The literature quoted overall in this chapter is extensive. Overall, it appears that sufferers may over-recruit cortex in response to challenge, and thus fatigue.

Johnson returns without her partner this time, in reviewing the most essential chapter in such a section, looking at depression. Straight away she introduces gender as a variable, as it should be, given the epidemiology of depression, CFS and so on. White matter hyperintensity again looms, as it did in CFS. The cytokines are studied briefly, as well as genetics. It is a very short, very limited chapter, and the editors should have demanded more than its ten pages plus references, but it is about the same length as other chapters.

Allen and Escobar take on somatization, the last and most brief chapter. I guess in a book that purports to be a window on the brain, via fatigue, the emphasis is not on the psychiatric.

Section four examines the general medical conditions of HIV, lupus, cancer, heart disease, and so on. The HIV chapter from Dufour, Dube and Breitbart is thorough and long enough although two pages shorter than the depression chapter, but somehow more fulfilling. Duntley discusses aspects of sleep, fatigue versus sleepiness, and fatigue and the brain focused on the role of sleep, in a chapter almost without headings. Sleepiness and fatigue are separate entities, perhaps even from a pharmacological viewpoint. It is a tight, excellent chapter with strong standpoints taken in evaluating the literature. Siegel and Schneiderman discuss cardiac issues, and both sickness behavior and the acute-phase response, coming back to the cytokines as Johnson did, and the value of anti-inflammatory medications. Lupus and related autoimmune disorders take up on that inflammatory theme, Kozora in the writer's box, with an intense look at measurement and mechanisms of fatigue here, and a very wide look at other conditions that contribute putatively to fatigue in Lupus sufferers. Again, as in earlier in the book, there is a move towards a biopsychosocial approach as a model for fatigue in Lupus. A small section deals with treatment, as small as elsewhere.

Jacobsen and Donovan approach breast cancer using studies on women who are treated for it via radiotherapy and/or chemotherapy, as well as autologous bone marrow transplant. Fatigue is studied closely with cognitive effects, something not all chapters do despite the tone of the book. Complaints again are much more closely with fatigue, more so than with performance on cognitive tasks, as was the case with CFS and mild brain injury again. Two pages of unanswered questions provide fertile ground for further study, especially with regard to toxicity.

Klimas, Fletcher, Maher and Lawrence band together in search of answers to the perplexing question of psychoneuroimmunology, and the connections to fatigue. Again, as before, the sickness behavior, fatigue and immune system of the sufferer are compared and contrasted.

The most potentially useful section, given the paucity of evidence in other chapters, is Section five that tackles the treatment of the conditions that have gone before. Lange, Cook and Natelson review the impact of fatigue on rehabilitation, but their single chapter is all there is in Section five. Behavioral treatments, pharmacological interventions, exercise training, and the relation of outcomes on fatigue are reviewed, with all three recommended in combination, with a view to avoiding the trap of a sedentary response.

DeLuca winds up with a summary chapter that sets out to once again define fatigue, and separate it into primary mechanisms, and the other, secondary mechanisms including deconditioning, anxiety, stress and depression, effects of medication and impact of sleep hygiene. As with any such attempt, and as before in this book, this separation may be spurious, as one may lead to the other in any order, as a circular system may do in any condition.

As a book on the subject, DeLuca's collection stands out pretty much alone, without competition, and it certainly does what it sets out to do, which is penetrate the phenomenology of fatigue, and peer through such a window into the brain. How the brain is defined here is not stated, as for many, such as my colleagues in Neuroscience, the brain is not just inside the cranium, but bounded by a wide spectrum of associated mechanisms in ANS, CNS, endocrine, lymph and blood that connect the whole body as one mechanism. This perhaps narrow focus of the DeLuca approach leads to some artificial boundary creation such as one sees in the final summation, but it doesn't detract much from the usefulness of the book to anyone in the social, psycho, neuro, or related sciences. There is not much to be gained in terms of understanding exactly how fatigue demonstrates the mechanisms of brain or mind, given the dissociation between subjective and objectively measured complaints in regard to cognitive fall-off. However, the book comes close enough to advance our knowledge in this tricky subject, which perhaps has no peer apart from pain as a phenomenon. Perhaps DeLuca will provide such a text.


2006 Roy Sugarrman

 Roy Sugarman, PhD, Conjoint Senior Lecturer in Psychiatry, University of New South Wales, A-Dir of Psychology, Royal Rehab Centre Sydney, Australia


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