+3 Neurological Dysfunction

From: <a href="http://jnm.snmjournals.org/content/55/6/945.full">Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study</a>

The neuropsychologic symptoms in CFS/ME suggest that the central nervous system is involved in the pathophysiology, and several studies including ours have shown central nervous system abnormalities in CFS/ME patients. Our previous study (<a id="xref-ref-2-1" class="xref-bibr" href="http://jnm.snmjournals.org/content/55/6/945.full#ref-2">2</a>) with PET showed hypoperfusion and reduction of biosynthesis of neurotransmitters such as glutamate, aspartate, and γ-aminobutyric acid through acetylcarnitine in the frontal, cingulate, temporal, and occipital cortices; basal ganglia; and hippocampus in CFS/ME patients. CFS/ME patients also had a decrease in serotonin transporter densities in the rostral sector of the anterior cingulate cortex, and the serotonin transporter density in the middle sector of the cingulate cortex was negatively correlated with pain score (<a id="xref-ref-3-1" class="xref-bibr" href="http://jnm.snmjournals.org/content/55/6/945.full#ref-3">3</a>). Furthermore, our voxel-based morphometry studies demonstrated volume reduction of the bilateral prefrontal cortices in CFS/ME patients, and the volume reduction level in the right prefrontal cortex was associated with the severity of fatigue (<a id="xref-ref-4-1" class="xref-bibr" href="http://jnm.snmjournals.org/content/55/6/945.full#ref-4">4</a>).

From: From the 2012 IC Primer, pages 4-5:

Neurological Abnormalities

Neurocognitive, sleep, autonomic and sensory disturbances, pain, headaches, and paresthesias are prominent neurological signs and symptoms. Cognitive impairments including slow processing of information, poor attention, word finding, and working memory are some of the most functionally disabling symptoms. [1, 73, 74]

Structural and functional abnormalities within the brain and spinal cord are consistent with pathological dysfunction of the regulatory centers and communication networks of the brain, CNS and ANS, and are essential for effective ongoing self-organization. [1, 75] Reduced brainstem gray matter volume is consistent with insult to the midbrain at fatigue onset.

Feedback control loops may suppress cerebral motor and cognitive activity, disrupt CNS homeostasis, and reset elements of the ANS. [76] These abnormalities play crucial roles in neurological and neurocognitive symptoms. [1, 5, 11, 57, 65] Greater source activity and more parts of the brain are utilized in cognitive processing, which supports patients’ perception of greater effort. [73, 77, 78] Reduced duration of uninterrupted sleep may explain reported unrefreshed sleep, pain and overwhelming fatigue. [79] These observed pathological changes are consistent with neurological disorders but not psychiatric conditions.

[Image description] 3D Comparison VS Adult Norms II – Avg. activity sampling By Dr. Ismael Mena 2010 [80]

Extensive areas of hypoperfusion are characteristic of ME: HMPAO c99m radiopharmaceutical for brain blood flow assessment. Images of the patient are reconstructed and compared against normal age matched data-base by means of Oasis Segami USA Software. In color gray normal perfusion equal to mean + 2 St Dev, colors blue, green and black, 2-5 St dev.below the normal mean denoting hypoperfusion. Left lateral view shows marked hypoperfusion in the lateral aspects of the temporal lobe, extending to the frontal and parietal lobes. Left medial view shows extensive hypoperfusion in the limbic system involving anterior, medial and posterior cingulates. There is left temporal medial hypoperfusion that denotes hypofunction in the projection of the hippocampus. Both posterior cingulate and hippocampal hypofunction denote cognitive impairment. (Ventricular system is in color white.) Finally, there is hypoperfusion in the occipital lobe. Ismael Mena, MD, nuclear medicine [80]

[Table, pages 4-5]

Neurological Structural & Functional Abnormalities
Hypoperfusion [80-84] (Neuro-SPECT, arterial spinning labeling)
↓ regional blood flow (rCBF), ↓ absolute cortical blood flow [46, 85]
↓ hypoperfusion in brainstem distinguishes ME from depression [83]
↓ further reduction in cerebral blood flow after exercise Greater involvement of the brain correlates with greater severity [46]

Punctate lesions – white matter hyperintensities (MRI)

↑ Plaque or hyperintensities in the white matter & tracts is consistent with demyelination or inflammation & increase risk of cerebrovascular events [86, 87]
• brainstem injury and loss of homeostasis [76]

Reduced brain matter – (MRI)

↓ Reduced regional gray and white matter volumes are consistent with impaired memory and visual processing. [88]
↓ global reduction of gray matter volume [54, 89]
↓ gray matter volume in midbrain & pulse pressure suggest impaired cerebrovascular auto-regulation [76]
↓ white midbrain matter volume decreased with fatigue duration [76]

Hypometabolism – (PET)

↓ metabolism of glucose in the brain, [36] ↓ metabolism in brain stem differentiates ME from depression [46, 83]

Neurocognitive – (fMRI, qEEG & SPECT)

↑ Greater effort is required - elevated source current & more regions of the brain are utilized in cognitive activity & fatiguing tasks: poor processing of auditory & spatial information, poor working memory. [73, 77, 78]
↓ slower performance in visual imagery & motor tasks - ventral anterior cingulate cortex was active when controls made an error but not in patients. [54]
↓ reduced blood flow in temporal lobes may contribute to memory and cognitive impairment & fatigue [80, 81]

Pain and Fatigue – mRNA assays

↑ Elevated sensory signaling perceived by the brain as pain and fatigue [11, 57, 90]

Musculoskeletal – (surface EEG scalp)

CNS signals are altered when controlling voluntary muscle activities, especially when they are fatiguing. [90]

↓ poor and slower motor performance 90 & abnormal spatial and temporal symmetry of gait [91]

Sleep – (EEG)

↑ prolonged sleep onset latency [79]
↓ disruption of REM sleep & reduced duration of uninterrupted sleep [92, 93]
↑ increased alpha intrusion into delta sleep [79]

Cerebral spinal fluid - (spinal tap) increased opening pressure on lumbar puncture Proteomes distinguish ME from post-treatment Lyme disease and controls. [94]

↑ increased lymphocytes 95 and protein [94, 95]
• IL-10 increased with granulocyte-macrophage (GM), colony-stimulating factor (CSF) suppression [95] 
↑ elevated lactate is consistent with reduced cortical blood flow, mitochondrial dysfunction & oxidative stress [96]
Lateral ventricular: 297% vs. anxiety disorder & 348% vs. controls [96]

Spinal cord and ganglia - (autopsy)
↑neuroinflammation in the dorsal root ganglia, (modulators of peripheral sensory information traveling to the brain) [97]

[References cited above scroll dwn]

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From: <a href="https://link.springer.com/article/10.1007/s12035-018-0928-9#Sec9">A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications | SpringerLink</a>

One of the largest voxel-based morphometry brain MRI cross-sectional studies at a 3-T magnetic field strength was that carried out by Puri and colleagues, which compared 26 CFS/ME/SEID patients with 26 age- and sex-matched controls [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR72">72</a>]. The patient group had reduced grey matter in the following three regions. First, the occipital lobes, including both poles, the superior division of the left lateral cortex and the supracalcrine cortex also on the left side of the brain. Second, the angular gyrus of the right hemisphere. Third, the posterior division of the left parahippocampal gyrus. Reduced white matter was found in the patient group in the left occipital lobe [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR72">72</a>]. These particular findings are consistent with the symptom of impaired memory which is well described in CFS/ME/SEID, and they also point to the possibility of visual processing abnormalities and the possibility of discrepancies existing between intentions and corresponding actions [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR72">72</a>]. This has been described as just one of several structural neuroimaging studies which have shown that CFS/ME/SEID is associated with significant neuroanatomical changes.

Furthermore, as Shan and colleagues found in their longitudinal MRI study of 15 patients and 10 controls, who were scanned (at 1.5 T) at baseline and 6-year follow-up, significant neuroanatomical changes occur over time [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR73">73</a>]. In the case of this study, there was a decrease in white matter in the left inferior fronto-occipital fasciculus, which was not seen in the control group [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR73">73</a>]. It should be noted, however, that not all recent longitudinal MRI studies have shown evidence of changes. Notably, the longitudinal study of Perrin and colleagues proved negative [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR74">74</a>].

The chemistry of the brain has also been studied in this disorder, using magnetic resonance spectroscopy (MRS). The first systematic proton-MRS study of CFS/ME patients compared with age- and sex-matched controls was that of Puri and colleagues, who in 2002 reported that CFS was associated with a relative increase of choline-containing compounds in the occipital cortex [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR75">75</a>]. The following year, Chaudhuri and colleagues similarly systematically studied the left basal ganglia of CFS/ME patients and age- and sex-matched controls using proton-MRS; they also found a relative increase of choline-containing compounds in this part of the brain [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR76">76</a>]. These MRS findings may point to a problem with phospholipid metabolism, increased membrane turnover owing to gliosis or changes in intra-membrane signalling [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR75">75</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR76">76</a>]. They may also be consistent with Perrin’s much earlier prediction of increased central levels of acetylcholine [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR77">77</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-018-0928-9#CR78">78</a>].

Thus, there is good evidence of the existence of neuroanatomical and neurochemical changes in CFS/ME/SEID. This is also ample evidence of neurophysiological changes, which are discussed in the next section.

----

Using an advanced imaging technique — diffusion-tensor imaging, which is especially suited to assessing the integrity of white matter — Zeineh and his colleagues identified a consistent abnormality in a particular part of a nerve tract in the right hemisphere of CFS patients’ brains. This tract, which connects two parts of the brain called the frontal lobe and temporal lobe, is called the right arcuate fasciculus, and in CFS patients it assumed an abnormal appearance.

Bolstering these observations was the third finding: a thickening of the gray matter at the two areas of the brain connected by the right arcuate fasciculus in CFS patients, compared with controls. from: <a href="http://med.stanford.edu/news/all-news/2014/10/study-finds-brain-abnormalities-in-chronic-fatigue-patients.html">Study finds brain abnormalities in chronic fatigue patients | News Center | Stanford Medicine</a>

Bell and Streeten identified the low blood volume, problems with the veins, and rapid heart rates 15 years ago in ME/CFS. We know that smaller than usual hearts are also present in ME/CFS and POTS and people with idiopathic exercise intolerance (who have not been diagnosed with ME/CFS). Researchers are taking a deeper look at blood volume, and we know that the inflammation in the lower brain may have something to do with it.
From: 'The Blood Volume Paradox in Chronic Fatigue Syndrome (ME/CFS) and POTS' http://www.prohealth.com/library/showarticle.cfm?libid=29236

From: <a href="https://link.springer.com/article/10.1007/s12035-017-0598-z">A Comparison of Neuroimaging Abnormalities in Multiple Sclerosis, Major Depression and Chronic Fatigue Syndrome (Myalgic Encephalomyelitis): is There a Common Cause? | SpringerLink</a>

<h3 class="Heading">Resting-State Functional Conductivity in CFS</h3>

Several authors have reported abnormal patterns of functional connectivity in patients afforded a diagnosis of CFS according to international criteria, whose magnitude correlates with levels of fatigue and pain [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR174">174</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR175">175</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR176">176</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR177">177</a>]. The precise patterns of impairment are highly variable however.

Wortinger and fellow workers reported a significant decrease in functional connectivity of the salience network to the right posterior insula in adolescent CFS patients compared with age-matched healthy controls. Interestingly, this decrease was negatively associated with the severity of fatigue [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR174">174</a>]. In addition, this research team reported a positive association between pain severity and salience network functional connectivity to the left middle insula and caudate which differed between the two groups [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR174">174</a>]. Kim et al. also reported an association between altered patterns and strength of functional connectivity and fatigue severity in CFS. In this instance, the authors reported increased resting-state connectivity between the posterior cingulate cortex and the rostral and dorsal ACC whose magnitude significantly correlated with fatigue levels measured by the Chalder Fatigue Scale score while controlling for depression [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR175">175</a>]. Gay and fellow workers have also reported widespread impairments in functional connectivity, in this case within the lateral prefrontal cortex and between the occipital lobes and other brain regions [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR176">176</a>]. These authors also reported impaired connectivity between the left anterior midcingulate cortex and the sensory motor network and between the left posterior cingulate cortex and the salience network [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR176">176</a>]. Importantly, the magnitude of each of these connective impairments correlated with the severity of reported fatigue. On the other hand, Boissoneault and others reported a pattern of increased functional connectivity within and between brain regions in their trial cohort compared with healthy controls. In particular, their CFS participants displayed increased connectivity in the bilateral superior frontal gyrus, ACC, precuneus, thalamus, supplementary motor area, right postcentral gyrus and posterior cingulate gyrus [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR177">177</a>]. This contrasted markedly with healthy participants, who displayed greater functional connectivity in the left parahippocampal gyrus, right insula, right precentral gyrus and hippocampus. It is noteworthy however that the relatively reduced level of connectivity in the left parahippocampal gyrus seen in CFS correlated with fatigue severity [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR177">177</a>].

This team also examined the patterns of dynamic and static functional connectivity in CFS compared with unaffected controls during a fatiguing cognitive task and reported major group differences. Specifically, Boissoneault and others reported decreased dynamic connectivity between the hippocampus and right superior parietal lobule and increased static inferior frontal gyrus connectivity to occipital and temporal structures and to the cerebellum [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR178">178</a>]. It is also noteworthy that healthy controls displayed greater dynamic connectivity increases than did CFS patients between the temporo-occipital regions and insula structures and between thalamus/striatum and the precuneus [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR178">178</a>]. Moreover, the degree of static or dynamic connectivity impairment correlated with the self-reported fatigue in CFS [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR178">178</a>]. It is difficult to determine a typical pattern of impaired functional connectivity in CFS by a consideration of these studies. It would appear to be different from those displayed in MS and MDD, but clearly, more studies are needed to confirm this, and a study examining resting functional state abnormalities containing CFS, MDD and MS patients allowing direct comparisons to be made could be very informative. Factors likely to affect functional connectivity include peripheral inflammation, disease severity, disease progression and genetic heterogeneity.

</section>

<h3 class="Heading">White Matter Abnormalities in CFS</h3>

Early research investigating potential neuroanatomical abnormalities using MRI focused on WM using observer-dependent analysis [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR14">14</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR179">179</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR180">180</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR181">181</a>]. Natelson and others reported subcortical WM hyperintensities in 52 subjects fulfilling the original CDC selection criteria [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR182">182</a>] compared with a control group who had undergone MRI investigation for head trauma [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR179">179</a>]. On the other hand, Greco and others reported widespread demyelination in many of their CFS participants but at a group level, WM hyperintensities were not significantly different from healthy controls [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR180">180</a>]. However, Lange and others also reported significantly increased WM hyperintensities in their CFS group who were free of comorbid anxiety or depression compared with healthy controls and CFS subjects with co-morbid psychopathology [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR183">183</a>]. Interestingly, when the data obtained from the two CFS groups were combined, the levels of WM hyperintensities were not significantly different from the control group [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR183">183</a>]. In another large study involving 48 CFS patients, Cook and others reported widespread WM abnormalities in their cohort whose extent correlated with symptom severity [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR14">14</a>]. It should also be noted that a more recent MRI study using observer-dependent methods failed to detect any WM abnormalities in their CFS cohort although these patients were not recruited according to international consensus guidelines [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR184">184</a>].

Recent studies based on T1- and T2-weighted MRI using VBM have universally reported significantly increased WM abnormalities in CFS subjects selected according to the “Fukuda” CDC criteria compared with healthy participants [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR185">185</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR186">186</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR187">187</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR188">188</a>]. Puri and others reported reduced WM voxel volumes in the left occipital lobe while Barnden and others reported reduced WM voxel volumes in the frontal cortex, caudate and hypothalamus [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR185">185</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR186">186</a>]. Pertinently, Shan and others reported decreased WM volume in the left frontal occipital lobe and the fasciculus whose extent increased with self and clinically assessed symptom severity and also worsened over time [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR188">188</a>]. Finally, Barnden and others reported reduced WM volume in the prefrontal cortex, the ventrolateral thalamus and internal capsule even following correction for the potential effects of anxiety and depression [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR187">187</a>].

</section>

<h3 class="Heading">Grey Matter Abnormalities in CFS</h3>

Several research teams utilising VBM have reported reduced global or regional GM volumes in those with CFS [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR185">185</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR188">188</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR189">189</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR190">190</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR191">191</a>]. Puri and fellow workers in a study consisting of 26 CFS participants and 26 age- and sex-matched healthy controls reported significantly reduced GM volume in the left and right occipital poles, left lateral occipital cortex (superior division), left supracalcrine cortex, the posterior division of the left parahippocampal gyrus and the right angular gyrus [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR185">185</a>]. Okada and fellow workers on the other hand reported reduced GM volume in the right prefrontal cortex [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR189">189</a>]. It is also worthy of note that these authors also reported that the extent of GM volume reduction in the right prefrontal cortex correlated with the severity of reported fatigue [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR189">189</a>]. However, it should also be noted that this was a relatively small study consisting of just 16 CFS participants and 16 healthy controls [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR189">189</a>].

The results reported by deLange and others appear to be particularly interesting as their studies were specifically designed to examine potential relationships between the severity of symptoms in CFS and cerebral abnormalities and the effect of cognitive-behavioural therapy (CBT) on those cerebral abnormalities respectively [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR190">190</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR191">191</a>]. In the first relatively large study consisting of 28 CFS patients and 28 healthy controls, these authors reported significant reductions in global GM volume in CFS and that the extent of such reductions correlated with the degree of physical disability [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR190">190</a>]. In the later study, these authors also reported a global reduction in GM volume which increased significantly, albeit slightly (approximately 6%), following a course of CBT [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR191">191</a>]. Finally, in their longitudinal MRI study, Shan and others have recently reported a progressive decrease in WM volumes in the left inferior fronto–occipital fasciculus in a cohort of 15 CFS participants (unchanged in 10 normal controls), with decreased regional WM volumes in adjacent regions and GM volume reduction in contralateral regions over a 6-year period; these regional WM and GM volumes once again correlated with illness severity [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR188">188</a>].

</section>

<h3 class="Heading">Abnormalities in Cerebral Perfusion in CFS</h3>

Most of the SPECT studies investigating potential CBF abnormalities in CFS have reported areas of significant cerebral hypoperfusion, at either a global [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR20">20</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR192">192</a>] or regional level [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR193">193</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR194">194</a>] compared with unaffected controls. However, a minority of researchers reported no significant CBF impairments in comparison with unaffected controls or MDD participants [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR195">195</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR196">196</a>]. The reasons for such discrepant findings are unclear, but fewer participants and differences in selection methods may be relevant. The much larger studies conducted by Ichise, Schwartz, Costa and Goldstein, and their colleagues [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR20">20</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR192">192</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR193">193</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR194">194</a>] appear worthy of particular consideration as they examined multiple brain regions and perhaps even more importantly, apart from Ichise and others [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR192">192</a>], examined differences in patterns of abnormal perfusion between participants with CFS and MDD, which is currently a contentious area.

Ischise et al. compared rCBF in 60 CFS participants and 14 healthy controls and reported significant reductions in cortical/cerebellar rCBF ratios in the frontal, temporal, parietal and occipital lobes, providing objective evidence of widespread functional impairment of the brain in the vast majority of their CFS subjects [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR192">192</a>]. Schwartz et al. examined SPECT data differences in terms of regional perfusional deficits and mid-cerebral uptake indices between 45 CFS participants, 14 MDD participants, 27 participants with AIDS dementia complex (ADC) and 38 healthy controls [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR20">20</a>]. These authors noted more areas of impaired frontal and temporal perfusion in the ADC group compared with those with CFS or MDD. However, the mid-cerebral uptake index was lower in patients with ADC and CFS than in the MDD and healthy controls groups [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR20">20</a>].

The largest study examining potential 99mTc-HMPAO SPECT differences between CFS and MDD patients was carried out by Costa and others [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR193">193</a>]. It included 40 healthy participants, 67 CFS participants (both with and without psychiatric co-morbidity) and 29 early- and late-onset MDD participants [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR193">193</a>]. These authors reported significantly greater global and brain-stem hypoperfusion in CFS participants free of psychiatric symptoms compared with controls and MDD participants, which was not apparent in CFS participants displaying symptoms of anxiety and depression [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR193">193</a>]. Goldstein and others compared high-resolution 99mTc-HMPAO SPECT imaging patterns of rCBF in 33 CFS subjects (55 ± 10 years), 26 age-matched MDD participants and 19 healthy participants in an attempt to investigate the potential pathophysiology of CFS [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR194">194</a>]. Importantly, they reported dorsofrontal hypoperfusion as the dominant profile in CFS while hypoperfusion seen in MDD was predominantly in the right orbitofrontal lobe, left temporal lobe and, in particular, the left anterior frontal lobes [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR194">194</a>].

More recent research using xenon-computed tomography, ASL and high-resolution SPECT reported consistently impaired CBF at a global and regional level at rest and during exercise [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR197">197</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR198">198</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR199">199</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR200">200</a>]. Yoshiuchi and others reported reduced CBF in the right and left hemisphere in CFS participants free of psychiatric comorbidity compared with healthy controls but also noted that hypoperfusion in CFS patients with psychiatric comorbidity appeared to be exclusively limited to the left hemisphere [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR198">198</a>]. These results have been broadly replicated by Biswal and others who reported impaired regional and global CBF in the vast majority of their participants with evidence of regional hyperperfusion in a minority [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR197">197</a>]. Evidence of hyperperfusion in some CFS subjects has also been supplied by Machale and others who reported significantly increased hyperperfusion in the left thalamus in CFS compared with a pattern of hyperperfusion in the left prefrontal cortex of MDD [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR200">200</a>]. Finally, Patrick-Neary and others reported significantly decreased CBF in CFS participants during maximal exercise compared with healthy controls which they suggested as a cause of the profound disability experienced by many patients [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR199">199</a>].

The potential capacity of SPECT to differentiate CFS from MDD may be highly significant as CFS is a purely descriptive diagnosis reliant on phenotype only, and there is accumulating evidence that the diagnosis identifies a clinically and aetiologically heterogeneous syndrome rather than a discrete biological entity even when such a diagnosis is made via the application of international guidelines [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR1">1</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR3">3</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR201">201</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR202">202</a>]. Unsurprisingly, research in this area has been bedevilled by a lack of reproducibility which is also the case in many other areas where diagnostic categories are descriptive and homogeneity of causation is assumed (reviewed in [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR203">203</a>]). This issue in ‘CFS research’ is even more complex because of the frequent use of unvalidated criteria which only mandate the presence of chronic mental and physical tiredness [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR204">204</a>] or where a diagnosis is based on the presence of intermittent symptoms based on a population study of fatigue in a localised population [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR205">205</a>]. Hence, a method for increasing the homogeneity of a study population and excluding patients with MDD is to be welcomed. The question of heterogeneity is also relevant to the next section of this paper which briefly examines mechanisms whereby systemic inflammation could be a major element initiating and maintaining neuropathology in different illnesses even though investigation with an array of neuroimaging techniques produces very different and often illness-specific results.

</section>

</div>

</section>

<h2 class="Heading" data-role="collapsible-handle">Factors Affecting Severity and Specificity of Neuropathology</h2>

There is widespread agreement that the relationship between the presence of systemic inflammation and various dimensions of neuropathology is established via the conveyance of inflammatory signals to the brain through a range of humoral and neural routes culminating in the activation of microglia and astrocytes [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR206">206</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR207">207</a>]. Once activated, these glial cells secrete a range of inflammatory molecules such as pro-inflammatory cytokines, reactive oxygen species, reactive nitrogen species, prostaglandins and quinolinic acid [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR208">208</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR209">209</a>]. These are well-documented effects and have been described in a number of detailed reviews [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR210">210</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR211">211</a>].

Another source of neuropathology is more indirect however and stems from the loss or corruption of the regulatory functions exerted by these glial cells via a sophisticated communication system with neurones and oligodendrocytes founded on the secretion of exosomes containing mRNAs, miRNAs, caspases and P2X7 (reviewed in [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR212">212</a>]). This is a highly complex area, but the key point from the perspective of this paper is that abnormally expressed microglial exosomal miRNAs appear to be independent contributors to the development maintenance and illness-specific patterns of neuroinflammation seen in many different neurodegenerative and neuroprogressive disorders [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR213">213</a>]. Thus, microglial activation following prolonged systemic inflammation could produce an illness-specific or at least a range of characteristic WM abnormalities depending on a particular signature of abnormally expressed miRNAs. The mechanisms underpinning this phenomenon are currently unknown but may lie in the recently discovered capacity of at least some miRNAs to activate toll-like receptors and are another mechanism underpinning ‘sterile’ immune activation [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR214">214</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR215">215</a>].

Microglia also display distinct regional differences in density and transcriptional identity particularly in bioenergetic and immunoregulatory pathways [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR216">216</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR217">217</a>]. This underpins observations of region-specific sensitivities to microglial dysfunction and in particular responses to different pathogen-associated molecular patterns [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR216">216</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR217">217</a>]. Hence, this provides another mechanism whereby systemic inflammation could produce geographically variable neuropathology. Another highly pertinent example of the role of microglial genetics in creating unique patterns of abnormalities can be found from recent data in MS, where microglia deficient in the production of caspase-8 are considered to be the source of necroptotic markers seen in active plaques of MS patients. These glial cells are likely one of the main drivers of neuronal and oligodendrocyte destruction seen in this illness [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR218">218</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR219">219</a>]. The heterogeneous responses of microglia to external or internal stimuli are also under epigenetic regulation involving DNA methylation, histone acetylation and the expression of a wide range of miRNAs [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR220">220</a>]. It is also noteworthy that different genomic patterns of DNA methylation within and outside glial cells are associated with different patterns of neuropathology in distinct brain regions [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR221">221</a>].

Predictably, astrocytes also display extensive variability in biochemical, biophysical and immunoregulatory properties in distinct brain regions (reviewed in [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR222">222</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR223">223</a>]). The signalling pathways orchestrated by astrocytes are also strongly influenced by genetics [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR224">224</a>]. Importantly, some of the neuroprotective functions of astrocytes are also under epigenetic control. Reactive microglia also compromise astrocytic function and survival in an inflammatory environment with the latter property resulting from a decrease of histone acetylation in astrocytes and a silencing of Nrf-2-mediated antioxidant defences [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR225">225</a>].

Antioxidant defence systems also demonstrate pronounced regional differences in composition and efficacy. For example, thioredoxin and thioredoxin reductase levels vary in different brain regions [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR226">226</a>]. This is also true of glutathione transferase, glutathione reductase and glutathione peroxidase, with the former two enzymes being reduced in the striatum, neocortex, cerebellum and hippocampus, whereas expression of the last enzyme appears to be reduced in the striatum, cerebellum, cortex and corpus callosum [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR227">227</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR228">228</a>]. The expression and activity of NADPH oxidases also displays considerable variation in different brain regions [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR229">229</a>]. Selenium distribution across different brain regions is also heterogeneous, with the highest concentrations being in the parietal inferior lobule, putamen and occipital cortex and the lowest levels in the cerebellum and medulla [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR230">230</a>].

Different discrete neuronal populations existing in different brain regions display differential susceptibility to neurodegenerative stressors which is a phenomenon often described as selective neuronal vulnerability (SNV). Well-documented examples include neurones in the entorhinal cortex, frontal cortex, hippocampal CA1 region and amygdala, which are the most susceptible to neurodegenerative death in populations of neurones most sensitive to the neurodegeneration associated with Alzheimer’s disease [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR231">231</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR232">232</a>]. The increased susceptibility of dopaminergic neurones of the substantia nigra to neurodegenerative destruction in Parkinson’s disease is equally well documented [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR233">233</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR234">234</a>]. It should be stressed that the pattern and extent of neural damage seen in different neurodegenerative disease is not just dependent on SNV but also stems from specific factors unique to the aetiology of the illness (reviewed in [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR235">235</a>]). SNV also exists within populations in the same brain region. For example, the hippocampal CA1 neurones are much more vulnerable than are CA3 neurones to global cerebral ischaemia [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR236">236</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR237">237</a>] and oxidative stress [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR238">238</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR239">239</a>].

Brain volume and structure are strongly influenced by genetic factors [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR240">240</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR241">241</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR242">242</a>] and resting-state functional connectivity [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR243">243</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR244">244</a>], GM and WM volume [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR245">245</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR246">246</a>] and CBF [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR247">247</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR248">248</a>] are sensitive to environmentally induced epigenetic changes in gene methylation and/or acetylation and/or changes in the expression of a wide range of miRNAs. These factors may also produce heterogeneity in neuroimaging phenotypes between individuals with the same illness or between illnesses even if systemic inflammation is a major driver of neuropathology in each instance.

</div>

</section>

<h2 class="Heading" data-role="collapsible-handle">Conclusions and Future Directions</h2>

We begin by briefly summarising the key neuroimaging findings.

In MS, there is evidence of impaired neural connectivity and functional dissociation on resting-state fMRI, which correlates with the severity of disability. Cortical demyelination and reduced cerebral perfusion also occur. Early GM atrophy appears to be predictive of the subsequent level of disability and of the prognosis.

MDD is associated with dysfunction of functional connectivity and both microstructural and macroscopic WM abnormalities, including disrupted tracts. There is evidence of GM volume loss in several regions.

CFS is associated with cerebral hypoperfusion, while large VBM studies have shown evidence of GM and WM changes.

The evidence given in this paper points to the likelihood that systemic inflammation may be a major underlying cause of structural and functional neuroimaging abnormalities reported in seemingly diverse disorders including MS, MDD and CFS. Furthermore, reported inter-patient and inter-illness differences may be a function of regional genetic, epigenetic and environmental variations in microglial and astrocytic functioning.

While SPECT appears to be able to differentiate CFS from MDD, its use of ionising radiation makes it unlikely to be a neuroimaging modality of choice in the future for this purpose. Rather, efforts are likely to be undertaken to develop corresponding functional magnetic resonance-based techniques instead. Not only are magnetic resonance techniques free of the use of ionising radiation, they also afford a higher resolution than does SPECT (even high-resolution SPECT). In this vein, a further development is likely to be the use of machine learning classification methodologies, which may, for example, be able in the near future to differentiate different disorders and, within a given disorder, be able to classify patients with a given diagnosis. Finally, there is also a strong case for further combining neuroimaging techniques with investigative modalities from the fields of biochemistry, neurophysiology, environmental medicine, immunology and epigenetics.

From: Oxford Textbook of Neurorehabilitation

edited by Volker Dietz, Nick Ward.

The applicability of motor learning to neurorehabilitation (Chapter)

<p class="author" style="background: #F3F3F3; font-variant-ligatures: normal; font-variant-caps: normal; orphans: 2; text-align: start; widows: 2; -webkit-text-stroke-width: 0px; text-decoration-style: initial; text-decoration-color: initial; word-spacing: 0px; margin: 0in 0in 7.5pt 0in;">John W. Krakauer

Neurological disorders are due to abnormalities of the structure or function of the nervous system. Those associated with fatigue affect diverse brain regions, however, and fatigue is also prominent in medical and psychiatric conditions, in which brain structural abnormalities are subtle or absent. Consequently fatigue is unlikely to be localized to a discrete brain region.

A study in patients who had had penetrating TBI found that fatigue was associated with ventromedal prefrontal cortex damage. Reduced gray matter volume is reported in CFS, with increased prefrontal cortex volume following treatment with cognitive behavioral therapy (CBT). In summary, when structural abnormalities are identified they implicated involvement of frontal and subcortical brain regions in fatigue.

As fatigue likely involve distributed brain regions, functional imaging may provide greater insights into its mechanisms. These approaches generally support the concept that fatigue is associated with dysfunction of cortical-subcortical circuitry, particularly circuits involved in attention and executive function. in MS there is decreased regional glucose metabolism in the frontal cortex and basal ganglia of fatigue patients. In TBI brain activity is increased in the middle frontal lobe, basal ganglia, and anterior cingulate during a speeded cognitive task; in PD decreases in frontal lobe perfusion are greater in patients with fatigue than those without (which was associated with executive function impairments); and CFS patients had differing patterns of activation of prefrontal cortical regions compared to healthy controls. Functional Imaging studies of fatigue stroke patients have not been undertaken, but post-stroke fatigue has been related to attentional and executive impairment.

In summary, convergent data across neurological conditions suggest dysfunction in the striatal-thalamic-frontal system is important in fatigue. These impairments may necessitate higher levels of mental effort for complex tasks, which increases subjective fatigue. In conditions with damaged brain structure (e.g. MS, TBI) recruitment of expanded pools of cortical neurons likely reflects brain plasticity unmasking latent pathways. Though adaptive, it maybe energy intensive, excessive use of neuronal pools results in fatigue. In CFS disruption again seems present but likely arises through different routes, which may include mechanisms such as sustained abnormalities of attentional focus

Inflammation is associated with fatigue, as evident from the lethargy of acute infections. This is mediated by pro-inflammatory cytokines, which act on the brain to result in drowsiness, loss of appetite, decreased activity and withdrawal from social interaction. The association between treatment with interferon-a (IFN-a) and fatigue (which is dissociable from depression) is well recognized. As inflammatory degenerative disorders, elevated cytokines are particularly relevant to fatigue in MS and systemic lupus erythematosus (SLE). Cytokines are however also elevated post-stroke and TBI, in CFS, and even in PD, and depression, likely also contributing to fatigue in these conditions.

Alterations in the hypothalamic-pituitary-adrenal (HPA) axis are among the most replicated findings in CFS, mild hypocortisolaemia being consistently reported and attributed to enhanced negative feedback in the HPA axis. This contrasts with the increased HPA axis activity and raised cortisol levels seen in depression. Whereas hormonal changes are relatively subtle in MS and CFS, in TBI, (and obviously pituitary stroke), they can be gross and necessitate replacement treatment. In TBI these abnormalities are not restricted to the acute phase, with as many as 25% of long-term survivors showing one or more pituitary hormone deficiencies. As well as hypocortisolaemia and hypothyroidism being obvious causes of fatigue, an association with lowered growth and sex hormone levels following TBI has been reported.

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+3 Neurological Dysfunction

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