Decreased basal ganglia function and relationship to fatigue in CFS

Abstract

Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation. Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation.

In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls.

For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses. Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects.

These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

Decreased Basal Ganglia Activation in Subjects with Chronic Fatigue Syndrome: Association with Symptoms of Fatigue, by  Andrew H. Miller et al in PLoS ONE 9(5) May 23, 2014

Press release: Brain imaging reveals clues about chronic fatigue syndrome

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Reduced blood flow following reduced nitrergic nitric oxide in POTS

Abstract

Cognitive deficits are characteristic of postural tachycardia syndrome (POTS). Intact nitrergic nitric oxide (NO) is important to cerebral blood flow (CBF) regulation, to neurovascular coupling, and to cognitive efficacy. POTS patients often experience defective (NO) mediated vasodilation caused by oxidative stress. We previously showed dilation of the middle cerebral artery (MCA) in response to a bolus administration of the NO donor sodium nitroprusside (SNP) in healthy volunteers. We hypothesized a blunted MCA response to SNP in POTS.

 

Using combined transcranial-Doppler-ultrasound to measure CBF velocity (CBFv), and near-infrared spectroscopy (NIRS) to measure cerebral hemoglobin oxygenation while supine. The responses of 17 POTS patients were compared with 12 healthy controls (ages 14-28). CBFv in POTS and control were not different at baseline (75 ± 3 vs. 71 ±2 cm • s-1 P =0.31) and decreased to a lesser degree with SNP in POTS (to 71 ± 3 vs 62 ± 2 cm • s-1; P = 0.02). The changes in total and oxygenated hemoglobin (8.83 ± 0.45 and 8.13 ± 0.48 µmol/kg tissue) were markedly reduced in POTS compared to control (14.2 ± 1.4 and 13.6 ± 1.6 µmol/kg tissue), primarily due to increased venous efflux.

 

The data indicate reduced cerebral oxygenation, blunting of cerebral arterial vasodilation and heightened cerebral venodilation. We conclude based on the current study outcomes decreased bioavailability of NO is apparent in the vascular beds resulting in a down regulation of NO receptor sites, ultimately leading to blunted responses to exogenous NO.

 

Blunted Cerebral Blood Flow Velocity in Response to a Nitric Oxide Donor in Postural Tachycardia Syndrome (POTS), by Andrew Thomas Del Pozzi et al in American Journal of Physiology – Heart and Circulatory Physiology, 30 May 2014

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Cerebrospinal fluid pressure may be problem in CFS

Abstract

 

Objective

Unsuspected idiopathic intracranial hypertension (IIH) is found in a significant minority of patients attending clinics with named headache syndromes, if it is specifically sought out. Chronic fatigue syndrome is frequently associated with headache. Could the same be true of chronic fatigue? Moreover, there are striking similarities between the two conditions. Could they be related? Attempting to answer these questions, we describe the results of a change in clinical practice aimed at capturing patients with chronic fatigue who might have IIH.

 

Design

Cross-sectional.

 

Setting

Hospital outpatient and radiology departments.

 

Participants

Patients attending a specialist clinic with chronic fatigue syndrome and headache who had lumbar puncture to exclude raised intracranial pressure.

 

Main outcome measures

Intracranial pressure measured at lumbar puncture and the effect on headache of cerebrospinal fluid drainage.

 

Results

Mean cerebrospinal fluid pressure was 19cm H2O (range 12–41cm H2O). Four patients fulfilled the criteria for IIH. Thirteen others did not have pressures high enough to diagnose IIH but still reported an improvement in headache after drainage of cerebrospinal fluid. Some patients also volunteered an improvement in other symptoms, including fatigue. No patient had any clinical signs of raised intracranial pressure.

 

Conclusions

An unknown, but possibly substantial, minority of patients with chronic fatigue syndrome may actually have IIH. An unknown, but much larger, proportion of patients with chronic fatigue syndrome do not have IIH by current criteria but respond to lumbar puncture in the same way as patients who do. This suggests that the two conditions may be related.

Lumbar puncture, chronic fatigue syndrome and idiopathic intracranial hypertension: a cross-sectional study by N Higgins, J Pickard, A Lever in JRSM Short Rep. 2013 Nov 21;4

 

Comments by Cort Johnson:

Pressure building? Study suggests Cerebral Spinal Fluid pressure may be causing problems in Chronic Fatigue Syndrome 

 

 

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ME/CFS brain and tissue bank protocol

Abstract (provisional)

 

Background

Our aim, having previously investigated through a qualitative study involving extensive discussions with experts and patients the issues involved in establishing and maintaining a disease specific brain and tissue bank for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), was to develop a protocol for a UK ME/CFS repository of high quality human tissue from well characterised subjects with ME/CFS and controls suitable for a broad range of research applications. This would involve a specific donor program coupled with rapid tissue collection and processing, supplemented by comprehensive prospectively collected clinical, laboratory and self-assessment data from cases and controls.

 

Findings

We reviewed the operations of existing tissue banks from published literature and from their internal protocols and standard operating procedures (SOPs). On this basis, we developed the protocol presented here, which was designed to meet high technical and ethical standards and legal requirements and was based on recommendations of the MRC UK Brain Banks Network and the Brain Net Europe II network. The facility would be most efficient and cost-effective if incorporated into an existing tissue bank. Tissue collection would be rapid and follow robust protocols to ensure preservation sufficient for a wide range of research uses. A central tissue bank would have resources both for wide-scale donor recruitment and rapid response to donor death for prompt harvesting and processing of tissue.

 

Conclusion

An ME/CFS brain and tissue bank could be established using this protocol. Success would depend on careful consideration of logistic, technical, legal and ethical issues, continuous consultation with patients and the donor population, and a sustainable model of funding ideally involving research councils, health services, and patient charities. This initiative could revolutionise the understanding of this still poorly-understood disease and enhance development of diagnostic biomarkers and treatments.

 

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Considerations in establishing a post-mortem brain and tissue bank for the study of myalgic encephalomyelitis/chronic fatigue syndrome: a proposed protocol by Luis Nacul, Dominic G O’Donovan, Eliana M Lacerda, Djordje Gveric, Kirstin Goldring, Alison Hall, Erinna Bowman and Derek Pheby in BMC Research Notes 2014, 7:370  Published: 18 June 2014

 

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Why those with treatable diseases get more sympathy than ME

Martha Gill, a blogger on politics and neurosciences comments:

According to reports, a third of people who think they have ME may actually be suffering from something else – a disease called postural tachycardia syndrome (PoTS). It has the same symptoms – tiredness, dizziness, fainting – but it’s treatable.

 

Great news for them, but the discovery, I suspect, will also have a rather strange consequence. Those who have suddenly stopped having ME and suddenly started having PoTS will get a lot more sympathy.

 

Not because the underlying cause is any clearer or more “real” – it’s still extravagantly vague (according to our report this morning, it could be the result of “a viral infection or hormonal changes” – read: anything). But because these patients can be treated.

 

People with ME have famously received rather short shrift. Back in the 1970s, psychiatrists labelled cases a “mass hysteria”. It wasn’t until 1993 that it was finally accepted as a real condition, but even then, people with the disorder had to struggle to convince their doctors, friends and employers they weren’t simply imagining the whole thing. In an effort to make people take it seriously, the term “chronic fatigue syndrome” (too vague) was changed to “myalgic encephalopathy” – but “yuppie flu” and “shirker syndrome” remained popular alternatives.

 

The patient lobby has so far concentrated on raising awareness of the realities of the disease – stories of people’s long, hopeless struggles with the condition are all over the internet. They have tried to raise the profile of medical findings around ME, and its association with various, more “valid” diseases: infection with Epstein Barr virus, for example, or Lyme disease. Still the prejudice drags on. But perhaps the patient lobby has been barking up the wrong tree. Perhaps they should have been spreading a message of hope instead – that a cure can’t be too far off.

 

It’s odd, but sometimes, when bad, unsolvable things happen to people, we start to like them a great deal less. The psychologist Melvin Lerner talked about the “just world hypothesis” – the idea that we hate injustice so much that, if someone seems to be undergoing an unfair punishment, we start inventing crimes to fit it. Especially if we can’t help them escape.

One of his classic demonstrations placed a group of volunteers are behind a screen, from where they can see a woman sitting on a chair, with electrodes fixed to her. They are told she is about to undergo a learning experiment.

 

The learning experiment turns out to be a little burlesque. The woman (secretly an actress) is asked questions, and when she gets them wrong, she appears to get electrocuted. The volunteers (by now thoroughly alarmed) – see her scream and flail around.

 

One group is then given the chance to rescue her – and they invariably do. When asked why, they reply that she is innocent, and didn’t deserve the treatment.

 

A second group of volunteers is not given the chance to rescue her, but are instead told various explanations for her treatment. Some are told she is getting money for her pains, some are told she gets no reward at all. A final group are told she is sacrificing herself in order to save the other volunteers.

 

Now comes the interesting bit: the less the victim was paid, the worse the volunteers thought of her. Most despised of all was the martyr – she clearly deserved what she got.

 

Lerner came to a disturbing conclusion: “The sight of an innocent person suffering without possibility of reward or compensation motivated people to devalue the attractiveness of the victim in order to bring about a more appropriate fit between her fate and her character.”

 

If someone’s story is too bad, and too hopeless, we find it hard to sympathise. It just seems to demand too much. Unfair, perhaps, but that’s just how we’re wired – and those trying to garner attention for worthy causes should know this. Put some hope in there too.

 

ME, ‘yuppie flu’, and why those with treatable diseases get more sympathy by Martha Gill in the Telegraph online, June 18th, 2014

 

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POTS affects mostly young women

Abstract

Objective

To examine a large UK cohort of patients with postural tachycardia syndrome (PoTS), to compare demographic characteristics, symptoms and treatment of PoTS at one centre compared to the largest patient group PoTS UK and to verify if their functional limitation is similar to patients with chronic fatigue syndrome (CFS).

 

Design

A cross-sectional study assessed the frequency of symptoms and their associated variables. Patients and setting Two PoTS cohorts were: (1) recruited via PoTS UK, (2) diagnosed at Newcastle Hospitals National Health Service (NHS) Foundation Trust 2009–2012. Patients with PoTS were then compared to a matched cohort with CFS.

 

Main outcome measures Patients’ detailed demographics, time to diagnosis, education, disability, medications, comorbidity and precipitants. Symptom assessment tools captured, Fatigue Impact Scale, Epworth Sleepiness Scale, Orthostatic Grading Scale (OGS), Hospital Anxiety and Depression Scale, Health Assessment Questionnaire, Cognitive Failures Questionnaire.

 

Results

136 patients with PoTS participated (84 members of PoTS UK (170 cohort; 50% return) and 52 (87 cohort; 60%) from Newcastle Clinics). The PoTS UK population was significantly younger than the clinic patients, with significantly fewer men (p=0.005). Over 60% had a university or postgraduate degree. Significantly more of the PoTS UK cohort were working, with hours worked being significantly higher (p=0.001). Time to diagnosis was significantly longer in the PoTS UK cohort (p=0.04). Symptom severity was comparable between cohorts. The PoTS total group was compared with a matched CFS cohort; despite comparable levels of fatigue and sleepiness, autonomic symptom burden (OGS) was statistically significantly higher. The most common treatment regime included β-blockers. Overall, 21 treatment combinations were described. Up to 1/3 were taking no treatment.

 

Conclusions

Patients with PoTS are predominantly women, young, well educated and have significant and debilitating symptoms that impact significantly on quality of life. Despite this, there is no consistent treatment.

 

Postural tachycardia syndrome is associated with significant symptoms and functional impairment predominantly affecting young women: a UK perspective, by Claire McDonald, Sharon Koshi, Lorna Busner, Lesley Kavi, Julia L Newton in BMJ Open 2014, 4:6

 

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Post-traumatic hypopituitarism (PTHP) often misdiagnosed as CFS

  • Patients misdiagnosed with CFS when they have brain damage
  • Post-traumatic hypopituitarism (PTHP) is often cause by head injury
  • Symptoms include depression, obesity, fatigue and chronic pain

Numerous studies have shown that between 20 and 30 per cent of the 135,000 patients who suffer a serious head injury also experience damage to the pituitary gland, which is situated below the brain, behind the nasal cavity.

The gland produces vital hormones that govern many bodily functions, including growth and repair, the sleep-wake cycle and how we react to stress. If the pea-sized organ is damaged, it may stop producing one or more of the essential hormones, triggering the wide-ranging symptoms of hypopituitarism.

Studies suggest there could be between 18,000 and 30,000 cases in the UK each year.

Treatment involves lifelong hormone replacement therapy, which is said to be highly effective but costs up to £6,000 a year.

More information in the Daily Mail: How doctors are failing to spot the brain injury that could be behind 30,000 cases of ‘chronic fatigue’

 

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Blood flow increases in the brain in POTS

Abstract

Decreased upright cerebral blood flow (CBF) with hyperpnea and hypocapnia is seen in a minority of patients with postural tachycardia syndrome (POTS).

More often, CBF is not decreased despite upright neurocognitive dysfunction. This may result from time-dependent changes in CBF. We hypothesized that increased oscillations in CBF occurs in POTS (N=12) compared to healthy controls (N=9), and tested by measuring CBF velocity (CBFv) by transcranial Doppler ultrasound of the middle cerebral artery, mean arterial pressure (MAP) and related parameters, supine and during 70o upright tilt. Autospectra for mean CBFv and MAP, and transfer function analysis were obtained over the frequency range of 0.0078 to 0.4 Hz. Upright HR was increased in POTS

(125±8 vs 86±2 bpm), as was diastolic BP (74±3 vs 65±3 mmHg) compared to control, while peripheral resistance, cardiac output, and mean CBFv increased similarly with tilt. Upright BP variability (BPV), low frequency (LF) power (.04 – 0.13 Hz) , and peak frequency of BPV were increased in POTS (24.3±4.1, and 18.4±4.1 mmHg2/Hz at .091 Hz vs 11.8±3.3, and 8.8 ± 2 mmHg2/Hz c at 0.071 Hz), as was upright overall CBFv variability, low frequency power and peak frequency of CBFv variability (29.3±4.7, and 22.1±2.7 [cm/s]2/Hz at .092 Hz vs 14.7±2.6, and 6.7 ± 1.2 [cm/s]2/Hz at 0.077Hz). Autospectra were sharply peaked in POTS.

LF phase was decreased in POTS (-14 ± 4 vs -25 ± 10 degrees) while upright. LF gain was increased (1.51 ± 0.09 vs 0.86 ± 0.12 [cm/s]/ mmHg) while coherence was increased (0.96 ± 0.01 vs 0.80 ± 0.04).

Increased oscillatory BP in upright POTS patients is closely coupled to oscillatory CBFv over a narrow bandwidth corresponding to the Mayer wave frequency. Therefore combined increased oscillatory BP and increased LF gain markedly increases CBFv oscillations in a narrow bandwidth. This close coupling of CBF to MAP indicates impaired cerebral autoregulation that may underlie upright neurocognitive dysfunction in POTS.

Increases in Oscillatory Cerebral Blood Flow Velocity in Postural Tachycardia Syndrome, by Marvin S. Medow et al in Front. Physiol. 5:234

 

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Neuropsychological impairment in women with CFS

Abstract

This study examines neuropsychological impairments associated with chronic fatigue syndrome (CFS) and explores their association with related clinical factors.

Sixty-eight women with CFS were assessed with a neuropsychological battery. Raw scores were adjusted for age and gender and were converted to T scores according to normative data extracted from a local sample of 250 healthy subjects. Neuropsychological dysfunction was calculated using summary impairment indexes (proportion of test scores outside normal limits-T score <40-for each cognitive domain). Finally, a linear regression was calculated to identify predictors of cognitive deficit, including intrinsic factors of the disease (level of fatigue and length of illness) and extrinsic factors (emotional factors, age, and education).

Approximately 50% of scores showed impairment in attention and motor functioning, and nearly 40% showed impairment in speed information processing and executive functioning. Fatigue predicted attention and executive functioning impairment, and emotional factors predicted verbal memory dysfunction.

According to our findings, cognitive dysfunction in CFS could be explained by pathophysiological processes of the disease. One implication of this would be the need to identify homogeneous subgroups of patients with CFS by taking into account common factors, which, in turn, would help to identify more specific cognitive profiles, which could then serve to implement appropriate therapeutic measures accordingly.

Neuropsychological impairment in female patients with chronic fatigue syndrome: a preliminary study by P Santamarina-Perez in Appl Neuropsychol Adult. 2014;21(2):120-7.

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Brain neuron damage level in CFS similar to MS

Abstract

 

Objective: This study examined the levels of a major regulator of neuronal survival, brain derived neurotrophic factor (BDNF) in two populations; individuals with multiple sclerosis and chronic fatigue syndrome. BDNF is a protein involved in the maintenance and maturation of both peripheral and central neurons. In patients with multiple sclerosis, BDNF expression is often decreased and believed to reflect ineffective repair mechanisms. As a preliminary exploration, we examined the production of BDNF on the part of peripheral blood mononuclear cells in three groups: patients with Chronic Fatigue Syndrome (CFS [n=15]), patients with multiple sclerosis (n=57), and a set of putatively healthy controls (n=37).

 

Methods: Mononuclear cells were extracted from peripheral blood samples and cultured for 48 hours. Production of BDNF was evaluated from phyto-haemagglutinin (PHA) and phorbol-12-myristate-13-acetate (PMA) stimulated and unstimulated cells. BDNF levels were determined using a commercially available enzyme linked immune absorbent assay

(sensitivity: 62.5-4,000 pg/mL).

 

Results: Both CFS and MS samples displayed nearly identical levels of BDNF, levels that were 25 percent of that displayed by the healthy control sample. For unstimulated cells, the BDNF values were 404.71 pg/ml for the CFS sample, 573.33 pg/ml for the MS sample and ,114.15 pg/ml for the control sample. For stimulated cells, the BDNF values were 442.55 pg/ml for the CFS sample, 367.33 pg/ml for the stimulated MS sample, and 432.24 pg/ml for the stimulated control sample.

 

Conclusion: The deceased production of BDNF on the part of MS patients is consistent with the literature. However, the decreased production in those with CFS was unexpected and a novel finding. This finding could reflect a reduced ability to maintain neuronal structure and function in those with CFS. Future studies are needed to evaluate for neuronal damage in those with CFS.

 

Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue Syndrome and Multiple Sclerosis, by Matthew Sorenson, Leonard Jason, Jonna Peterson, Joshua Herrington, and Herbert Mathews in J Neurol Neurophysiol 2014, S12:013

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