Increasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor encoded by NFE2L2. Under oxidative stress, Nrf2 does not undergo its normal cytoplasmic degradation but instead travels to the nucleus, where it binds to a DNA promoter and initiates transcription of anti-oxidative genes. Nrf2 upregulation is associated with increased cellular levels of glutathione disulfide, glutathione peroxidase, glutathione transferases, thioredoxin and thioredoxin reductase. Given its key role in governing the cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder and schizophrenia, which are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide and peroxynitrite. These processes lead to extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA. Intake of N-acetylcysteine, coenzyme Q10 and melatonin is accompanied by increased Nrf2 activity. N-acetylcysteine intake is associated with improved cerebral mitochondrial function, decreased central oxidative and nitrosative stress, reduced neuroinflammation, alleviation of endoplasmic reticular stress and suppression of the unfolded protein response. Coenzyme Q10, which acts as a superoxide scavenger in neuroglial mitochondria, instigates mitohormesis, ameliorates lipid peroxidation in the inner mitochondrial membrane, activates uncoupling proteins, promotes mitochondrial biogenesis and has positive effects on the plasma membrane redox system. Melatonin, which scavenges mitochondrial free radicals, inhibits mitochondrial nitric oxide synthase, restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, ameliorates increased permeability of the blood-brain barrier and intestine and counters neuroinflammation and glutamate excitotoxicity.

The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it?

Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.

Removal of DNA adducts.

DNA adducts are associated with a number of diseases, including cancer. Based on a recent report by our group, the aim of this study was to test the hypothesis that DNA adducts can be removed by means of one or more of the following three intervention programmes: intermittent whole-body hyperthermia; detoxification; and cell repair. The number of DNA adducts and total DNA adduct concentrations were measured in 104 patients who underwent one or more of the three intervention programmes. DNA adduct assessments were carried out on extracted genomic DNA by gas-liquid chromatography, with any DNA adducts found being localised using DNA microarrays. The baseline median number of DNA adducts was 2. The follow-up median number of adducts was highly significantly lower at 0 (p < 0.000000000000003). The mean total DNA adduct concentration at baseline was 9.308 ng/mL, and highly significantly lower at follow-up at 1.553 ng/mL (p < 0.000000000000006). Of the three intervention programmes, only the intermittent whole-body hyperthermia was associated with a significant reduction in DNA adducts. This study offers support for the hypothesis that DNA adducts can be removed by intermittent whole-body hyperthermia. The intermittent hyperthermia used involved infrared-A (wavelength 700-1400 nm, or, equivalently, a frequency of 215-430 THz) being preferentially delivered to the whole body, apart from the head, for up to one hour per session, with gradual core body temperature elevation usually occurring during the first 20-30 min. These results may offer an explanation at the molecular level for other reported clinical benefits of intermittent whole-body hyperthermia.

Fructose-associated hepatotoxicity indexed by the lactate dehydrogenase isoenzyme LDH-5.

Modern diets have become increasingly rich in fructose, for example through the addition of high-fructose corn syrup to many foods and drinks. It has been suggested that this might lead to hepatotoxicity, including the development of non-alcoholic fatty liver disease. After entering hepatocytes via insulin-independent glucose transporter 2 transmembrane carrier proteins, fructose is phosphorylated to fructose-1-phosphate in a reaction catalysed by fructokinase (ketohexokinase). In turn, fructose-1-phosphate is hydrolysed by aldolase B to glyceraldehydes. Glyceraldehydes may enter gluconeogenesis via fructose-1,6-bisphosphate and fructose-6-phosphate; glyceraldehydes may also enter glycogenolysis via pyruvate. The last pathway involves conversion of pyruvate to acetyl-CoA. Alternatively, pyruvate may be converted, via the action of the hepatic lactate dehydrogenase isoenzyme LDH-5, into lactate. In liver damage, the LDH-5 isoenzyme becomes elevated, predominantly in serum/plasma. We therefore hypothesised that if dietary fructose is associated with hepatotoxicity, there should be a positive correlation between erythrocyte fructose-6-phosphate and plasma LDH-5. This hypothesis was tested by assaying venous blood samples taken from 39 patients at rest, three hours after eating. Quantitative Fourier transform infrared spectrometry following gel electrophoresis was used to assay erythrocyte fructose-6-phosphate levels. Similarly, plasma LDH-5 concentrations were spectrophotometrically analysed, using the pyruvate-lactate reaction, following electrophoretic separation of the LDH isoenzymes. A significant positive correlation was found between the two variables (r = 0.44, p = 0.0047). This result, which supports our hypothesis, is evidence in favour of the possibility that dietary fructose is associated with hepatotoxicity. In addition to being a marker of hepatic damage, LDH-5 may play a more direct epigenetic role in causing liver damage; acute hepatic injury is associated with nuclear translocation of LDH, causing the production of lactate from pyruvate in the nucleus; in turn, the lactate inhibits histone deacetylase and is associated with upregulation of genes associated with the damage response, leading to cell death.

Inverse relationship between human erythrocyte fructose-6-phosphate and short-chain fatty acid levels.

In muscle cells, fructose is initially metabolised to fructose-6-phosphate. In the liver, fructose is metabolised to fructose-1-phosphate and thence to glyceraldehydes, which in turn can either enter glycogenolysis via pyruvate or gluconeogenesis via fructose-1,6-bisphosphate and fructose-6-phosphate. High levels of fructose-1-phosphate inhibit both glycogenolysis and gluconeogenesis. We hypothesised that, if systemically absorbed short-chain fatty acids constitute a major metabolic fate of unabsorbed dietary fructose, then levels of erythrocyte fructose-6-phosphate would be inversely correlated with plasma levels of short-chain fatty acids. The aim of this study was to test this hypothesis in respect of the three main short-chain fatty acids acetate, propionate and butyrate. Venous blood samples from 39 patients (16 male, 23 female, mean (standard error) age 42.4 (3.3) years) were analysed. Erythrocyte fructose-6-phosphate was measured using quantitative Fourier transform infrared spectrometry following gel electrophoresis, while plasma acetate, propionate and butyrate levels were measured using gas-liquid chromatography. The erythrocyte fructose-6-phosphate level was inversely correlated with the plasma acetate (r = -0.30, p = 0.06), propionate (r = -0.31, p = 0.05) and butyrate (r = -0.40, p = 0.01). These results support our hypothesis. The conversion of unabsorbed dietary fructose into short-chain fatty acids may represent a protective mechanism against the adverse effects of hypoglycaemia.

Neuromuscular taping reduces blood pressure in systemic arterial hypertension.

Systemic arterial hypertension, a well-known cause of morbidity, is associated with dysfunction of the autonomic nervous system. Neuromuscular taping (also known as kinesio taping, medical taping and Vendje neuromuscular) allows movement and muscle activity to treat pain, muscle disorders and lymphoedema, in which its mode of action may involve muscular stimulation leading to increased local blood circulation or stimulating dermatological, muscular and fascial structures with a form of passive massage. We hypothesised that neuromuscular taping may reduce blood pressure in systemic arterial hypertension. This hypothesis was tested by carrying out the first pilot study of its kind to determine whether the non-invasive technique of neuromuscular taping can reduce blood pressure in patients suffering from systemic arterial hypertension. Neuromuscular taping was symmetrically applied to the back, between C1 and T2, of seven hypertensive patients for 5-7 days. Cardiovascular autonomic parameters were assessed at baseline and at the end of the study. Taping was associated with falls in mean arterial blood pressure (p = .001), mean systolic blood pressure (p < .01), mean diastolic pressure (p < .01) and cardiac vagal tone at rest (p = .063). The beneficial effects on blood pressure appeared to last for at least five days post-neuromuscular taping. There is an indication, given the reduction in cardiac vagal tone at rest, that the mechanism of action of this intervention involves modulation of the brainstem parasympathetic system during cardiovascular control. Further studies are indicated to replicate the present findings, further investigate the effects of taping on autonomic functioning, and establish the optimum time-period and taping positioning.

The relationship between plasma vascular endothelial growth factor and erythrocyte 2,3-bisphosphoglycerate: The putative role of chronic hypoxia.

The non-invasive assessment of chronic tissue hypoxia is difficult. Pulse oximetry only allows the peripheral oxygen saturation to be measured, while the detection of hyperlactataemia needs to take into account the fact that the accumulation of lactic acid may result from several causes other than prolonged tissue hypoxia. Arterial blood oxygen measurement is invasive and often does not give a good indication of the level of tissue hypoxia. Other suggested methods include the use of positron emission tomography, magnetic resonance T2∗ relaxation time measurement, photoacoustics and high-frequency ultrasound. Tissue hypoxia leads to increased levels of hypoxia-inducible factor-1α, which in turn upregulates VEGFA, leading to increased levels of vascular endothelial growth factor (VEGF), which promote angiogenesis. Hypoxia lasting for more than a few hours is associated with increased synthesis in erythrocytes of 2,3-bisphosphoglycerate (BPG), a powerful regulator of the allosteric properties of haemoglobin, via the Rapoport-Luebering phosphoglycerate cycle. We therefore hypothesised that plasma VEGF and erythrocyte BPG levels should be positively correlated. Venous blood samples from 34 patients (18 male, mean age (standard error) 43.4 (3.2) y) were analysed; plasma VEGF was measured using an enzyme-linked immunosorbent assay while the erythrocyte BPG was assessed by quantitative Fourier transform infrared spectrometry following gel electrophoresis. The Pearson product-moment correlation between the two variables was 0.622 (p < 0.0001). Based on our findings, we suggest that it may be useful to measure both erythrocyte BPG and plasma VEGF, together, when assessing chronic hypoxia; elevated levels of both are likely to indicate hypoxia.

Carbon dioxide therapy in hypocapnic respiratory failure.

Oxygen therapy, usually administered by a facemask or nasal cannulae, is the current default treatment of respiratory failure. Since respiration entails intake of oxygen and release of carbon dioxide from tissues as waste product, the notion of administering carbon dioxide in respiratory failure appears counter-intuitive. However, carbon dioxide stimulates the chemosensitive area of the medulla, known as the central respiratory chemoreceptor, which activates the respiratory groups of neurones in the brainstem and stimulates inspiration thereby initiating oxygen intake during normal breathing. This vital initiation of normal breathing is via a reduction in the pH of the cerebrospinal fluid and the medullary interstitial fluid. We hypothesise that in cases of type I respiratory failure in which the PaCO2 is low, administration of carbon dioxide by inhalation would stimulate the respiratory groups of brainstem neurones and facilitate breathing, which would be of therapeutic value. Preliminary clinical evidence in favour of this hypothesis is presented and we recommend that a formal randomised study be carried out.

The Putative Role of Environmental Mercury in the Pathogenesis and Pathophysiology of Autism Spectrum Disorders and Subtypes.

Exposure to organic forms of mercury has the theoretical capacity to generate a range of immune abnormalities coupled with chronic nitro-oxidative stress seen in children with autism spectrum disorder (ASD). The paper discusses possible mechanisms explaining the neurotoxic effects of mercury and possible associations between mercury exposure and ASD subtypes. Environmental mercury is neurotoxic at doses well below the current reference levels considered to be safe, with evidence of neurotoxicity in children exposed to environmental sources including fish consumption and ethylmercury-containing vaccines. Possible neurotoxic mechanisms of mercury include direct effects on sulfhydryl groups, pericytes and cerebral endothelial cells, accumulation within astrocytes, microglial activation, induction of chronic oxidative stress, activation of immune-inflammatory pathways and impairment of mitochondrial functioning. (Epi-)genetic factors which may increase susceptibility to the toxic effects of mercury in ASD include the following: a greater propensity of males to the long-term neurotoxic effects of postnatal exposure and genetic polymorphisms in glutathione transferases and other glutathione-related genes and in selenoproteins. Furthermore, immune and inflammatory responses to immunisations with mercury-containing adjuvants are strongly influenced by polymorphisms in the human leukocyte antigen (HLA) region and by genes encoding effector proteins such as cytokines and pattern recognition receptors. Some epidemiological studies investigating a possible relationship between high environmental exposure to methylmercury and impaired neurodevelopment have reported a positive dose-dependent effect. Retrospective studies, on the other hand, reported no relationship between a range of ethylmercury-containing vaccines and chronic neuropathology or ASD. On the basis of these results, we would argue that more clinically relevant research is required to examine whether environmental mercury is associated with ASD or subtypes. Specific recommendations for future research are discussed.

Cell Death Pathways: a Novel Therapeutic Approach for Neuroscientists.

In the first part, the following mechanisms involved in different forms of cell death are considered, with a view to identifying potential therapeutic targets: tumour necrosis factor receptors (TNFRs) and their engagement by tumour necrosis factor-alpha (TNF-α); poly [ADP-ribose] polymerase (PARP)-1 cleavage; the apoptosis signalling kinase (ASK)-c-Jun N-terminal kinase (JNK) axis; lysosomal permeability; activation of programmed necrotic cell death; oxidative stress, caspase-3 inhibition and parthanatos; activation of inflammasomes by reactive oxygen species and the development of pyroptosis; oxidative stress, calcium dyshomeostasis and iron in the development of lysosomal-mediated necrosis and lysosomal membrane permeability; and oxidative stress, lipid peroxidation, iron dyshomeostasis and ferroptosis. In the second part, there is a consideration of the role of lethal and sub-lethal activation of these pathways in the pathogenesis and pathophysiology of neurodegenerative and neuroprogressive disorders, with particular reference to the TNF-α-TNFR signalling axis; dysregulation of ASK-1-JNK signalling; prolonged or chronic PARP-1 activation; the role of pyroptosis and chronic inflammasome activation; and the roles of lysosomal permeabilisation, necroptosis and ferroptosis. Finally, it is suggested that, in addition to targeting oxidative stress and inflammatory processes generally, neuropsychiatric disorders may respond to therapeutic targeting of TNF-α, PARP-1, the Nod-like receptor NLRP3 inflammasome and the necrosomal molecular switch receptor-interacting protein kinase-3, since their widespread activation can drive and/or exacerbate peripheral inflammation and neuroinflammation even in the absence of cell death. To this end, the use is proposed of a combination of the tetracycline derivative minocycline and N-acetylcysteine as adjunctive treatment for a range of neuropsychiatric disorders.

The effect of artesunate on short-term memory in Lyme borreliosis.

Lyme borreliosis is associated with memory deficits. While this may be related to cerebral infection by Borrelia bacteria, it may also be caused by concomitant co-infection by Babesia protozoa. The anti-malarial artemisinin-derivative artesunate has been shown to be effective against a number of Babesia species and to have efficacy against human cerebral malaria. We hypothesised that concomitant administration of artesunate in Lyme borreliosis patients would help alleviate the severity of self-reported short-term memory impairment. This hypothesis was tested in a small pilot study in which patients were treated with both an intravenous antibiotic and oral artesunate (20mg four times per day); treatment was associated with a reduction in the severity of short-term memory difficulties (P≃0.08). In light of these findings, we recommend that a formal randomised, placebo-controlled study be carried out.

The potential use of cholestyramine to reduce the risk of developing Clostridium difficile-associated diarrhoea in patients receiving long-term intravenous ceftriaxone.

Intravenous pharmacotherapy with the third-generation cephalosporin ceftriaxone is unfortunately associated with a relatively high incidence of Clostridium difficile-associated diarrhoea. Cholestyramine (colestyramine) is an anion-binding resin which can bind luminal C.difficile toxin A (TcdA) and toxin B (TcdB) and which may be beneficial in the treatment of recurrent antibiotic-associated pseudomembranous colitis. We therefore hypothesised that concomitant oral cholestyramine might reduce the risk of C.difficile-associated diarrhoea in patients receiving long-term intravenous ceftriaxone. A pilot study was carried out in which it was found that only three out of 46 (6.5%) such patients being treated with 2 g ceftriaxone daily for Lyme borreliosis, who also received 4 g cholestyramine daily, developed C.difficile-associated diarrhoea. This is smaller than a published report of the incidence of this complication in six out of 26 (23.1%) patients following 1-3 days' treatment with 1 g intravenous ceftriaxone, but without oral cholestyramine (p=0.06). We therefore recommend that a larger, double-blind placebo-controlled trial be carried out to test this hypothesis.

The risk of lead contamination in bone broth diets.

The preparation and consumption of bone broth is being increasingly recommended to patients, for example as part of the gut and psychology syndrome (GAPS) diet for autism, attention-deficit hyperactivity disorder, dyslexia, dyspraxia, depression and schizophrenia, and as part of the paleolithic diet. However, bones are known to sequester the heavy metal lead, contamination with which is widespread throughout the modern environment. Such sequestered lead can then be mobilised from the bones. We therefore hypothesised that bone broth might carry a risk of being contaminated with lead. A small, blinded, controlled study of lead concentrations in three different types of organic chicken broth showed that such broths do indeed contain several times the lead concentration of the water with which the broth is made. In particular, broth made from skin and cartilage taken off the bone once the chicken had been cooked with the bones in situ, and chicken-bone broth, were both found to have markedly high lead concentrations, of 9.5 and 7.01 µg L(-1), respectively (compared with a control value for tap water treated in the same way of 0.89 µg L(-1)). In view of the dangers of lead consumption to the human body, we recommend that doctors and nutritionists take the risk of lead contamination into consideration when advising patients about bone broth diets.

Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study.

OBJECTIVE: It is not established whether myalgic encephalomyelitis/chronic fatigue syndrome (CFS) is associated with structural brain changes. The aim of this study was to investigate this by conducting the largest voxel-based morphometry study to date in CFS. METHODS: High-resolution structural 3 T cerebral MRI scanning was carried out in 26 patients with CFS and 26 age- and gender-matched healthy volunteers. Voxel-wise generalised linear modelling was applied to the processed MR data using permutation-based non-parametric testing, forming clusters at t>2.3 and testing clusters for significance at p<0.05, corrected for multiple comparisons across space. RESULTS: Significant voxels (p<0.05, corrected for multiple comparisons) depicting reduced grey matter volume in the CFS group were noted in the occipital lobes (right and left occipital poles; left lateral occipital cortex, superior division; and left supracalcrine cortex), the right angular gyrus and the posterior division of the left parahippocampal gyrus. Significant voxels (p<0.05, corrected for multiple comparisons) depicting reduced white matter volume in the CFS group were also noted in the left occipital lobe. CONCLUSION: These data support the hypothesis that significant neuroanatomical changes occur in CFS, and are consistent with the complaint of impaired memory that is common in this illness; they also suggest that subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movements, may occur in CFS.

Indexation of cerebral cell membrane phospholipid catabolism by the non-invasively determined cerebral 31-phosphorus neurospectroscopic phosphodiester peak.

Breakdown of mammalian cerebral cell membrane phospholipids releases phosphorylated polar head groups from the sn-3 phospholipid position, including phosphorylcholine and phosphorylethanolamine. Glycerophosphorylcholine and glycerophosphorylethanolamine are on their catabolic pathways and have been assigned to the phosphodiester narrow resonance obtained from 31-phosphorus neurospectroscopy, accounting for approximately 38% of the overall signal; therefore in human in vivo 31-phosphorus neurospectroscopy neuropsychiatric studies this narrow resonance has been used to index the catabolism of cerebral cell membrane phospholipids non-invasively. However, for ethical reasons direct assessment of this assumption has not hitherto been possible in humans. Recently, it has become possible to analyze signal directly from the cell membrane motion-restricted phospholipids by analysis of a broad resonance signal. It was therefore hypothesized that there should be a negative correlation between the phosphodiester narrow resonance and the broad resonance signal if the former does indeed index cell membrane phospholipid catabolism. Cerebral 31-phosphorus magnetic resonance spectroscopy was carried out in 54 human subjects (mean age 38 years; 41 male), including normal volunteers and patients with schizophrenia, in order potentially to widen the range of phosphodiester and broad resonance values. Spectra were obtained from 70 × 70 × 70 mm(3) voxels using an image-selected in vivo spectroscopy pulse sequence. There was a highly significant negative correlation between the phosphodiester resonances and the broad resonance signals (r=-0.509, P<0.0001). This result is consistent with the hypothesis that the phosphodiester narrow resonance does index cell membrane phospholipid catabolism in non-invasive human neuropsychiatric studies.

The overweight: obesity and plasma lipids in adults with intellectual disability and mental illness.

BACKGROUND: Previous studies in adults with intellectual disabilities (ID) have reported a higher prevalence of obesity than in the general population, and a trend to an increase in the prevalence of excess weight. However, little information is available on body weight status and lipids levels of adults with ID and co-existing mental illness. The aim of this study was to address this information gap, by conducting a stepwise multiple regression analysis to predict BMI, thereby allowing the investigation of (semi-)partial correlations, which assess the extent to which a particular predictor variable is associated with BMI over and above the other predictors. METHODS: A study of the patients with ID and psychiatric illness registered in the service. Collected data included body mass index (BMI), age, gender, the presence of additional physical conditions, residential status, mental illness and use the psychotropic medication. We analysed the lipid profile including serum cholesterol together with low-density lipoprotein, high-density lipoprotein (HDL), triglycerides and the serum cholesterol/HDL ratio. Data for these variables were entered into a stepwise multiple linear regression to predict BMI. RESULTS: 28% of the participants were overweight and 41% obese. Most of the obese patients were men with mild ID (P = 0.039). Level of ID (P = 0.003), gender (P = 0.001) and serum triglycerides (P = 0.026) had significant predictive value in the regression model. There were no significant differences in either the mean serum cholesterol levels or the mean triglyceride levels between those taking and those not taking first-generation antipsychotics, second-generation antipsychotics or anti-epileptic medication. CONCLUSIONS: The rate of obesity in our sample was higher than in previous studies. The most predictive combination of predictors to predict BMI was ID level, gender and serum triglyceride levels. Serum triglyceride and cholesterol levels did not appear to be unduly affected by first- or second-generation antipsychotic medication or by antiepileptic medication.

Increased tenderness in the left third intercostal space in adult patients with myalgic encephalomyelitis: a controlled study.

A clinical sign has not thus far been associated with myalgic encephalo myelitis (ME). The present study involved systematic clinical examination that included inspection, palpation, percussion and auscultation of the thorax of 42 ME patients and 20 age-matched healthy controls while sitting. Left lateral third intercostal space tenderness was noted in 34 (81%) of the patients and in none of the controls, a difference that was highly statistically significant. This finding may be related to changes in lymphatic function and to the descending course of the thoracic duct. Further studies, preferably blinded and combined with appropriate imaging, are required.

Reduction in left supplementary motor area grey matter in adult female fibromyalgia sufferers with marked fatigue and without affective disorder: a pilot controlled 3-T magnetic resonance imaging voxel-based morphometry study.

This study aimed to test the hypothesis that structural grey matter brain changes might occur in the chronic intractable pain disorder fibromyalgia when this is associated with marked fatigue in the absence of a DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision) diagnosis of affective disorder. High-resolution 3-T cerebral magnetic resonance imaging scans were acquired in 10 female, right-handed, non-smoking, white Caucasian subjects: five patients with fibromyalgia associated with marked fatigue and five age-matched healthy women. Voxel-wise generalized linear modelling of the processed neuroanatomical data using permutation-based non-parametric testing, forming clusters at t > 2.3 and testing clusters for significance at P < 0.05, corrected for multiple comparisons across space, revealed significantly lower grey matter density in the patients with fibromyalgia and marked fatigue in the left supplementary motor area. This brain region plays an important role in cognitive or executive control and in the translation of painful cognition; these functions are impaired in fibromyalgia associated with marked fatigue.