The role of long-term physical exercise on performance and brain activation during the Stroop colour word task in fibromyalgia patients.

The Stroop colour word test (SCWT) has been widely used to assess changes in cognitive performance such as processing speed, selective attention and the degree of automaticity. Moreover, the SCWT has proven to be a valuable tool to assess neuronal plasticity that is coupled to improvement in performance in clinical populations. In a previous study, we showed impaired cognitive processing during SCWT along with reduced task-related activations in patients with fibromyalgia. In this study, we used SCWT and functional magnetic resonance imagingFMRI to investigate the effects of a 15-week physical exercise intervention on cognitive performance, task-related cortical activation and distraction-induced analgesia (DIA) in patients with fibromyalgia and healthy controls. The exercise intervention yielded reduced fibromyalgia symptoms, improved cognitive processing and increased task-related activation of amygdala, but no effect on DIA. Our results suggest beneficial effects of physical exercise on cognitive functioning in FM.

Modality and sex differences in pain sensitivity during human endotoxemia.

Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8ng/kg dose being -64±30kPa P=.04; with the 0.6ng/kg dose -58±55kPa, P<.01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (P's>.70). Suprathreshold noxious pain was not affected by LPS in men (P's⩾.15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P=.01), and showed a tendency to rate noxious cold pain as more painful (P=.06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P<.01, for men P=.27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that women's pain perception and modulation is more sensitive to immune activation than men's.

Acceptance and commitment therapy for fibromyalgia: a randomized controlled trial.

BACKGROUND: Fibromyalgia (FM) is characterized by widespread pain and co-morbid symptoms such as fatigue and depression. For FM, medical treatments alone appear insufficient. Recent meta-analyses point to the utility of cognitive behaviour therapy (CBT), but effects are moderate. Within the continuous development of CBT, the empirical support for acceptance and commitment therapy (ACT) has increased rapidly. ACT focuses on improving functioning by increasing the patient's ability to act in accordance with personal values also in the presence of pain and distress (i.e., psychological flexibility). However, no study has yet explored the utility of ACT in FM. OBJECTIVES: To evaluate the efficacy of ACT for FM and the role of psychological inflexibility as a mediator of improvement. METHODS: In this randomized controlled trial, ACT was evaluated in comparison to a waiting list control condition. Forty women diagnosed with FM participated in the study. Assessments were made pre- and post-treatment and at 3 months of follow-up. The ACT intervention consisted of 12 weekly group sessions. RESULTS: Significant differences in favour of ACT were seen in pain-related functioning, FM impact, mental health-related quality of life, self-efficacy, depression, anxiety and psychological inflexibility. Changes in psychological inflexibility during the course of treatment were found to mediate pre- to follow-up improvements in outcome variables. CONCLUSIONS: The results correspond with previous studies on ACT for chronic pain and suggest the utility of ACT for FM as well as the role of psychological inflexibility as a mediator of improvement.

Using fMRI to evaluate the effects of milnacipran on central pain processing in patients with fibromyalgia.

Background In recent years, the prescription of serotonin-noradrenalin reuptake inhibitors (SNRIs) for treatment of fibromyalgia (FM) has increased with reports of their efficacy. The SNRI milnacipran is approved by the U.S. Food and Drug Administration (FDA) for treatment of FM, yet, the mechanisms by which milnacipran reduces FM symptoms are unknown. A large number of neuroimaging studies have demonstrated altered brain function in patients with FM but the effect of milnacipran on central pain processing has not been investigated. The primary objective of this study was to assess the effect of milnacipran on sensitivity to pressure-evoked pain in FM. Secondary objectives were to assess the effect of milnacipran on cerebral processing of pressure-evoked pain using fMRI and the tolerability and safety of milnacipran 200 mg/day in FM. Methods 92 patients were randomized to either 13-weeks milnacipran treatment (200 mg/day) or placebo in this double-blind, placebo-controlled multicenter clinical trial. Psychophysical measures and functional MRI (fMRI) assessments were performed before and after treatment using a computer-controlled pressure-pain stimulator. Here, we present the results of several a priori defined statistical analyses. Results Milnacipran-treated patients displayed a trend toward lower pressure-pain sensitivity after treatment, compared to placebo, and the difference was greater at higher pain intensities. A single group fMRI analysis of milnacipran-treated patients indicated increased pain-evoked brain activity in the caudatus nucleus, anterior insula and amygdala after treatment, compared to before treatment; regions implicated in pain inhibitory processes. A 2 × 2 repeated measures fMRI analysis, comparing milnacipran and placebo, before and after treatment, showed that milnacipran-treated patients had greater pain-evoked activity in the precuneus/posterior cingulate cortex after treatment; a region previously implicated in intrinsic brain function and FM pathology. This finding was only significant when uncorrected for multiple comparisons. The safety analysis revealed that patients from both treatment groups had treatment-emergent adverse events where nausea was the most common complaint, reported by 43.5% of placebo patients and 71.7% of milnacipran-treated patients. Patients on milnacipran were more likely to discontinue treatment because of side effects. Conclusions Our results provide preliminary indications of increased pain inhibitory responses in milnacipran-treated FM patients, compared to placebo. The psychophysical assessments did not reach statistical significance but reveal a trend toward higher pressure-pain tolerance after treatment with milnacipran, compared to placebo, especially for higher pain intensities. Our fMRI analyses point toward increased activation of the precuneus/posterior cingulum in patients treated with milnacipran, however results were not corrected for multiple comparisons. The precuneus/posterior cingulum is a key region of the default mode network and has previously been associated with abnormal function in FM. Future studies may further explore activity within the default mode network as a potential biomarker for abnormal central pain processing. Implications The present study provides novel insights for future studies where functional neuroimaging may be used to elucidate the central mechanisms of common pharmacological treatments for chronic pain. Furthermore, our results point toward a potential mechanism for pain normalization in response to milnacipran, involving regions of the default mode network although this finding needs to be replicated in future studies.

Perfusion abnormalities in hemimegalencephaly.

INTRODUCTION: Cerebrovascular changes are rarely discussed in patients with hemimegalencephaly. These alterations have previously been associated with epileptical activity. CASE: We report the case of a 36-week gestation neonate presenting with total right hemimegalencephaly, as demonstrated by a magnetic resonance imaging (MRI) performed in the first days of life. Perfusion-weighted imaging displayed a clear hypervascularization of the right hemisphere. Diffusion-tensor imaging showed an arrangement of white matter fibers concentrically around the ventricle on the right hemisphere. AngioMRI showed an obvious asymmetry in the size of the middle cerebral arteries, with the right middle cerebral artery being prominent. The baby was free of clinical seizures during his first week of life. An electroencephalogram at that time displayed an asymmetric background activity, but no electrical seizures. CONCLUSION: Perfusion anomalies in hemimegalencephaly may not necessarily be related to epileptical activity, but may be related to vessel alterations.

Progressive unilateral hemispheric atrophy in an infant with neurofibromatosis.

INTRODUCTION: Cerebrovascular diseases are rarely seen in neurofibromatosis type 1. These include vascular occlusive disease, moyamoya vessels, aneurysms, arteriovenous malformations and fistulae. CASE REPORT: We describe the case of an infant with genetically proven neurofibromatosis type 1 and progressive brain hemiatrophy over months, due to primary narrowing of intracranial carotid artery branches, as demonstrated by successive brain imaging. She presented with refractory seizures and a progressive hemiparesis associated with developmental delay. Surgical material from hemispherotomy done at 18 months showed severe abnormalities of the small vessels. CONCLUSION: Cerebrovascular changes seen in neurofibromatosis can be diffuse and progressive, with secondary hemiparesis, epilepsy and developmental delay.

Ictal bradycardia in a young child with focal cortical dysplasia in the right insular cortex.

We report on a three and a half year old child with episodic sinus bradycardia during habitual seizures and prolonged interictal discharges due to focal cortical dysplasia in the anterior 2/3 of the insula and the inferior frontal cortex. Seizure-induced bradycardia is rarely reported in children. Bradycardia is suspected to be related to sudden death, a rare complication of a chronic seizure disorder. Several well-documented cases in adult patients reveal a high incidence of temporal epilepsy, but MRI and PET studies in healthy subjects suggest a major role of the insular cortex, especially the right, in cardiac regulation. Our finding underlines the predominance of the right insula in cardiac control, which already seems to be present in children.

In vivo evaluation of the biodistribution of 11C-labeled PD153035 in rats without and with neuroblastoma implants.

The biodistribution of 11C-labeled 4-(3-bromoanilino)-6,7-dimethoxyquinazoline, an inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase, has been evaluated in vivo in rats using positron emission tomography (PET). Time-activity data obtained after i.v. administration in one rat revealed that the radiotracer rapidly cleared from plasma with subsequent uptake in major organs of the body (brain, heart, liver, gastrointestinal tract and bladder). Uptake in proliferating tissue in rats with human neuroblastoma xenografts indicate that [O-11C-methyl]PD153035 shows promise as a new agent for in vivo imaging of tumors with PET.

Accumulation of FDG in axillary sweat glands in hyperhidrosis: a pitfall in whole-body PET examination.

A diabetic male with severe autonomic neuropathy and recently discovered Hodgkin's disease demonstrated bilateral uptake of [2-18F]-2-fluoro-2-deoxy-d-glucose (FDG) in the axillary sweat glands during profuse sweating caused by hypoglycaemia at positron emission tomography examination. It is not yet clear whether the sweating interfered with the distribution of the radiopharmaceutical. Regardless of the cause or mechanism for the uptake, the finding is clinically relevant. A bilateral symmetrical accumulation of FDG in the axillae of a tumour patient does not necessarily indicate malignant involvement of the lymph nodes.

Cerebral effects of nicotine during cognition in smokers and non-smokers.

For the smoker, nicotine has a positive effect on attention, cognition and mood. Conversely, nicotine abstinence is characterized by uncomfortable psychological effects such as impaired attention, but also irritability. We postulated that nicotine exerts an effect on cerebral areas important for attention and mood. Regional cerebral blood flow (rCBF), as an index for cerebral activity, was measured in both smokers and non-smokers. They were scanned during performance of a psychometric task with and without i.v. infusion of nicotine (1-methyl-2-[3-pyridyll] pyrrolidine). Nicotine induced rCBF decreases in the anterior cingulate cortex and the cerebellum, and concomitant increases in the occipital cortex. The changes were similar in nature and magnitude in smokers and non-smokers. Thus, specific changes were induced in areas pertaining to the anterior attention system and to higher order visual cortex. We conclude that these effects on cerebral activity provide insights into the desired positive effects of nicotine on cognition as well as the negative effects experienced during nicotine abstinence.

Global cerebral blood flow during infusion of adenosine in humans: assessment by magnetic resonance imaging and positron emission tomography.

Adenosine, an endogenous vasodilator, induces a cerebral vasodilation at hypotensive infusion rates in anaesthetized humans. At lower doses (< 100 micrograms kg-1 min-1), adenosine has shown to have an analgesic effect. This study was undertaken to investigate whether a low dose, causing tolerable symptoms of peripheral vasodilation affects the global cerebral blood flow (CBF). In nine healthy volunteers CBF measurements were made using axial magnetic resonance (MR) phase images of the internal carotid and vertebral arteries at the level of C2-3. Quantitative assessment of CBF was also obtained with positron emission tomography (PET) technique, using intravenous bolus [15O]butanol as tracer in four of the subject at another occasion. During normoventilation (5.4 +/- 0.2 kPa, mean +/- s.e.m.), the cerebral blood flow measured by magnetic resonance imaging technique, as the sum of the flows in both carotid and vertebral arteries, was 863 +/- 66 mL min-1, equivalent to about 64 +/- 5 mL 100 g-1 min-1. The cerebral blood flow measured by positron emission tomography technique, was 59 +/- 4 mL 100 g-1 min-1. All subjects had a normal CO2 reactivity. When adenosine was infused (84 +/- 7 micrograms kg-1 min-1.) the cerebral blood flow, measured by magnetic resonance imaging was 60 +/- 5 mL 100 g-1 min-1. The end tidal CO2 level was slightly lower (0.2 +/- 0.1 kPa) during adenosine infusion than during normoventilation. In the subgroup there was no difference in cerebral blood flow as measured by magnetic resonance imaging or positron emission tomography. In conclusion, adenosine infusion at tolerable doses in healthy volunteers does not affect global cerebral blood flow in unanaesthetized humans.

In vivo biodistribution of [N-11C-methyl]KF 17837 using 3-D-PET: evaluation as a ligand for the study of adenosine A2A receptors.

(KF 17837, (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine, was 11C-labelled by methylation at N-7 of the nor-compound, KF 17440, using [11C]methyl iodide. Radiochemical conversions of 50% or 70-80% were obtained using sodium hydride or potassium carbonate, respectively, as base. Total synthesis time was 40-45 min, including isolation by semipreparative liquid chromatography. Cerebral uptake of [N-11C-methyl]KF 17837 in Cynomolgus monkeys, evaluated using positron emission tomography (PET), was so low that regional differences in distribution kinetics were revealed first after increasing injected dose 3-fold and using 3-D mode of data acquisition. At all times, the relative regional retention (maximum striatum:cerebellum: cortex approximately 1.1:1:0.8 at 20 min) was considerably different from the known relative density of A2A receptors in these regions. Radioactivity decreased more rapidly in the cortex than in the striatum and cerebellum (by 20% vs. 3-7%, respectively, between 5 and 50 min). Addition of carrier to [N-11C-methyl]KF 17837 only marginally affected the cerebral radiotracer uptake. By contrast, in the heart the initial tracer uptake was high and the elimination kinetics was enhanced by adding unlabelled carrier. We have thus shown that KF 17837 passes the blood-brain barrier, though to a very low extent. This fact and the apparently high nonspecific binding in vivo of [N-11C-methyl]KF 17837 in regions with low receptor densities limits its usefulness as a ligand for quantification of the adenosine A2A receptors in the primate brain.

The spectrum of acquired cognitive disturbances in children with partial epilepsy and continuous spike-waves during sleep. A 4-year follow-up case study with prolonged reversible learning arrest and dysfluency.

We report a longitudinal study (7-11 years) of a previously normal boy (MR) who presented from the age of 5 years with rare partial motor seizures and atypical 'absences'. The history revealed a stagnation in development and speech difficulties a few months before onset of his epilepsy. The first waking electroencephalogram (EEG) showed rare generalized discharges during hyperventilation. Magnetic resonance imaging revealed an arachnoid cyst in the frontotemporal region. Although his epilepsy never became severe, he experienced important learning difficulties. Subsequent EEGs became increasingly active with left focal epileptic activity and continuous spike-waves during sleep (CSWS) present from the first sleep EEG. The first neuropsychological evaluation (7 years) showed a speech dysfluency, word finding and naming problems, inattention and low intelligence quotient. Carbamazepine was changed to clobazam and later ethosuximide was added with a rapid improvement (within 1 month) in linguistic and cognitive performances as well as in behaviour. Furthermore, the patient showed considerable progress in acquisition over the next months whereas learning to read had previously been very difficult. The epileptic activity gradually disappeared and he was able to follow regular school at an age-appropriate level. This case adds a new facet to the already recognized more obvious acquired neuropsychological disturbances known to occur in some partial childhood epilepsy syndromes with CSWS (aphasia, dementia). It manifested as prolonged insidious stagnation in learning and subtle language disability. This study documents rapid specific language improvement with change in anti-epileptic drugs and a restored immediate and long-term learning capacity, suggesting a direct but 'hidden' role of epilepsy.

A one-step immunohistochemical method for detection of blood-brain barrier disturbances for immunoglobulins in lesioned rat brain with special reference to false-positive labelling in immunohistochemistry.

Disturbances of the blood-brain barrier (BBB) following brain lesions lead to extravasation of serum proteins that can be detected by immunohistochemical methods in tissue sections. Here, extravasated immunoglobulins were visualized by a 1-step technique using rabbit anti-rat immunoglobulins conjugated to horseradish peroxidase (HRP). This method is associated with a lower background staining than the conventional 3-step peroxidase-antiperoxidase (PAP) technique using rabbit antibodies against rat whole-serum proteins or immunoglobulins (IgG). Further tests using a direct conjugate of rabbit anti-rat immunoglobulins to fluorescein isothiocyanate (FITC) showed usefulness of the approach for fluorescence microscopy. Additional experiments showed that antibodies directed against mouse immunoglobulins as used for detection of mouse monoclonal antibodies can cross-react with extravasated rat immunoglobulins. Therefore, immunohistochemical studies on lesioned rat brain should routinely include a visualization of areas containing extravasated serum proteins including immunoglobulins.

In vivo distribution of [11C]-busulfan in cynomolgus monkey and in the brain of a human patient.

The in vivo distribution of the antileukemic agent busulfan labeled with the positron-emitting radionuclide carbon 11 was investigated in cynomolgus monkeys and in a human patient using positron emission tomography. After i.v. injection of the radiotracer, its regional uptake was monitored for about 1 h in the monkey's body and, in a separate experiment, in the monkey's brain. The concentration of radioactivity in the liver, which showed the highest levels of all the organs scanned, increased throughout the experiment and was 9-fold that in the brain at the end of the experiment. [11C]-Busulfan rapidly crossed the blood-brain barrier. The radioactivity peaked in both the cortex and the white matter showing a ratio of 1.25, at 3 min but declined quickly to yield a ratio of approximately 1 after 30 min. In the human brain, radioactivity in the cerebellum, cortex, and white matter reached a maximum within 5 min showing a cortex:white matter ratio of 1.6. The activity in the cortex declined to yield a ratio of 1 within 30 min. Of the delivered dose, 20% penetrated into the brain.

Metabolic alterations underlying the development of hypermetabolic necrosis in the substantia nigra in status epilepticus.

The substantia nigra pars reticulata (SNPR) has previously been shown to undergo tissue necrosis following status epilepticus induced by flurothyl in the rat. Even if the rat is ventilated, the SNPR develops necrosis if the epileptic period lasts more than 30 min. Rat brains were frozen in situ after 20 and 60 min of seizure activity and after 60 min of seizure activity followed by 60 min recovery. Labile energy metabolites were then analyzed in the SNPR and in the periaqueductal grey matter (PAG, control region). In the PAG, the metabolite changes during status epilepticus were similar to those reported for cerebral cortex and hippocampus. Measurements showed an unchanged ATP content and energy charge (97% and 98% of control, respectively) and an accumulation of lactate to 9.2 +/- 0.6 mumol/g in the 60-min group. In the PAG, all metabolites measured had returned to control values after 60 min of recovery. In the SNPR, the perturbation of the energy metabolites was much more pronounced during status epilepticus. The concentration of ATP decreased to 75 +/- 3%, the energy charge to 91% +/- 12% and the adenylate pool to 86.7 +/- 5.7% of control. Lactate accumulated to concentrations of 16.1 +/- 1.8 mumol/g and 24.9 +/- 2.3 mumol/g in the 20-min and 60-min groups, respectively. The concentration of lactate was still increased above control after 60 min recovery, whereas the concentration of ATP and the energy charge were lower than control. The findings demonstrate that sustained and intense neuronal activation can cause metabolic disturbance and thereby lead to necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral metabolic changes during and following fluorothyl-induced seizures in ventilated rats.

The objective of the present study was to assess metabolic changes in the neocortex and hippocampus of well-oxygenated or moderately hypoxic rats in which fluorothyl-induced seizures were sustained for 5 or 20 min, or which were allowed recovery periods of 5, 15, or 45 min following cessation of 20-min seizure activity by withdrawal of the convulsant gas. Sustained fluorothyl-induced seizures were found to cause metabolic alterations qualitatively and quantitatively similar to those previously observed with other commonly used convulsants. Thus, although the phosphorylation state of the adenine nucleotide pool remained only moderately perturbed, if at all, there were decreases in tissue concentrations of phosphocreatine and glycogen, and increases in those of cyclic AMP, lactate, and pyruvate, with a calculated fall in intracellular pH of about 0.15 units and a rise in the cytoplasmic NADH/NAD+ ratio. The enhanced metabolic rate was reflected in a marked reduction in the tissue-to-plasma glucose concentration ratio. Induced moderate hypoxia (arterial PO2 40-50 mm Hg) had no metabolic effect after 5 min of seizures but moderately increased lactate concentrations after 20 min (from about 10 to about 15 mumol X g-1). On cessation of seizure discharge cyclic AMP and phosphocreatine concentrations normalized already within 5 min, whereas glycogen and lactate concentrations normalized more slowly. In the neocortex (but not the hippocampus) postepileptic tissue-to-plasma glucose concentration ratios rose above control, probably reflecting metabolic depression. The results suggest that intracellular pH promptly returned to control, and that postepileptic alkalosis developed. They also suggest that some elevation of the NADH/NAD+ ratio persisted even after 45 min of recovery.

Influence of lesions of the noradrenergic locus coeruleus system on the cerebral metabolic response to bicuculline-induced seizures.

The objective of the present study was to explore if lesions of the ascending noradrenergic pathways, originating in the locus coeruleus, modulate the cerebral metabolic response to bicuculline-induced seizures in rats. Bilateral noradrenergic lesions were performed by 6-hydroxydopamine injections in the caudal mesencephalon, 12-22 days before seizures were induced in animals ventilated on N2O:O2 (75:25). After 5 min of seizures the brain was frozen in situ and cerebral cortex and hippocampus were sampled for analysis. Labile phosphates, glycolytic metabolites, cyclic nucleotides, and free fatty acids were measured. In another series, lesioned animals were used for measurements of cerebral oxygen consumption. The noradrenergic lesions neither modified the electroencephalographically recorded seizure discharge, nor did they alter cerebral oxygen consumption or cerebral energy state. However, when compared to sham-operated animals, those with noradrenergic lesions had significantly higher (115% and 68%) glycogen concentrations and lower (50% and 52%) cyclic AMP concentrations in cerebral cortex and hippocampus, respectively, demonstrating the marked influence of noradrenergic activity on adenylate cyclase activity and glycogenolysis. The lesions failed to modulate the rise in free fatty acids in the cerebral cortex, or the cyclic GMP concentrations in the cerebral cortex and hippocampus. Thus, increased noradrenergic activity during status epilepticus does not seem responsible for lipolysis or for activation of guanylate cyclase.