Ethyl-eicosapentaenoic acid in first-episode psychosis : a 1H-MRS study

Ethyl-eicosapentaenoic acid (E-EPA) is an omega-3 fatty acid that has been used in a range of neuropsychiatric conditions with some benefits. However, its mechanism of action is unknown. Here, we investigate its effects on in vivo brain metabolism in first-episode psychosis (FEP). Proton magnetic resonance spectroscopy at 3 T was performed in the temporal lobes of 24 FEP patients before and after 12 weeks of treatment in the context of a larger double-blind, placebo-controlled E-EPA augmentation study. Treatment group effects for glutathione (F1,12=6.1, p=0.03), and a hemisphere-by-group interaction for glutamine/glutamate (F1,20=4.4, p=0.049) were found. Glutathione increased bilaterally and glutamate/glutamine increased in the left hemisphere following E-EPA administration. Improvement in negative symptoms correlated with metabolic brain changes, particularly glutathione (r=-0.57). These results suggest that E-EPA augmentation alters glutathione availability and modulates the glutamine/glutamate cycle in early psychosis, with some of the metabolic brain changes being correlated with negative symptom improvement. Larger confirmatory studies of these postulated metabolic brain effects of E-EPA are warranted.

A 1H-MRS investigation of the medial temporal lobe in antipsychotic-naïve and early-treated first episode psychosis

Schizophrenia is associated with significant brain abnormalities, including changes in brain metabolites as measured by proton magnetic resonance spectroscopy (MRS). What remains unclear is the extent to which these changes are a consequence of the emergence of psychotic disorders or the result of treatment with antipsychotic medication. We assessed 34 patients with first episode psychosis (15 antipsychotic naïve) and 19 age- and gender-matched controls using short-echo MRS in the medial temporal lobe bilaterally. Overall, there were no differences in any metabolite, regardless of treatment status. However, when the analysis was limited to patients with a diagnosis of schizophrenia, schizophreniform or schizoaffective disorder, significant elevations of creatine/phosphocreatine (Cr/PCr) and myo-inositol (mI) were found in the treated group. These data indicate a relative absence of temporal lobe metabolic abnormalities in first episode psychosis, but suggest that some treatment-related changes in mI might be apparent in patients with schizophrenia-spectrum diagnoses. Seemingly illness-related Cr/PCr elevations were also specific to the diagnosis of schizophrenia-spectrum disorder and seem worthy of future study.

Magnetic resonance spectroscopy in seizure disorders

Key points • The clinical aims of MR spectroscopy (MRS) in seizure disorders are to help identify, localize and characterize epileptogenic foci. • Lateralizing MRS abnormalities in temporal lobe epilepsy (TLE) may be used clinically in combination with structural and T2 MRI measurements together with other techniques such as EEG, PET and SPECT. • Characteristic metabolite abnormalities are decreased N-acetylaspartate (NAA) with increased choline (Cho) and myoinositol (mI) (short-echo time). • Contralateral metabolite abnormalities are frequently seen in TLE, but are of uncertain significance. • In extra-temporal epilepsy, metabolite abnormalities may be seen where MR imaging (MRI) is normal; but may not be sufficiently localized to be useful clinically. • MRS may help to characterize epileptogenic lesions visible on MRI (aggressive vs. indolent neoplastic, dysplasia). • Spectral editing techniques are required to evaluate specific epilepsy-relevant metabolites (e.g. -aminobutyric acid (GABA)), which may be useful in drug development and evaluation. • MRS with phosphorus (31P) and other nuclei probe metabolism of epilepsy, but are less useful clinically. • There is potential for assessing the of drug mode of action and efficacy through 13C carbon metabolite measurements, while changes in sodium homeostasis resulting from seizure activity may be detected with 23Na MRS.

Implications of lipid biology for the pathogenesis of schizophrenia

Objective: Preclinical and clinical data suggest that lipid biology is integral to brain development and neurodegeneration. Both aspects are proposed as being important in the pathogenesis of schizophrenia. The purpose of this paper is to examine the implications of lipid biology, in particular the role of essential fatty acids (EFA), for schizophrenia. Methods: Medline databases were searched from 1966 to 2001 followed by the crosschecking of references. Results: Most studies investigating lipids in schizophrenia described reduced EFA, altered glycerophospholipids and an increased activity of a calcium-independent phospholipase A2 in blood cells and in post-mortem brain tissue. Additionally, in vivo brain phosphorus-31 Magnetic Resonance Spectroscopy (31P-MRS) demonstrated lower phosphomonoesters (implying reduced membrane precursors) in first- and multi-episode patients. In contrast, phosphodiesters were elevated mainly in first-episode patients (implying increased membrane breakdown products), whereas inconclusive results were found in chronic patients. EFA supplementation trials in chronic patient populations with residual symptoms have demonstrated conflicting results. More consistent results were observed in the early and symptomatic stages of illness, especially if EFA with a high proportion of eicosapentaenoic acid was used. Conclusion: Peripheral blood cell, brain necropsy and 31P-MRS analysis reveal a disturbed lipid biology, suggesting generalized membrane alterations in schizophrenia. 31P-MRS data suggest increased membrane turnover at illness onset and persisting membrane abnormalities in established schizophrenia. Cellular processes regulating membrane lipid metabolism are potential new targets for antipsychotic drugs and might explain the mechanism of action of treatments such as eicosapentaenoic acid.

Single voxel Magnetic Resonance Spectroscopic (1H-MRS) analysis of deep brain structures after traumatic prefrontal brain injury (TBI) in rat

Chronic difficulties arising from mild brain injury (TBI) are difficult to predict because the processes underlying changes after TBI are poorly understood. In mild brain injury the extent of neuropsychiatric and cognitive symptoms correspond poorly to overt tissue loss (Barth 1983; Liu 2010). Cellular, immune and hormonal cascades occurring after injury and continuing during the healing process may impact uninjured brain regions sensitive to the effects of physiological and emotional stress, which receive projections from the injury site. Changes in these most basic properties due to injury or disease have profound implications for virtually every aspect of brain function through disruption of neurotransmitter, neuroendocrine and metabolic systems. In order to screen for changes in transmitter and metabolic activity, in this study we developed Single voxel proton Magnetic Resonance Spectroscopy (1H-MRS) for use in both injured and control animals. We first evaluated if 1H-MRS could be used to evaluate in vivo, alterations in brain metabolism and catabolism of the prefrontal cortex, amygdala and ventral hippocampus in both control and injured animals after controlled cortical impact injury to the rat prefrontal cortex. We found that metabolite measurements for Myo-Inositol, Choline, creatine, Glutamate+Glutamine, and N-acetyl-acetate are attainable in deep brain structures in vivo in injured and controls rats. We next seek to evaluate longitudinally, in vivo, alterations in brain metabolism and catabolism of the prefrontal cortex, amygdala and ventral hippocampus during the first month after controlled cortical impact injury to the rat prefrontal cortex. These ongoing studies will provide data on the changes in transmitters and metabolites over time in injured and non-injured subjects. These studies address some of the fundamental questions about how mild brain injury has such diverse effects on overall brain health and function.

Mrs Klein

Described as ‘ferociously sharp’, Crossbow Production’s Mrs Klein is about the formidable psychoanalyst Melanie Klein whose ruthlessly ‘objective’ case studies of her children won her acclaim as both an inspiring and appalling woman. Did her ‘study’ drive her son to suicide? Starring Therese Collie (La Boite), Louise Brehmer (QTC, La Boite) and Caroline Beck (New York Broadway credits). Directed by Dr Christian Heim. Live classical music and sharp wit combine to make this a memorable production.

The relationship between substrate metabolism, exercise and appetite control : does glycogen availability influence the motivation to eat, energy intake or food choice?

The way in which metabolic fuels are utilised can alter the expression of behaviour in the interests of regulating energy balance and fuel availability. This is consistent with the notion that the regulation of appetite is a psychobiological process, in which physiological mediators act as drivers of behaviour. The glycogenostatic theory suggests that glycogen availability is central in eliciting negative feedback signals to restore energy homeostasis. Due to its limited storage capacity, carbohydrate availability is tightly regulated and its restoration is a high metabolic priority following depletion. It has been proposed that such depletion may act as a biological cue to stimulate compensatory energy intake in an effort to restore availability. Due to the increased energy demand, aerobic exercise may act as a biological cue to trigger compensatory eating as a result of perturbations to muscle and liver glycogen stores. However, studies manipulating glycogen availability over short-term periods (1-3 days) using exercise, diet or both have often produced equivocal findings. There is limited but growing evidence to suggest that carbohydrate balance is involved in the short-term regulation of food intake, with a negative carbohydrate balance having been shown to predict greater ad libitum feeding. Furthermore, a negative carbohydrate balance has been shown to be predictive of weight gain. However, further research is needed to support these findings as the current research in this area is limited. In addition, the specific neural or hormonal signal through which carbohydrate availability could regulate energy intake is at present unknown. Identification of this signal or pathway is imperative if a casual relationship is to be established. Without this, the possibility remains that the associations found between carbohydrate balance and food intake are incidental.

Age, muscle fatigue, and walking endurance in pre-menopausal women

Aging is associated with loss of endurance; however, aging is also associated with decreased fatigue during maximal isometric contractions. The aims of this study were to examine the relationship between age and walking endurance (WE) and maximal isometric fatigue (MIF) and to determine which metabolic/fitness components explain the expected age effects on WE and MIF. Subjects were 96 pre-menopausal women. Oxygen uptake (walking economy) was assessed during a 3-mph walk; aerobic capacity and WE by progressive treadmill test; knee extension strength by isometric contractions, MIF during a 90-s isometric plantar flexion (muscle metabolism measured by 31P MRS). Age was related to increased walking economy (low VO2, r = −0.19, P < 0.03) and muscle metabolic economy (force/ATP, 0.34, P = 0.01), and reduced MIF (−0.26, P < 0.03). However, age was associated with reduced WE (−0.28, P < 0.01). Multiple regression showed that muscle metabolic economy explained the age-related decrease in MIF (partial r for MIF and age −0.13, P = 0.35) whereas walking economy did not explain the age-related decrease in WE (partial r for WE and age −0.25, P < 0.02). Inclusion of VO2max and knee endurance strength accounted for the age-related decreased WE (partial r for WE and age = 0.03, P > 0.80). In premenopausal women, age is related to WE and MIF. In addition, these results support the hypothesis that age-related increases in metabolic economy may decrease MIF. However, decreased muscle strength and oxidative capacity are related to WE.

Modulation of depth-dependent properties in tissue-engineered cartilage with a semi-permeable membrane and perfusion : a continuum model of matrix metabolism and transport

The functional properties of cartilaginous tissues are determined predominantly by the content, distribution, and organization of proteoglycan and collagen in the extracellular matrix. Extracellular matrix accumulates in tissue-engineered cartilage constructs by metabolism and transport of matrix molecules, processes that are modulated by physical and chemical factors. Constructs incubated under free-swelling conditions with freely permeable or highly permeable membranes exhibit symmetric surface regions of soft tissue. The variation in tissue properties with depth from the surfaces suggests the hypothesis that the transport processes mediated by the boundary conditions govern the distribution of proteoglycan in such constructs. A continuum model (DiMicco and Sah in Transport Porus Med 50:57-73, 2003) was extended to test the effects of membrane permeability and perfusion on proteoglycan accumulation in tissue-engineered cartilage. The concentrations of soluble, bound, and degraded proteoglycan were analyzed as functions of time, space, and non-dimensional parameters for several experimental configurations. The results of the model suggest that the boundary condition at the membrane surface and the rate of perfusion, described by non-dimensional parameters, are important determinants of the pattern of proteoglycan accumulation. With perfusion, the proteoglycan profile is skewed, and decreases or increases in magnitude depending on the level of flow-based stimulation. Utilization of a semi-permeable membrane with or without unidirectional flow may lead to tissues with depth-increasing proteoglycan content, resembling native articular cartilage.