Measurement of glucose metabolism in the occipital lobe and frontal cortex after oral administration of [1-13C]glucose at 9.4 T.

For the first time, labeling effects after oral intake of [1-13C]glucose are observed in the human brain with pure 1H detection at 9.4 T. Spectral time series were acquired using a short-TE 1H MRS MC-semiLASER (Metabolite Cycling semi Localization by Adiabatic SElective Refocusing) sequence in two voxels of 5.4 mL in the frontal cortex and the occipital lobe. High-quality time-courses of [4-13C]glutamate, [4-13C]glutamine, [3-13C]glutamate + glutamine, [2-13C] glutamate+glutamine and [3-13C]aspartate for individual volunteers and additionally, group-averaged time-courses of labeled and non-labeled brain glucose could be obtained. Using a one-compartment model, mean metabolic rates were calculated for each voxel position: The mean rate of the TCA-cycle (Vtca) value was determined to be 1.36 and 0.93 µmol min-1 g-1, the mean rate of glutamine synthesis (Vgln) was calculated to be 0.23 and 0.45 µmol min-1 g-1, the mean exchange rate between cytosolic amino acids and mitochondrial Krebs cycle intermediates (Vx) rate was found to be 0.57 and 1.21 µmol min-1 g-1 for the occipital lobe and the frontal cortex, respectively. These values were in agreement with previously reported data. Altogether, it can be shown that this most simple technique combining oral administration of [1-13C]Glc with pure 1H MRS acquisition is suitable to measure metabolic rates.

Safety and efficacy of occipital nerve stimulation for attack prevention in medically intractable chronic cluster headache (ICON): a randomised, double-blind, multicentre, phase 3, electrical dose-controlled trial.

BACKGROUND: Occipital nerve stimulation (ONS) has shown promising results in small uncontrolled trials in patients with medically intractable chronic cluster headache (MICCH). We aimed to establish whether ONS could serve as an effective treatment for patients with MICCH. METHODS: The ONS in MICCH (ICON) study is an investigator-initiated, international, multicentre, randomised, double-blind, phase 3, electrical dose-controlled clinical trial. The study took place at four hospitals in the Netherlands, one hospital in Belgium, one in Germany, and one in Hungary. After 12 weeks' baseline observation, patients with MICCH, at least four attacks per week, and history of being non-responsive to at least three standard preventive drugs, were randomly allocated (at a 1:1 ratio using a computer-generated permuted block) to 24 weeks of occipital nerve stimulation at either 100% or 30% of the individually determined range between paraesthesia threshold and near-discomfort (double-blind study phase). Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy. In weeks 25-48, participants received individually optimised open-label ONS. The primary outcome was the weekly mean attack frequency in weeks 21-24 compared with baseline across all patients and, if a decrease was shown, to show a group-wise difference. The trial is closed to recruitment (ClinicalTrials.gov NCT01151631). FINDINGS: Patients were enrolled between Oct 12, 2010, and Dec 3, 2017. We enrolled 150 patients and randomly assigned 131 (87%) to treatment; 65 (50%) patients to 100% ONS and 66 (50%) to 30% ONS. One of the 66 patients assigned to 30% ONS was not implanted and was therefore excluded from the intention-to-treat analysis. Because the weekly mean attack frequencies at baseline were skewed (median 15·75; IQR 9·44 to 24·75) we used log transformation to analyse the data and medians to present the results. Median weekly mean attack frequencies in the total population decreased from baseline to 7·38 (2·50 to 18·50; p<0·0001) in weeks 21-24, a median change of -5·21 (-11·18 to -0·19; p<0·0001) attacks per week. In the 100% ONS stimulation group, mean attack frequency decreased from 17·58 (9·83 to 29·33) at baseline to 9·50 (3·00 to 21·25) at 21-24 weeks (median change from baseline -4·08, -11·92 to -0·25), and for the 30% ONS stimulation group, mean attack frequency decreased from 15·00 (9·25 to 22·33) to 6·75 (1·50 to 16·50; -6·50, -10·83 to -0·08). The difference in median weekly mean attack frequency between groups at the end of the masked phase in weeks 21-24 was -2·42 (95% CI -5·17 to 3·33). In the masked study phase, 129 adverse events occurred with 100% ONS and 95 occurred with 30% ONS. None of the adverse events was unexpected but 17 with 100% ONS and eight with 30% ONS were labelled as serious, given they required brief hospital admission for minor hardware-related issues. The most common adverse events were local pain, impaired wound healing, neck stiffness, and hardware damage. INTERPRETATION: In patients with MICCH, both 100% ONS intensity and 30% ONS intensity substantially reduced attack frequency and were safe and well tolerated. Future research should focus on optimising stimulation protocols and disentangling the underlying mechanism of action. FUNDING: The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.

Carbonic anhydrase activity in the frontal lobe of human brain.

Carbonic anhydrase (CA) plays an important role in many biological processes. Recent technological advances have demonstrated the feasibility of measuring CA activity in the occipital lobe of human subjects in vivo. In this work we report, for the first time, in vivo measurement of CA activity in the frontal lobe of human brain, where structural and function abnormalities are strongly associated with symptoms of major psychiatric disorders. Despite the much larger magnetic field distortion in the frontal lobe, the pseudo first-order bicarbonate dehydration rate constant was determined with high precision using in vivo 13 C magnetic resonance magnetization transfer spectroscopy following oral administration of [U-13 C6 ]glucose. Nuclear Overhauser effect pulses were used to increase the signal-to-noise ratio; no proton decoupling was applied. The unidirectional dehydration rate constant of bicarbonate was found to be 0.26 ± 0.07 s-1 , which is not statistically different from the dehydration rate constant in the occipital lobe determined in our previous study, indicating that CA activity in the two brain regions is essentially indistinguishable. These results demonstrate the feasibility of characterizing CA activity in the frontal lobe for future psychiatric studies.

Herring roe oil supplementation alters microglial cell gene expression and reduces peripheral inflammation after immune activation in a neonatal piglet model.

Neonatal brain development can be disrupted by infection that results in microglial cell activation and neuroinflammation. Studies indicate that polyunsaturated fatty acids (PUFAs) and their metabolites can resolve inflammation. It is not known if dietary PUFA increases lipid metabolites in brain or reduces neuroinflammation in neonates. We hypothesized that dietary PUFAs might suppress neuroinflammation by inhibiting pro-inflammatory cytokine over-production and promoting inflammatory resolution in the periphery and brain. Piglets were obtained on postnatal day (PD) 2 and randomly assigned to herring roe oil (HRO) or control (CON) diet. HRO was included at 2 g/kg powdered diet. HRO increased DHA levels in occipital lobe and the DHA to arachidonic acid (ARA) ratio in hippocampal tissue. HRO decreased ARA metabolites in occipital lobe. HRO failed to attenuate microglial pro-inflammatory cytokine production ex vivo. HRO did not affect fever or circulating resolvin D1 levels. HRO decreased circulating neutrophils and liver inflammatory gene expression, but increased resolution marker gene expression in liver post LPS. HRO upregulated CXCL16, TGFBR1, and C1QA in microglial cells. HRO supplementation exerted beneficial effects on inflammation in the periphery, but further studies are needed to evaluate the specific effects of omega-3 supplementation on microglial cell physiology in the neonate.

Quantification of in vivo transverse relaxation of glutamate in the frontal cortex of human brain by radio frequency pulse-driven longitudinal steady state.

PURPOSE: The principal excitatory neurotransmitter glutamate plays an important role in many central nervous system disorders. Because glutamate resides predominantly in glutamatergic neurons, its relaxation properties reflect the intracellular environment of glutamatergic neurons. This study developed an improved echo time-independent technique for measuring transverse relaxation time and demonstrated that this radio frequency (RF)-driven longitudinal steady state technique can reliably measure glutamate transverse relaxation in the frontal cortex, where structural and functional abnormalities have been associated with psychiatric symptoms. METHOD: Bloch and Monte Carlo simulations were performed to improve and optimize the RF-driven, longitudinal, steady-state (MARzss) technique to significantly shorten scan time and increase measurement precision. Optimized four-flip angle measurements at 0°,12°, 24°, and 36° with matched repetition time were used in nine human subjects (6F, 3M; 27-49 years old) at 7 Tesla. Longitudinal and transverse relaxation rates for glutamate were measured from a 2 x 2 x 2 cm3 voxel placed in three different brain regions: gray matter-dominated medial prefrontal lobe, white matter-dominated left frontal lobe, and gray matter-dominated occipital lobe. RESULTS: Compared to the original MARzss technique, the scan time per voxel for measuring glutamate transverse relaxation was shortened by more than 50%. In the medial frontal, left frontal, and occipital voxels, the glutamate T2 was found to be 117.5±12.9 ms (mean ± standard deviation, n = 9), 107.3±12.1 (n = 9), and 124.4±16.6 ms (n = 8), respectively. CONCLUSIONS: The improvements described in this study make the MARZSS technique a viable tool for reliably measuring glutamate relaxation from human subjects in a typical clinical setting. It is expected that this improved technique can be applied to characterize the intracellular environment of glutamatergic neurons in a variety of brain disorders.

Dose-dependent effects of the selective serotonin reuptake inhibitor citalopram: A combined SPECT and phMRI study.

BACKGROUND: Serotonin transporter blockers, like citalopram, dose-dependently bind to the serotonin transporter. Pharmacological magnetic resonance imaging (phMRI) can be used to non-invasively monitor effects of serotonergic medication. Although previous studies showed that phMRI can measure the effect of a single dose of serotoninergic medication, it is currently unclear whether it can also detect dose-dependent effects. AIMS: To investigate the dose-dependent phMRI response to citalopram and compared this with serotonin transporter occupancy, measured with single photon emission computed tomography (SPECT). METHODS: Forty-five healthy females were randomized to pre-treatment with placebo, a low (4 mg) or clinically standard (16 mg) oral citalopram dose. Prior to citalopram, and 3 h after, subjects underwent SPECT scanning. Subsequently, a phMRI scan with a citalopram challenge (7.5 mg intravenously) was conducted. Change in cerebral blood flow in response to the citalopram challenge was assessed in the thalamus and occipital cortex (control region). RESULTS: Citalopram dose-dependently affected serotonin transporter occupancy, as measured with SPECT. In addition, citalopram dose-dependently affected the phMRI response to intravenous citalopram in the thalamus (but not occipital cortex), but phMRI was less sensitive in distinguishing between groups than SPECT. Serotonin transporter occupancy showed a trend-significant correlation to thalamic cerebral blood flow change. CONCLUSION: These results suggest that phMRI likely suffers from higher variation than SPECT, but that these techniques probably also assess different functional aspects of the serotonergic synapse; therefore phMRI could complement positron emission tomography/SPECT for measuring effects of serotonergic medication.

Cerebral Magnesium Levels in Preeclampsia; A Phosphorus Magnetic Resonance Spectroscopy Study.

BACKGROUND: Magnesium sulfate (MgSO4) is used as a prophylaxis for eclamptic seizures. The exact mechanism of action is not fully established. We used phosphorus magnetic resonance spectroscopy (31P-MRS) to investigate if cerebral magnesium (Mg2+) levels differ between women with preeclampsia, normal pregnant, and nonpregnant women. METHODS: This cross-sectional study comprised 28 women with preeclampsia, 30 women with normal pregnancies in corresponding gestational week (range: 23-41 weeks) and 11 nonpregnant healthy controls. All women underwent 31P-MRS from the parieto-occipital region of the brain and were interviewed about cerebral symptoms. Differences between groups were assessed by analysis of variance and Tukey's post-hoc test. Correlations between Mg2+ levels and specific neurological symptoms were estimated with Spearman's rank test. RESULTS: Mean maternal cerebral Mg2+ levels were lower in women with preeclampsia (0.12 mM ± 0.02) compared to normal pregnant controls (0.14 mM ± 0.03) (P = 0.04). Nonpregnant and normal pregnant women did not differ in Mg2+ levels. Among women with preeclampsia, lower Mg2+ levels correlated with presence of visual disturbances (P = 0.04). Plasma levels of Mg2+ did not differ between preeclampsia and normal pregnancy. CONCLUSIONS: Women with preeclampsia have reduced cerebral Mg2+ levels, which could explain the potent antiseizure prophylactic properties of MgSO4. Within the preeclampsia group, women with visual disturbances have lower levels of Mg2+ than those without such symptoms.

Light-Emitting Diode (LED) therapy improves occipital cortex damage by decreasing apoptosis and increasing BDNF-expressing cells in methanol-induced toxicity in rats.

Methanol-induced retinal toxicity, frequently associated with elevated free radicals and cell edema, is characterized by progressive retinal ganglion cell (RGC) death and vision loss. Previous studies investigated the effect of photomodulation on RGCs, but not the visual cortex. In this study, the effect of 670nm Light-Emitting Diode (LED) therapy on RGCs and visual cortex recovery was investigated in a seven-day methanol-induced retinal toxicity protocol in rats. Methanol administration showed a reduction in the number of RGCs, loss of neurons (neuronal nuclear antigen, NeuN+), activation of glial fibrillary acidic protein (GFAP+) expressing cells, suppression of brain-derived neurotrophic factor (BDNF+) positive cells, increase in apoptosis (caspase 3+) and enhancement of nitric oxide (NO) release in serum and brain. On the other hand, LED therapy significantly reduced RGC death, in comparison to the methanol group. In addition, the number of BDNF positive cells was significantly higher in the visual cortex of LED-treated group, in comparison to methanol-intoxicated and control groups. Moreover, LED therapy caused a significant decrease in cell death (caspase 3+ cells) and a significant reduction in the NO levels, both in serum and brain tissue, in comparison to methanol-intoxicated rats. Overall, LED therapy demonstrated a number of beneficial effects in decreasing oxidative stress and in functional recovery of RGCs and visual cortex. Our data suggest that LED therapy could be a potential condidate as a non-invasive approach for treatment of retinal damage, which needs further clinicl studies.

Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study.

It has been hypothesized that dietary creatine could influence cognitive performance by increasing brain creatine in developing individuals. This double-blind, randomized, placebo-controlled, proof-of-principle study aimed to investigate the effects of creatine supplementation on cognitive function and brain creatine content in healthy youth. The sample comprised 67 healthy participants aged 10 to 12 years. The participants were given creatine or placebo supplementation for 7 days. At baseline and after the intervention, participants undertook a battery of cognitive tests. In a random subsample of participants, brain creatine content was also assessed in the regions of left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe by proton magnetic resonance spectroscopy (1H-MRS) technique. The scores obtained from verbal learning and executive functions tests did not significantly differ between groups at baseline or after the intervention (all p > 0.05). Creatine content was not significantly different between groups in left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe (all p > 0.05). In conclusion, a 7-day creatine supplementation protocol did not elicit improvements in brain creatine content or cognitive performance in healthy youth, suggesting that this population mainly relies on brain creatine synthesis rather than exogenous creatine intake to maintain brain creatine homeostasis.

Involvement of the endocannabinoid system in the physiological response to transient common carotid artery occlusion and reperfusion.

BACKGROUND: The transient global cerebral hypoperfusion/reperfusion achieved by induction of Bilateral Common Carotid Artery Occlusion followed by Reperfusion (BCCAO/R) may trigger a physiological response in an attempt to preserve tissue and function integrity. There are several candidate molecules among which the endocannabinoid system (ECS) and/or peroxisome-proliferator activated receptor-alpha (PPAR-alpha) may play a role in modulating oxidative stress and inflammation. The aims of the present study are to evaluate whether the ECS, the enzyme cyclooxygenase-2 (COX-2) and PPAR-alpha are involved during BCCAO/R in rat brain, and to identify possible markers of the ongoing BCCAO/R-induced challenge in plasma. METHODS: Adult Wistar rats underwent BCCAO/R with 30 min hypoperfusion followed by 60 min reperfusion. The frontal and temporal-occipital cortices and plasma were analyzed by high performance liquid chromatography-mass spectrometry (HPLC-MS) to determine concentrations of endocannabinoids (eCBs) and related molecules behaving as ligands of PPAR-alpha, and of oxidative-stress markers such as lipoperoxides, while Western Blot and immunohistochemistry were used to study protein expression of cannabinoid receptors, COX-2 and PPAR-alpha. Unpaired Student's t-test was used to evaluate statistical differences between groups. RESULTS: The acute BCCAO/R procedure is followed by increased brain tissue levels of the eCBs 2-arachidonoylglycerol and anandamide, palmitoylethanolamide, an avid ligand of PPAR-alpha, lipoperoxides, type 1 (CB1) and type 2 (CB2) cannabinoid receptors, and COX-2, and decreased brain tissue concentrations of docosahexaenoic acid (DHA), one of the major targets of lipid peroxidation. In plasma, increased levels of anandamide and lipoperoxides were observed. CONCLUSIONS: The BCCAO/R stimulated early molecular changes that can be easily traced in brain tissue and plasma, and that are indicative of the tissue physiological response to the reperfusion-induced oxidative stress and inflammation. The observed variations suggest that the positive modulation of the ECS and the increase of proinflammatory substances are directly correlated events. Increase of plasmatic levels of anandamide and lipoperoxides further suggests that dysregulation of these molecules may be taken as an indicator of an ongoing hypoperfusion/reperfusion challenge.

Creatine, Glutamine plus Glutamate, and Macromolecules Are Decreased in the Central White Matter of Premature Neonates around Term.

Preterm birth represents a high risk of neurodevelopmental disabilities when associated with white-matter damage. Recent studies have reported cognitive deficits in children born preterm without brain injury on MRI at term-equivalent age. Understanding the microstructural and metabolic underpinnings of these deficits is essential for their early detection. Here, we used diffusion-weighted imaging and single-voxel 1H magnetic resonance spectroscopy (MRS) to compare brain maturation at term-equivalent age in premature neonates with no evidence of white matter injury on conventional MRI except diffuse excessive high-signal intensity, and normal term neonates. Thirty-two infants, 16 term neonates (mean post-conceptional age at scan: 39.8±1 weeks) and 16 premature neonates (mean gestational age at birth: 29.1±2 weeks, mean post-conceptional age at scan: 39.2±1 weeks) were investigated. The MRI/MRS protocol performed at 1.5T involved diffusion-weighted MRI and localized 1H-MRS with the Point RESolved Spectroscopy (PRESS) sequence. Preterm neonates showed significantly higher ADC values in the temporal white matter (P<0.05), the occipital white matter (P<0.005) and the thalamus (P<0.05). The proton spectrum of the centrum semiovale was characterized by significantly lower taurine/H2O and macromolecules/H2O ratios (P<0.05) at a TE of 30 ms, and reduced (creatine+phosphocreatine)/H2O and (glutamine+glutamate)/H2O ratios (P<0.05) at a TE of 135 ms in the preterm neonates than in full-term neonates. Our findings indicate that premature neonates with normal conventional MRI present a delay in brain maturation affecting the white matter and the thalamus. Their brain metabolic profile is characterized by lower levels of creatine, glutamine plus glutamate, and macromolecules in the centrum semiovale, a finding suggesting altered energy metabolism and protein synthesis.

Unique Distribution of Benzodiazepine Receptors in the Brain during the First Two Years of Life.

BACKGROUND: 123I-iomazenil (IMZ) single-photon emission computed tomography (SPECT) is a tool for evaluating epileptic foci and brain damage. To apply the method to children, information regarding the age-specific expression of benzodiazepine receptors (BDZ-Rs) is required. Unfortunately, there is no information currently available for children <2 years of age. METHODS: We used IMZ SPECT once in infants aged 3-8 months and again at 2 years of age in order to describe the maturational changes in BDZ-R distribution. RESULTS: No neurological deficits were found in any of the infants at the first examination. The BDZ-Rs were more dominantly distributed in the occipital lobe than in the frontal lobe before the age of 2 years. The frontal-occipital gradients of the distribution were obvious in children <8 months of age. Magnetic resonance imaging showed a spreading of myelination toward the frontal lobes simultaneously with BDZ-R expression. CONCLUSION: Information regarding the alteration in the BDZ-R distribution pattern is useful when assessing infantile epilepsy and brain injury. The age-related pattern of BDZ-R distribution could correspond with myelination, cerebral blood flow, metabolism and behavioral development.

Reference genes for reverse transcription quantitative PCR in canine brain tissue.

BACKGROUND: In the last decade canine models have been used extensively to study genetic causes of neurological disorders such as epilepsy and Alzheimer's disease and unravel their pathophysiological pathways. Reverse transcription quantitative polymerase chain reaction is a sensitive and inexpensive method to study expression levels of genes involved in disease processes. Accurate normalisation with stably expressed so-called reference genes is crucial for reliable expression analysis. RESULTS: Following the minimum information for publication of quantitative real-time PCR experiments precise guidelines, the expression of ten frequently used reference genes, namely YWHAZ, HMBS, B2M, SDHA, GAPDH, HPRT, RPL13A, RPS5, RPS19 and GUSB was evaluated in seven brain regions (frontal lobe, parietal lobe, occipital lobe, temporal lobe, thalamus, hippocampus and cerebellum) and whole brain of healthy dogs. The stability of expression varied between different brain areas. Using the GeNorm and Normfinder software HMBS, GAPDH and HPRT were the most reliable reference genes for whole brain. Furthermore based on GeNorm calculations it was concluded that as little as two to three reference genes are sufficient to obtain reliable normalisation, irrespective the brain area. CONCLUSIONS: Our results amend/extend the limited previously published data on canine brain reference genes. Despite the excellent expression stability of HMBS, GAPDH and HRPT, the evaluation of expression stability of reference genes must be a standard and integral part of experimental design and subsequent data analysis.

Optimized (31)P MRS in the human brain at 7 T with a dedicated RF coil setup.

The design and construction of a dedicated RF coil setup for human brain imaging ((1)H) and spectroscopy ((31)P) at ultra-high magnetic field strength (7 T) is presented. The setup is optimized for signal handling at the resonance frequencies for (1)H (297.2 MHz) and (31)P (120.3 MHz). It consists of an eight-channel (1)H transmit-receive head coil with multi-transmit capabilities, and an insertable, actively detunable (31)P birdcage (transmit-receive and transmit only), which can be combined with a seven-channel receive-only (31)P array. The setup enables anatomical imaging and (31)P studies without removal of the coil or the patient. By separating transmit and receive channels and by optimized addition of array signals with whitened singular value decomposition we can obtain a sevenfold increase in SNR of (31)P signals in the occipital lobe of the human brain compared with the birdcage alone. These signals can be further enhanced by 30 ± 9% using the nuclear Overhauser effect by B1-shimmed low-power irradiation of water protons. Together, these features enable acquisition of (31)P MRSI at high spatial resolutions (3.0 cm(3) voxel) in the occipital lobe of the human brain in clinically acceptable scan times (~15 min).

Psychophysiological classification and experiment study for spontaneous EEG based on two novel mental tasks.

BACKGROUND: Study of imagination offers a perfect setting for study of a large variety of states of consciousness. OBJECTIVE: Here, we studied the characteristics of two electroencephalographic (EEG) patterns evoked by two different imaginary tasks and evaluated the binary classification performance. METHODS: Fifteen individuals (11 male and 4 female, age range of 22 to 33) participated in five sessions of 32-channel EEG recordings. Only by analyzing the subjects' output EEG signals from the central parieto-occipital region of PZ electrode, under the circumstances of consciousness of relaxation-meditation or tension-imagination, we carried out the experiment of feature extraction for spontaneous EEG, as the subjects were blindfolded but asked to open their eyes all the same. The Hilbert-Huang Transform (HHT) was utilized to obtain the Hilbert time-frequency amplitude spectrum, and then with the feature vector set extracted, a two-class Fisher linear discriminant analysis classifier was trained for classification of data epochs of those two tasks. RESULTS: The overall result was that about 90% (± 5%) of the epochs could be correctly classified to their originating task. CONCLUSION: This study not only brings new opportunities for consciousness studies, but also provides a new classification paradigm for achieving control of robots based on the brain-computer interface (BCI).

Exploratory Metabolomic Analyses Reveal Compounds Correlated with Lutein Concentration in Frontal Cortex, Hippocampus, and Occipital Cortex of Human Infant Brain.

Lutein is a dietary carotenoid well known for its role as an antioxidant in the macula, and recent reports implicate a role for lutein in cognitive function. Lutein is the dominant carotenoid in both pediatric and geriatric brain tissue. In addition, cognitive function in older adults correlated with macular and postmortem brain lutein concentrations. Furthermore, lutein was found to preferentially accumulate in the infant brain in comparison to other carotenoids that are predominant in diet. While lutein is consistently related to cognitive function, the mechanisms by which lutein may influence cognition are not clear. In an effort to identify potential mechanisms through which lutein might influence neurodevelopment, an exploratory study relating metabolite signatures and lutein was completed. Post-mortem metabolomic analyses were performed on human infant brain tissues in three regions important for learning and memory: the frontal cortex, hippocampus, and occipital cortex. Metabolomic profiles were compared to lutein concentration, and correlations were identified and reported here. A total of 1276 correlations were carried out across all brain regions. Of 427 metabolites analyzed, 257 were metabolites of known identity. Unidentified metabolite correlations (510) were excluded. In addition, moderate correlations with xenobiotic relationships (2) or those driven by single outliers (3) were excluded from further study. Lutein concentrations correlated with lipid pathway metabolites, energy pathway metabolites, brain osmolytes, amino acid neurotransmitters, and the antioxidant homocarnosine. These correlations were often brain region-specific. Revealing relationships between lutein and metabolic pathways may help identify potential candidates on which to complete further analyses and may shed light on important roles of lutein in the human brain during development.

Initial experience with seven tesla magnetic resonance spectroscopy of hypothalamic GABA during hyperinsulinemic euglycemia and hypoglycemia in healthy humans.

PURPOSE: Hypothalamic GABA signaling has been shown to regulate the hormonal response to hypoglycemia in animals. The hypothalamus is a challenging brain region for magnetic resonance spectroscopy (MRS) due to its small size and central location. To investigate the feasibility of measuring GABA in the hypothalamus in humans, ultra-high field MRS was used. METHODS: GABA levels in the hypothalamus and occipital cortex (control region) were measured in healthy volunteers during euglycemia and hypoglycemia at 7 tesla using short-echo STEAM (TE = 8 ms, TR = 5 s). RESULTS: Hypothalamic GABA levels were quantified with a mean within-session test-retest coefficient of variance of 9%. Relatively high GABA levels were observed in the hypothalamus compared with other brain regions. Hypothalamic GABA levels were 3.5 ± 0.3 µmol/g during euglycemia (glucose 89 ± 6 mg/dL) vs. 3.0 ± 0.4 µmol/g during hypoglycemia (glucose 61 ± 3 mg/dL) (P = 0.06, N = 7). In the occipital cortex, GABA levels remained constant at 1.4 ± 0.4 vs.1.4 ± 0.3 µmol/g (P = 0.3, N = 5) as glucose fell from 91 ± 4 to 61 ± 4 mg/dL. CONCLUSION: GABA concentration can be quantified in the human hypothalamus and shows a trend toward decrease in response to an acute fall in blood glucose. These methods can be used to further investigate role of GABA signaling in the counterregulatory response to hypoglycemia in humans.

Neurochemical changes in the rat occipital cortex and hippocampus after repetitive and profound hypoglycemia during the neonatal period: an ex vivo ¹H magnetic resonance spectroscopy study.

The brain of a human neonate is more vulnerable to hypoglycemia than that of pediatric and adult patients. Repetitive and profound hypoglycemia during the neonatal period (RPHN) causes brain damage and leads to severe neurologic sequelae. Ex vivo high-resolution (1)H nuclear magnetic resonance (NMR) spectroscopy was carried out in the present study to detect metabolite alterations in newborn and adolescent rats and investigate the effects of RPHN on their occipital cortex and hippocampus. Results showed that RPHN induces significant changes in a number of cerebral metabolites, and such changes are region-specific. Among the 16 metabolites detected by ex vivo (1)H NMR, RPHN significantly increased the levels of creatine, glutamate, glutamine, γ-aminobutyric acid, and aspartate, as well as other metabolites, including succine, taurine, and myo-inositol, in the occipital cortex of neonatal rats compared with the control. By contrast, changes in these neurochemicals were not significant in the hippocampus of neonatal rats. When the rats had developed into adolescence, the changes above were maintained and the levels of other metabolites, including lactate, N-acetyl aspartate, alanine, choline, glycine, acetate, and ascorbate, increased in the occipital cortex. By contrast, most of these metabolites were reduced in the hippocampus. These metabolic changes suggest that complementary mechanisms exist between these two brain areas. RPHN appears to affect occipital cortex and hippocampal activities, neurotransmitter transition, energy metabolism, and other metabolic equilibria in newborn rats; these effects are further aggravated when the newborn rats develop into adolescence. Changes in the metabolism of neurotransmitter system may be an adaptive measure of the central nervous system in response to RPHN.

Does magnetic resonance spectroscopy identify patients with minimal hepatic encephalopathy?

BACKGROUND AND PURPOSE: The results of a few studies suggest that magnetic resonance spectroscopy of the brain could allow detection of minimal hepatic encephalopathy. The goal of this study was to assess the ability of magnetic resonance spectroscopy to differentiate between cirrhotic patients with and without minimal hepatic encephalopathy. MATERIAL AND METHODS: Localized magnetic resonance spectroscopy was performed in the basal ganglia, occipital gray matter and frontal white matter in 46 patients with liver cirrhosis without overt encephalopathy and in 45 controls. Neurological and neuropsychological examination was performed in each participant. RESULTS: The patients with liver cirrhosis had a decreased ratio of myoinositol to creatine in occipital gray matter and frontal white matter (mean: 0.17 ± 0.05 vs. 0.20 ± 0.04, p = 0.01 and 0.15 ± 0.05 vs. 0.19 ± 0.04, p < 0.01, respectively) and a decreased ratio of choline to creatine in occipital gray matter (mean: 0.32 ± 0.07 vs. 0.36 ± 0.08, p = 0.03). Minimal hepatic encephalopathy was diagnosed in 7 patients. Metabolite ratios did not differ significantly between patients with and without minimal hepatic encephalopathy. Metabolite ratios did not differ significantly between patients with Child-Pugh A and those with Child-Pugh B. CONCLUSIONS: Magnetic resonance spectroscopy does not allow accurate diagnosis of minimal hepatic encephalopathy. A similar profile of metabolites in the brain is observed in cirrhotic patients without cognitive impairment.

Alteration of the pro-oxidant xanthine oxidase (XO) in the thalamus and occipital cortex of patients with schizophrenia.

OBJECTIVES: Mounting evidence shows that oxidative stress (OS) and the purine/adenosine system play a key role in the pathophysiology of schizophrenia. Lately, our group pointed out that not only antioxidants, but also the prooxidant system plays an important role in neuro-psychiatric disorders. Xanthine oxidase (XO) is an enzyme of special interest in this context, since it acts as a prooxidant, but its main product is a vastly important antioxidant, uric acid (UA). Furthermore, XO plays major part in the purine/adenosine metabolism, which has been hypothesised to play a role in schizophrenia as well. METHODS: We examined the activity of XO in the striato-cortico-limbic system of schizophrenic patients (SP) and controls using a commercially available activity assay. RESULTS: We found decreased activity of XO in the occipital cortex and thalamus of patients with psychosis. Furthermore, XO shows a significant positive correlation with chlorpromazine equivalents in the putamen and the temporal cortex. CONCLUSIONS: Nevertheless, our results might suggest a downregulation of cellular defence mechanisms in schizophrenia in several brain regions, which could account for neuronal alterations which have been described before. This demonstrates that more research is needed to fully understand the role of the complex enzyme XO in the pathophysiology of schizophrenia.