Female advantage in verbal learning revisited: a HUNT study.

The argument for a female advantage in word list learning is often based on partial observations that focus on a single component of the task. Using a large sample (N = 4403) of individuals 13-97 years of age from the general population, we investigated whether this advantage is consistently reflected in learning, recall, and recognition and how other cognitive abilities differentially support word list learning. A robust female advantage was found in all subcomponents of the task. Semantic clustering mediated the effects of short-term and working memory on long-delayed recall and recognition, and serial clustering on short-delayed recall. These indirect effects were moderated by sex, with men benefiting more from reliance on each clustering strategy than women. Auditory attention span mediated the effect of pattern separation on true positives in word recognition, and this effect was stronger in men than in women. Men had better short-term and working memory scores, but lower auditory attention span and were more vulnerable to interference both in delayed recall and recognition. Thus, our data suggest that auditory attention span and interference control (inhibition), rather than short-term or working memory scores, semantic and/or serial clustering on their own, underlie better performance on word list learning in women.

Investigating Intra-Individual Networks of Response Inhibition and Interference Resolution using 7T MRI.

Response inhibition and interference resolution are often considered subcomponents of an overarching inhibition system that utilizes the so-called cortico-basal-ganglia loop. Up until now, most previous functional magnetic resonance imaging (fMRI) literature has compared the two using between-subject designs, pooling data in the form of a meta-analysis or comparing different groups. Here, we investigate the overlap of activation patterns underlying response inhibition and interference resolution on a within-subject level, using ultra-high field MRI. In this model-based study, we furthered the functional analysis with cognitive modelling techniques to provide a more in-depth understanding of behaviour. We applied the stop-signal task and multi-source interference task to measure response inhibition and interference resolution, respectively. Our results lead us to conclude that these constructs are rooted in anatomically distinct brain areas and provide little evidence for spatial overlap. Across the two tasks, common BOLD responses were observed in the inferior frontal gyrus and anterior insula. Interference resolution relied more heavily on subcortical components, specifically nodes of the commonly referred to indirect and hyperdirect pathways, as well as the anterior cingulate cortex, and pre-supplementary motor area. Our data indicated that orbitofrontal cortex activation is specific to response inhibition. Our model-based approach provided evidence for the dissimilarity in behavioural dynamics between the two tasks. The current work exemplifies the importance of reducing inter-individual variance when comparing network patterns and the value of UHF-MRI for high resolution functional mapping.

Poor Response Inhibition and Symptoms of Inattentiveness Are Core Characteristics of Lifetime Illicit Substance Use among Young Adults in the General Norwegian Population: The HUNT Study.

BACKGROUND: Impairments in neurocognitive functioning are associated with substance use behavior. Previous studies in neurocognitive predictors of substance use typically use self-report measures rather than neuropsychological performance measures and suffer from low sample sizes and use of clinical diagnostic cut offs. METHODS: Crossectional data from the HUNT4 Study (Helseundersøkelsen i Trøndelag) was used to study executive neuropsychological performance and self-reported measures of neurocognitive function associated with a history of illicit substance use in a general population sample of young adults in Norway. We performed both between group comparisons and logistic regression modeling and controlled for mental health symptomatology. RESULTS: Subjects in our cohort with a self-reported use of illicit substances had significantly higher self-reported mental health and neurocognitive symptom load. A logistic regression model with substance use as response included sex, commission errors and self-reported inattentiveness and anxiety as significant predictors. After 10-fold cross-validation this model achieved a moderate area under the receiver-operator curve of 0.63. To handle the class imbalance typically found in such population data, we also calculated balanced accuracy with a optimal model cut off of 0.234 with a sensitivity of 0.50 and specificity of 0.76 as well as precision recall-area under the curve of 0.28. CONCLUSIONS: Subtle cognitive dysfunction differentiates subjects with and without a history of illicit substance use. Neurocognitive factors outperformed the effects of depressive symptoms on substance use behavior in this cohort. We highlight the need for using adequate statistical tools for evaluating the performance of models in unbalanced datasets.

Normative Data for Brainstem Structures, the Midbrain-to-Pons Ratio, and the Magnetic Resonance Parkinsonism Index.

BACKGROUND AND PURPOSE: Imaging biomarkers derived from different brainstem structures are suggested to differentiate among parkinsonian disorders, but clinical implementation requires normative data. The main objective was to establish high-quality, sex-specific data for relevant brainstem structures derived from MR imaging in healthy subjects from the general population in their sixth and seventh decades of life. MATERIALS AND METHODS: 3D T1WI acquired on the same 1.5T scanner of 996 individuals (527 women) between 50 and 66 years of age from a prospective population study was used. The area of the midbrain and pons and the widths of the middle cerebellar peduncles and superior cerebellar peduncles were measured, from which the midbrain-to-pons ratio and Magnetic Resonance Parkinsonism Index [MRPI = (Pons Area / Midbrain Area) × (Middle Cerebellar Peduncles / Superior Cerebellar Peduncles)] were calculated. Sex differences in brainstem measures and correlations to age, height, weight, and body mass index were investigated. RESULTS: Inter- and intrareliability for measuring the different brainstem structures showed good-to-excellent reliability (intraclass correlation coefficient = 0.785-0.988). There were significant sex differences for the pons area, width of the middle cerebellar peduncles and superior cerebellar peduncles, midbrain-to-pons ratio, and MRPI (all, P < .001; Cohen D = 0.44-0.98), but not for the midbrain area (P = .985). There were significant very weak-to-weak correlations between several of the brainstem measures and age, height, weight, and body mass index in both sexes. However, no systematic difference in distribution caused by these variables was found, and because age had the highest and most consistent correlations, age-/sex-specific percentiles for the brainstem measures were created. CONCLUSIONS: We present high-quality, sex-specific data and age-/sex-specific percentiles for the mentioned brainstem measures. These normative data can be implemented in the neuroradiologic work-up of patients with suspected brainstem atrophy to avoid the risk of misdiagnosis.

Two separate, large cohorts reveal potential modifiers of age-associated variation in visual reaction time performance.

To identify potential factors influencing age-related cognitive decline and disease, we created MindCrowd. MindCrowd is a cross-sectional web-based assessment of simple visual (sv) reaction time (RT) and paired-associate learning (PAL). svRT and PAL results were combined with 22 survey questions. Analysis of svRT revealed education and stroke as potential modifiers of changes in processing speed and memory from younger to older ages (ntotal = 75,666, nwomen = 47,700, nmen = 27,966; ages 18-85 years old, mean (M)Age = 46.54, standard deviation (SD)Age = 18.40). To complement this work, we evaluated complex visual recognition reaction time (cvrRT) in the UK Biobank (ntotal = 158,249 nwomen = 89,333 nmen = 68,916; ages 40-70 years old, MAge = 55.81, SDAge = 7.72). Similarities between the UK Biobank and MindCrowd were assessed using a subset of MindCrowd (UKBb MindCrowd) selected to mirror the UK Biobank demographics (ntotal = 39,795, nwomen = 29,640, nmen = 10,155; ages 40-70 years old, MAge = 56.59, SDAge = 8.16). An identical linear model (LM) was used to assess both cohorts. Analyses revealed similarities between MindCrowd and the UK Biobank across most results. Divergent findings from the UK Biobank included (1) a first-degree family history of Alzheimer's disease (FHAD) was associated with longer cvrRT. (2) Men with the least education were associated with longer cvrRTs comparable to women across all educational attainment levels. Divergent findings from UKBb MindCrowd included more education being associated with shorter svRTs and a history of smoking with longer svRTs from younger to older ages.

Smoking is associated with impaired verbal learning and memory performance in women more than men.

Vascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase the likelihood of cognitive impairment by exacerbating vascular disease risks. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific relationships between smoking and memory performance and with contradictory results. We investigated the associations between sex, smoking, and cardiovascular disease with verbal learning and memory function. Using MindCrowd, an observational web-based cohort of ~ 70,000 people aged 18-85, we investigated whether sex modifies the relationship between smoking and cardiovascular disease with verbal memory performance. We found significant interactions in that smoking is associated with verbal learning performance more in women and cardiovascular disease more in men across a wide age range. These results suggest that smoking and cardiovascular disease may impact verbal learning and memory throughout adulthood differently for men and women.

A prospective three-year follow-up study on the clinical significance of anti-neuronal antibodies in acute psychiatric disorders.

The clinical significance of anti-neuronal antibodies for psychiatric disorders is controversial. We investigated if a positive anti-neuronal antibody status at admission to acute psychiatric inpatient care was associated with a more severe neuropsychiatric phenotype and more frequent abnormalities during clinical work-up three years later. Patients admitted to acute psychiatric inpatient care who tested positive for N-methyl-D-aspartate receptor (NMDAR), contactin-associated protein 2 (CASPR2) and/or glutamic acid decarboxylase 65 (GAD65) antibodies (n = 24) were age - and sex matched with antibody-negative patients (1:2) from the same cohort (n = 48). All patients were invited to follow-up including psychometric testing (e.g. Symptom Checklist-90-Revised), serum and cerebrospinal fluid (CSF) sampling, EEG and 3 T brain MRI. Twelve antibody-positive (ab+) and 26 antibody-negative (ab-) patients consented to follow-up. Ab+ patients had more severe symptoms of depression (p = 0.03), psychoticism (p = 0.04) and agitation (p = 0.001) compared to ab- patients. There were no differences in CSF analysis (n = 6 ab+/12 ab-), EEG (n = 7 ab+/19 ab-) or brain MRI (n = 7 ab+/17 ab-) between the groups. In conclusion, anti-neuronal ab+ status during index admission was associated with more severe symptoms of depression, psychoticism and agitation at three-year follow-up. This supports the hypothesis that anti-neuronal antibodies may be of clinical significance in a subgroup of psychiatric patients.

Trajectories of brain development in school-age children born preterm with very low birth weight.

Preterm birth (gestational age < 37 weeks) with very low birth weight (VLBW, birth weight ≤ 1500 g) is associated with lifelong cognitive deficits, including in executive function, and persistent alterations in cortical and subcortical structures. However, it remains unclear whether "catch-up" growth is possible in the preterm/VLBW brain. Longitudinal structural MRI was conducted with children born preterm with VLBW (n = 41) and term-born peers participating in the Norwegian Mother and Child Cohort Study (MoBa) (n = 128) at two timepoints in early school age (mean ages 8.0 and 9.3 years). Images were analyzed with the FreeSurfer 5.3.0 longitudinal stream to assess differences in development of cortical thickness, surface area, and brain structure volumes, as well as associations with executive function development (NEPSY Statue and WMS-III Spatial Span scores) and perinatal health markers. No longitudinal group × time effects in cortical thickness, surface area, or subcortical volumes were seen, indicating similar brain growth trajectories in the groups over an approximately 16-month period in middle childhood. Higher IQ scores within the VLBW group were associated with greater surface area in left parieto-occipital and inferior temporal regions. Among VLBW preterm-born children, cortical surface area was smaller across the cortical mantle, and cortical thickness was thicker occipitally and frontally and thinner in lateral parietal and posterior temporal areas. Smaller volumes of corpus callosum, right globus pallidus, and right thalamus persisted in the VLBW group from timepoint 1 to 2. VLBW children had on average IQ 1 SD below term-born MoBa peers and significantly worse scores on WMS-III Spatial Span. Executive function scores did not show differential associations with morphometry between groups cross-sectionally or longitudinally. This study investigated divergent or "catch-up" growth in terms of cortical thickness, surface area, and volumes of subcortical gray matter structures and corpus callosum in children born preterm/VLBW and did not find group × time interactions. Greater surface area at mean age 9.3 in left parieto-occipital and inferior temporal cortex was associated with higher IQ in the VLBW group. These results suggest that preterm VLBW children may have altered cognitive networks, yet have structural growth trajectories that appear generally similar to their term-born peers in this early school age window.

Loss or Mislocalization of Aquaporin-4 Affects Diffusion Properties and Intermediary Metabolism in Gray Matter of Mice.

The first aim of this study was to determine how complete or perivascular loss of aquaporin-4 (AQP4) water channels affects membrane permeability for water in the mouse brain grey matter in the steady state. Time-dependent diffusion magnetic resonance imaging was performed on global Aqp4 knock out (KO) and α-syntrophin (α-syn) KO mice, in the latter perivascular AQP4 are mislocalized, but still functioning. Control animals were corresponding wild type (WT) mice. By combining in vivo diffusion measurements with the effective medium theory and previously measured extra-cellular volume fractions, the effects of membrane permeability and extracellular volume fraction were uncoupled for Aqp4 and α-syn KO. The second aim was to assess the effect of α-syn KO on cortical intermediary metabolism combining in vivo [1-13C]glucose and [1,2-13C]acetate injection with ex vivo 13C MR spectroscopy. Aqp4 KO increased the effective diffusion coefficient at long diffusion times by 5%, and a 14% decrease in membrane water permeability was estimated for Aqp4 KO compared with WT mice. α-syn KO did not affect the measured diffusion parameters. In the metabolic analyses, significantly lower amounts of [4-13C]glutamate and [4-13C]glutamine, and percent enrichment in [4-13C]glutamate were detected in the α-syn KO mice. [1,2-13C]acetate metabolism was unaffected in α-syn KO, but the contribution of astrocyte derived metabolites to GABA synthesis was significantly increased. Taken together, α-syn KO mice appeared to have decreased neuronal glucose metabolism, partly compensated for by utilization of astrocyte derived metabolites.

How Does the Accuracy of Intracranial Volume Measurements Affect Normalized Brain Volumes? Sample Size Estimates Based on 966 Subjects from the HUNT MRI Cohort.

BACKGROUND AND PURPOSE: The intracranial volume is commonly used for correcting regional brain volume measurements for variations in head size. Accurate intracranial volume measurements are important because errors will be propagated to the corrected regional brain volume measurements, possibly leading to biased data or decreased power. Our aims were to describe a fully automatic SPM-based method for estimating the intracranial volume and to explore the practical implications of different methods for obtaining the intracranial volume and normalization methods on statistical power. MATERIALS AND METHODS: We describe a method for calculating the intracranial volume that can use either T1-weighted or both T1- and T2-weighted MR images. The accuracy of the method was compared with manual measurements and automatic estimates by FreeSurfer and SPM-based methods. Sample size calculations on intracranial volume-corrected regional brain volumes with intracranial volume estimates from FreeSurfer, SPM, and our proposed method were used to explore the benefits of accurate intracranial volume estimates. RESULTS: The proposed method for estimating the intracranial volume compared favorably with the other methods evaluated here, with mean and absolute differences in manual measurements of -0.1% and 2.2%, respectively, and an intraclass correlation coefficient of 0.97 when using T1-weighted images. Using both T1- and T2-weighted images for estimating the intracranial volume slightly improved the accuracy. Sample size calculations showed that both the accuracy of intracranial volume estimates and the method for correcting the regional volume measurements affected the sample size. CONCLUSIONS: Accurate intracranial volume estimates are most important for ratio-corrected regional brain volumes, for which our proposed method can provide increased power in intracranial volume-corrected regional brain volume data.

Reward responsiveness in patients with chronic pain.

BACKGROUND: It is proposed that changes in reward processing in the brain are involved in the pathophysiology of pain based on experimental studies. The first aim of the present study was to investigate if reward drive and/or reward responsiveness was altered in patients with chronic pain (PCP) compared to controls matched for education, age and sex. The second aim was to investigate the relationship between reward processing and nucleus accumbens volume in PCP and controls. Nucleus accumbens is central in reward processing and its structure has been shown to be affected by chronic pain conditions in previous studies. METHODS: Reward drive and responsiveness were assessed with the Behavioral Inhibition Scale/Behavioral Activation Scale, and nucleus accumbens volumes obtained from T1-weighted brain MRIs obtained at 3T in 19 PCP of heterogeneous aetiologies and 20 age-, sex- and education-matched healthy controls. Anhedonia was assessed with Beck's Depression Inventory II. RESULTS: The PCP group had significantly reduced scores on the reward responsiveness, but not reward drive. There was a trend towards smaller nucleus accumbens volume in the PCP compared to control group. There was a significant positive partial correlation between reward responsiveness and nucleus accumbens volume in the PCP group adjusted for anhedonia, which was significantly different from the same relationship in the control group. CONCLUSIONS: Reward responsiveness is reduced in chronic pain patients of heterogeneous aetiology, and this reduction was associated with nucleus accumbens volume. Reduced reward responsiveness could be a marker of chronic pain vulnerability, and may indicate reduced opioid function.

White matter microstructure in chronic moderate-to-severe traumatic brain injury: Impact of acute-phase injury-related variables and associations with outcome measures.

This study examines how injury mechanisms and early neuroimaging and clinical measures impact white matter (WM) fractional anisotropy (FA), mean diffusivity (MD), and tract volumes in the chronic phase of traumatic brain injury (TBI) and how WM integrity in the chronic phase is associated with different outcome measures obtained at the same time. Diffusion tensor imaging (DTI) at 3 T was acquired more than 1 year after TBI in 49 moderate-to-severe-TBI survivors and 50 matched controls. DTI data were analyzed with tract-based spatial statistics and automated tractography. Moderate-to-severe TBI led to widespread FA decreases, MD increases, and tract volume reductions. In severe TBI and in acceleration/deceleration injuries, a specific FA loss was detected. A particular loss of FA was also present in the thalamus and the brainstem in all grades of diffuse axonal injury. Acute-phase Glasgow Coma Scale scores, number of microhemorrhages on T2*, lesion volume on fluid-attenuated inversion recovery, and duration of posttraumatic amnesia were associated with more widespread FA loss and MD increases in chronic TBI. Episodes of cerebral perfusion pressure <70 mmHg were specifically associated with reduced MD. Neither episodes of intracranial pressure >20 mmHg nor acute-phase Rotterdam CT scores were associated with WM changes. Glasgow Outcome Scale Extended scores and performance-based cognitive control functioning were associated with FA and MD changes, but self-reported cognitive control functioning was not. In conclusion, FA loss specifically reflects the primary injury severity and mechanism, whereas FA and MD changes are associated with objective measures of general and cognitive control functioning.

Structural brain changes after 4 wk of unilateral strength training of the lower limb.

Strength training enhances muscular strength and neural drive, but the underlying neuronal mechanisms remain unclear. This study used magnetic resonance imaging (MRI) to identify possible changes in corticospinal tract (CST) microstructure, cortical activation, and subcortical structure volumes following unilateral strength training of the plantar flexors. Mechanisms underlying cross-education of strength in the untrained leg were also investigated. Young, healthy adult volunteers were assigned to training (n = 12) or control (n = 9) groups. The 4 wk of training consisted of 16 sessions of 36 unilateral isometric plantar flexions. Maximum voluntary isometric contraction torque was tested pre- and posttraining. MRI investigation included a T1-weighted scan, diffusion tensor imaging and functional MRI. Probabilistic fiber tracking of the CST was performed on the diffusion tensor imaging images using a two-regions-of-interest approach. Fractional anisotropy and mean diffusivity were calculated for the left and right CST in each individual before and after training. Standard functional MRI analyses and volumetric analyses of subcortical structures were also performed. Maximum voluntary isometric contraction significantly increased in both the trained and untrained legs of the training group, but not the control group. A significant decrease in mean diffusivity was found in the left CST following strength training of the right leg. No significant changes were detected in the right CST. No significant changes in cortical activation were observed following training. A significant reduction in left putamen volume was found after training. This study provides the first evidence for strength training-related changes in white matter and putamen in the healthy adult brain.

OS046. Genome-wide association scans identify novel maternalsusceptibility loci for preeclampsia.

INTRODUCTION: We have successfully utilized a family-based study design to localize several positional candidate preeclampsia susceptibility genes to chromosomes 2q22(ACVR2A,LCT,LRP1B,RND3,GCA),5q (ERAP2) and 13q(TNFSF13B). We now report on our continued positional cloning efforts using an alternative genome-wide association (GWA) mapping strategy in large Caucasian case-control cohorts from Australia and Norway. OBJECTIVES: To identify maternal genetic risk loci for preeclampsia. METHODS: The unrelated Australian samples (545 cases,547 controls) were genotyped using Illumina BeadChip technology (700K loci) and have been analyzed using PLINK. All unrelated Norwegian samples were genotyped across several Illumina BeadChip substrates and consist of 847 cases (700K loci) and 638 controls. The Norwegian control samples originate from other HUNT studies pertaining to migraine (n=95,700K loci), lung cancer (n=89,370K loci) and normal brain pathology (n=454,2.5M loci). To analyze a concordant set of 2.5-3 million genotypes across all Norwegian samples we are currently using MaCH to impute those loci not directly genotyped. The Norwegian GWA data will be analyzed in SOLAR utilizing empirical kinship estimates to account for any distant relatedness. RESULTS: 1078 Australian samples (538 cases,540 controls) and 648, 175 SNPs passed our quality control metrics. Two SNP associations (rs7579169,p=3.6×10(-7); rs12711941,p=4.3×10(-7)) satisfied our genome-wide significant threshold (p<5.1×10(-7)). These SNPs reside less than 15kb downstream from the 3 terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. Sequencing of the INHBB locus in our patient cohort identified a third intergenic SNP to significantly associate with preeclampsia (rs7576192,p=1.5×10(-7)). These three SNPs confer risk (OR>1.56) and are in strong linkage disequilibrium with each other (r(2)>0.9) but not with any other genotyped SNP ±200kb. The analysis of the Norwegian GWAS is underway. CONCLUSION: The Australian GWAS has identified a novel preeclampsia risk locus on chromosome 2q. The INHBB gene closest to our SNP associations is a plausible positional candidate susceptibility gene. There is a substantive body of evidence implicating inhibins, activins and other members of the TGF-ßsuperfamily to have a role in the development of preeclampsia. The biological connection between ACVR2A and INHBB leads us to speculate that our linkage-based and GWA-based study designs, respectively, have identified a key biological pathway involved in susceptibility to preeclampsia.

Surgical resection of high-grade gliomas in eloquent regions guided by blood oxygenation level dependent functional magnetic resonance imaging, diffusion tensor tractography, and intraoperative navigated 3D ultrasound.

OBJECTIVE: The aims of this study of patients with high-grade gliomas in eloquent brain areas were 1) to assess the postoperative functional outcome, 2) to determine the extent of tumour resection in these difficult locations, 3) to evaluate the practical usefulness of navigated blood oxygenation level-dependent functional magnetic resonance imaging and diffusion tensor tractography. PATIENTS AND METHODS: 25 consecutive patients were included in the study. The patients' gross functional neurological status was determined using the 7-step modified Rankin scale. The extent of tumour resection was determined using pre- and postoperative T(1)-weighted or T(1)-weighted, contrast-enhanced MRI images. RESULTS: The average preoperative modified Rankin scale was 1.56+/-0.77, whereas the average postoperative modified Rankin scale was 1.08+/-1.29. There was a significant improvement in mean modified Rankin scale score after surgery. The mean percentage of residual tumour was calculated to 16+/-22% of the original tumour volume (median 8%). Blood oxygenation level-dependent functional magnetic resonance imaging and diffusion tensor tractography were performed in 23 and 18 patients, respectively. Blood oxygenation level-dependent functional magnetic resonance imaging and diffusion tensor tractography facilitated identification of probable functional regions in 91% and 94% of the respective investigations. CONCLUSION: We feel that the combination of blood oxygenation level-dependent functional magnetic resonance imaging, diffusion tensor tractography, and 3D ultrasound facilitated maximal tumour resection with minimal deficits. The method permits an image-based functional monitoring of the brain during surgery that may aid the preservation of motor and language function.

Functional neuronavigation combined with intra-operative 3D ultrasound: initial experiences during surgical resections close to eloquent brain areas and future directions in automatic brain shift compensation of preoperative data.

OBJECTIVE: The aims of this study were: 1) To develop protocols for, integration and assessment of the usefulness of high quality fMRI (functional magnetic resonance imaging) and DTI (diffusion tensor imaging) data in an ultrasound-based neuronavigation system. 2) To develop and demonstrate a co-registration method for automatic brain-shift correction of pre-operative MR data using intra-operative 3D ultrasound. METHODS: Twelve patients undergoing brain surgery were scanned to obtain structural and fMRI data before the operation. In six of these patients, DTI data was also obtained. The preoperative data was imported into a commercial ultrasound-based navigation system and used for surgical planning and guidance. Intra-operative ultrasound volumes were acquired when needed during surgery and the multimodal data was used for guidance and resection control. The use of the available image information during planning and surgery was recorded. An automatic voxel-based registration method between preoperative MRA and intra-operative 3D ultrasound angiography (Power Doppler) was developed and tested postoperatively. RESULTS: The study showed that it is possible to implement robust, high-quality protocols for fMRI and DTI and that the acquired data could be seamlessly integrated in an ultrasound-based neuronavigation system. Navigation based on fMRI data was found to be important for pre-operative planning in all twelve procedures. In five out of eleven cases the data was also found useful during the resection. DTI data was found to be useful for planning in all five cases where these data were imported into the navigation system. In two out of four cases DTI data was also considered important during the resection (in one case DTI data were acquired but not imported and in another case fMRI and DTI data could only be used for planning). Information regarding the location of important functional areas (fMRI) was more beneficial during the planning phase while DTI data was more helpful during the resection. Furthermore, the surgeon found it more user-friendly and efficient to interpret fMRI and DTI information when shown in a navigation system as compared to the traditional display on a light board or monitor. Updating MRI data for brain-shift using automatic co-registration of preoperative MRI with intra-operative ultrasound was feasible. CONCLUSION: In the present study we have demonstrated how both fMRI and DTI data can be acquired and integrated into a neuronavigation system for improved surgical planning and guidance. The surgeons reported that the integration of fMRI and DTI data in the navigation system represented valuable additional information presented in a user-friendly way and functional neuronavigation is now in routine use at our hospital. Furthermore, the present study showed that automatic ultrasound-based updates of important pre-operative MRI data are feasible and hence can be used to compensate for brain shift.

Effect of the pyrrolopyrimidine lipid peroxidation inhibitor U-101033E on neuronal and astrocytic metabolism and infarct volume in rats with transient middle cerebral artery occlusion.

The aim of the present study was to assess the effect of post ictal administration of the pyrrolopyrimidine lipid peroxidation inhibitor, U-101033E, on infarct volume and neuronal and astrocytic metabolism in rats with transient middle cerebral artery occlusion (MCAO). Rats were subjected to 120 min of MCAO followed by 140 min of reperfusion and randomly assigned to control (n=17) or U-101033E treatment (n=16). Drug infusion started 5 min after MCAO and lasted 220 min with a 15 min interruption during the reperfusion procedure. Sixteen rats underwent diffusion weighted imaging 260 min after ictus, from which the apparent diffusion coefficient (ADC) was determined. Seventeen rats received an iv bolus injection of [1-13C]glucose and [1,2-13C]acetate 245 min after ictus. Tissue extracts from two brain regions representing penumbra and ischemic core were analyzed with 13C NMRS and HPLC. U-101033E did not affect the volume of ischemic tissue estimated from the ADC maps. In the penumbra, U-101033E specifically decreased mitochondrial pyruvate metabolism via both pyruvate dehydrogenase and pyruvate carboxylase pathways. Thus, U-101033E impaired both neuronal and astrocytic mitochondrial pyruvate metabolism. At the same time anaerobic glucose usage was increased, leading to increased lactate labeling and content. Also alanine labeling was increased. The data do not support lactate as an important substrate for neuronal mitochondria in ischemia-reperfusion. A similar pattern of reduced mitochondrial pyruvate metabolism and increased cytosolic pyruvate metabolism was found in the irreversibly damaged ischemic core. The present study highlights the importance of other outcome measures than ischemic tissue volume for evaluation of drug efficacy in animal models, which in turn could increase the likelihood of success in clinical trials.

Glutamate and GABA metabolism in transient and permanent middle cerebral artery occlusion in rat: importance of astrocytes for neuronal survival.

The aim of the present study was to identify the distinguishing metabolic characteristics of brain tissue salvaged by reperfusion following focal cerebral ischemia. Rats were subjected to 120 min of middle cerebral artery occlusion followed by 120 min of reperfusion. The rats received an intravenous bolus injection of [1-(13)C]glucose plus [1,2-(13)C]acetate. Subsequently two brain regions considered to represent penumbra and ischemic core, i.e. the frontoparietal cortex and the lateral caudoputamen plus lower parietal cortex, respectively, were analyzed with (13)C NMRS and HPLC. The results demonstrated four metabolic events that distinguished the reperfused penumbra from the ischemic core. (1) Improved astrocytic metabolism demonstrated by increased amounts of [4,5-(13)C]glutamine and improved acetate oxidation. (2) Neuronal mitochondrial activity was better preserved although the flux of glucose via pyruvate dehydrogenase into the tricarboxylic acid (TCA) cycle in glutamatergic and GABAergic neurons was halved. However, NAA content was at control level. (3) Glutamatergic and GABAergic neurons used relatively more astrocytic metabolites derived from the pyruvate carboxylase pathway. (4) Lactate synthesis was not increased despite decreased glucose metabolism in the TCA cycle via pyruvate dehydrogenase. In the ischemic core both neuronal and astrocytic TCA cycle activity declined significantly despite reperfusion. The utilization of astrocytic precursors originating from the pyruvate carboxylase pathway was markedly reduced compared the pyruvate dehydrogenase pathway in glutamate, and completely stopped in GABA. The NAA level fell significantly and lactate accumulated. The results demonstrate that preservation of astrocytic metabolism is essential for neuronal survival and a predictor for recovery.

Differences in neurotransmitter synthesis and intermediary metabolism between glutamatergic and GABAergic neurons during 4 hours of middle cerebral artery occlusion in the rat: the role of astrocytes in neuronal survival.

Astrocytes are intimately involved in both glutamate and gamma-aminobutyric acid (GABA) synthesis, and ischemia-induced disruption of normal neuroastrocytic interactions may have important implications for neuronal survival. The effects of middle cerebral artery occlusion (MCAO) on neuronal and astrocytic intermediary metabolism were studied in rats 30, 60, 120, and 240 minutes after MCAO using in vivo injection of [1-13C]glucose and [1,2- 13C]acetate combined with ex vivo 13C magnetic resonance spectroscopy and high-performance liquid chromatography analysis of the ischemic core (lateral caudoputamen and lower parietal cortex) and penumbra (upper frontoparietal cortex). In the ischemic core, both neuronal and astrocytic metabolism were impaired from 30 minutes MCAO. There was a continuous loss of glutamate from glutamatergic neurons that was not replaced as neuronal glucose metabolism and use of astrocytic precursors gradually declined. In GABAergic neurons astrocytic precursors were not used in GABA synthesis at any time after MCAO, and neuronal glucose metabolism and GABA-shunt activity declined with time. No flux through the tricarboxylic acid cycle was found in GABAergic neurons at 240 minutes MCAO, indicating neuronal death. In the penumbra, the neurotransmitter pool of glutamate coming from astrocytic glutamine was preserved while neuronal metabolism progressively declined, implying that glutamine contributed significantly to glutamate excitotoxicity. In GABAergic neurons, astrocytic precursors were used to a limited extent during the initial 120 minutes, and tricarboxylic acid cycle activity was continued for 240 minutes. The present study showed the paradoxical role that astrocytes play in neuronal survival in ischemia, and changes in the use of astrocytic precursors appeared to contribute significantly to neuronal death, albeit through different mechanisms in glutamatergic and GABAergic neurons.