Asta Håberg

Preoperative blood oxygen level-dependent functional magnetic resonance imaging in patients with primary brain tumors: clinical application and outcome.

OBJECTIVEThis study sought to evaluate the ability of blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to successfully identify functional cortical areas in patients with primary brain tumors, to evaluate the use of the fMRI results in presurgical planning, and to assess the functional outcome of the patients with respect to the functional maps obtained with fMRI. METHODSThe study included 25 consecutive preoperative fMRI sessions in patients with primary brain tumors in or near sensorimotor and/or language cortices. All fMRI paradigms were analyzed and rated according to the degree of success. Several distances between tumor and functional cortex as delineated with BOLD fMRI were measured to assess the topographic relationship between these two structures. Pre- and postoperative neurological statuses were obtained from the patients’ journals. RESULTSAcquisition of BOLD fMRI images was successful in 80% of the cases. The primary cause of unsuccessful fMRI was echo-planar imaging signal voids that were the result of previous craniotomy; the secondary cause was excessive motion. The neurosurgeons used the fMRI results for preoperative planning in 75% of the cases in which fMRI was successful. The risk of postoperative loss of function tested with fMRI was significantly lower when the distance between tumor periphery and BOLD activity was 10 mm or more. CONCLUSIONThe majority of patients with primary brain tumors were capable of satisfactorily performing the fMRI paradigms, and the information obtained was used in the preoperative planning. A distance of 10 mm or more between the functional cortex, as delineated with fMRI, and the tumor significantly reduced the risk of postoperative loss of function.

A specific role of the human hippocampus in recall of temporal sequences.

There is a growing interest in how temporal order of episodic memories is represented within the medial temporal lobe (MTL). Animal studies suggest that the hippocampal formation (HF) is critical for retrieving the temporal order of past experiences. However, human imaging studies that have tested recency discrimination between pairs of previously encoded items have generally failed to report HF activation. We hypothesized that recalling a naturalistic sequence of past events would be particularly sensitive to HF function, attributable to greater involvement of associative processes. To test this prediction, we let subjects watch a novel movie and later, during functional magnetic resonance imaging, asked them to rearrange and “replay” scenes from the movie in correct order. To identify areas specifically involved in retrieval of temporal order, we used a control condition where subjects logically inferred the order of scenes from the same movie. Extensive MTL activation was observed during sequence recall. Activation within the right HF was specifically related to retrieval of temporal order and correlated positively with accuracy of sequence recall. Also, the bilateral parahippocampal cortex responded to retrieval of temporal order, but the activation here was not related to performance. Our study is the first to unequivocally demonstrate that correct sequence recall depends on HF.

13C MR Spectroscopy Study of Lactate as Substrate for Rat Brain

In order to address the question whether lactate in blood can serve as a precursor for cerebral metabolites, fully awake rats were injected intravenously with [U-13C]lactate or [U-13C]glucose followed 15 min later by decapitation. Incorporation of label from [U-13C]glucose was seen mainly in glutamate, GABA, glutamine, aspartate, alanine and lactate. More label was found in glutamate than glutamine, underscoring the predominantly neuronal metabolism of pyruvate from [U-13C]glucose. It was estimated that the neuronal metabolism of acetyl CoA from glucose accounts for at least 66% and the glial for no more than 34% of the total glucose consumption. When [U-13C]lactate was the precursor, label incorporation was similar to that observed from [U-13C]glucose, but much reduced. Plasma analysis revealed the presence of approximately equal amounts of [1,2,3-13C]- and [1,2-13C]glucose, showing gluconeogenesis from [U-13C]lactate. It was thus possible that the labeling seen in the cerebral amino acids originated from labeled glucose, not [U-13C]lactate. However, the presence of significantly more label in [U-13C]- than in [2,3-13C]alanine demonstrated that [U-13C]lactate did indeed cross the blood-brain barrier, and was metabolized further in the brain. Furthermore, contributions from pyruvate carboxylase (glial enzyme) were detectable in glutamine, glutamate and GABA, and were comparatively more pronounced in the glucose group. This indicated that relatively more pyruvate from lactate than glucose was metabolized in neurons. Surprisingly, the same amount of lactate was synthesized via the tricarboxylic acid cycle in both groups, indicating transfer of neurotransmitters from the neuronal to the astrocytic compartment, as previous studies have shown that this lactate is synthesized primarily in astrocytes. Taking into consideration that astrocytes take up glutamate more avidly than GABA, it is conceivable that neuronal lactate metabolism was more prominent in glutamatergic neurons.

Young adults born preterm with very low birth weight demonstrate widespread white matter alterations on brain DTI

Preterm birth with very low birth weight (VLBW, ≤1500 g) is connected to reduced white matter (WM) integrity in childhood and adolescence. These changes in WM are correlated to motor, sensory and neuropsychological impairments. CNS myelination continues into the early twenties, but the consequences of this for WM integrity in VLBWs have not been explored. DTI and tract based spatial statistics (TBSS) was carried out to test for voxelwise differences in fractional anisotropy (FA), eigenvalues and mean diffusivity (MD) between a preterm VLBW group (n=49) and a control group born at term (n=59) at 18-22 years of age. TBSS was also used to explore the relationship between perinatal clinical data and general cognitive ability (total IQ), respectively, and the DTI metrics (FA and MD), with gender and age as a confounder. In the VLBW group several major WM tracts particularly in the posterior region had significantly reduced FA caused by an increase in the two lowest eigenvalues. MD was significantly increased in the VLBWs in 50% of the same regions as the FA changes, but encompassing also more peripheral WM. In the VLBW group, FA was found to correlate positively with birth weight and negatively with number of days in intensive care and on mechanical ventilator, particularly in the corpus callosum. FA was found to correlate positively with total IQ in the young preterm adults. In the controls there was no correlation between FA and total IQ. Our results indicate that the neurologic sequelae of preterm birth with VLBW are a lifelong condition inducing structural and functional impairments also in adulthood in VLBW survivors. The greatest risk of having reduced WM integrity in adulthood was found in the most immature VLBW neonates requiring mechanical ventilation and long-term intensive care.

Motor Network Changes Associated With Successful Motor Skill Relearning After Acute Ischemic Stroke : A Longitudinal Functional Magnetic Resonance Imaging Study

Background. Motor learning mechanisms may be operative in stroke recovery and possibly reinforced by rehabilitative training. Objectives. To assess early motor network changes after acute ischemic stroke in patients treated with very early mobilization and task-oriented physical therapy in a comprehensive stroke unit, to investigate the association between neuronal activity and improvements in hand function, and to qualitatively explore the changes in neuronal activity in relation to motor learning. Methods. Patients were assessed by functional magnetic resonance imaging and by clinical tests within the first week after stroke and 3 months later. After discharge, all participants were offered functional training of the affected arm according to individual needs. Results. A total of 359 patients were screened, with 12 patients experiencing first-ever stroke, excluding primary sensorimotor cortex (MISI), with severe to moderately impaired hand function fulfilling the inclusion criteria. Laterality indexes (LIs) for MISI increase significantly during follow-up. There is increased cerebellar and striatal activation acutely, replaced by increased activation of ipsilesional MISI in the chronic phase. Bilateral somatosensory association areas and contralesional secondary somatosensory cortex (SII) area are also more active in the chronic phase. Activation of the latter region also correlates positively with improved hand function. Conclusions. Restoration of hand function is associated with highly lateralized MISI. Activity in bilateral somatosensory association area and contralesional SII may represent cortical plasticity involved in successful motor recovery. The changes in motor activity between acute and chronic phases seem to correspond to a motor learning process.

Computerized Working Memory Training Improves Function in Adolescents Born at Extremely Low Birth Weight

OBJECTIVE To evaluate the effect of a computerized working memory training program on both trained and non-trained verbal aspects of working memory and executive and memory functions in extremely low birth weight (ELBW; <1000 g) infants. STUDY DESIGN Sixteen ELBW infants and 19 term-born control subjects aged 14 to 15 years participated in the training program, and 11 adolescents were included as a non-intervention group. Extensive neuropsychological assessment was performed before and immediately after training and at a 6-month follow-up examination. Both training groups used the CogMed RM program at home 5 days a week for 5 weeks. RESULTS Both groups improved significantly on trained and non-trained working memory tasks and on other memory tests indicating a generalizing effect. Working memory capacity was improved, and effects were maintained at the 6-month follow-up examination. There was no significant improvement in the non-intervention group at the 6-week follow-up examination. CONCLUSIONS The computerized training program Cogmed RM was an effective intervention tool for improving memory and reducing core learning deficits in adolescents born at ELBW.

In vivo injection of [1-13C]glucose and [1,2-13C]acetate combined with ex vivo 13C nuclear magnetic resonance spectroscopy: a novel approach to the study of middle cerebral artery occlusion in the rat.

Astrocytes play a pivotal role in cerebral glutamate homeostasis. After 90 minutes of middle cerebral artery occlusion in the rat, the changes induced in neuronal and astrocytic metabolism and in the neuronal—astrocytic interactions were studied by combining in vivo injection of [1-13C]glucose and [1,2-13C]acetate with ex vivo 13C nuclear magnetic resonance spectroscopy and HPLC analysis of amino acids of the lateral caudoputamen and lower parietal cortex, representing the putative ischemic core, and the upper frontoparietal cortex, corresponding to the putative penumbra. In the putative ischemic core, evidence of compromised de novo glutamate synthesis located specifically in the glutamatergic neurons was detected, and a larger proportion of glutamate was derived from astrocytic glutamine. In the same region, pyruvate carboxylase activity, representing the anaplerotic pathway in the brain and exclusively located in astrocytes, was abolished. However, astrocytic glutamate uptake and conversion to glutamine took place, and cycling of intermediates in the astrocytic tricarboxylic acid cycle was elevated. In the putative penumbra, glutamate synthesis was improved compared with the ischemic core, the difference appeared to be brought on by better neuronal de novo glutamate synthesis, combined with normal levels of glutamate formed from astrocytic glutamine. In both ischemic regions, γ-aminobutyric acid synthesis directly from glucose was reduced to about half, indicating impaired pyruvate dehydrogenase activity; still, γ-aminobutyric acid reuptake and cycling was increased. The results obtained in the current study demonstrate that by combining in vivo injection of [1-13C]glucose and [1,2-13C]acetate with ex vivo 13C nuclear magnetic resonance spectroscopy, specific metabolic alterations in small regions within the rat brain suffering a focal ischemic lesion can be studied.

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 γ-aminobutric 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 vivo13C 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.

In vitro and ex vivo 13C-NMR Spectroscopy Studies of Pyruvate Recycling in Brain

Pyruvate recycling is a well established pathway in the liver, but in the brain, the cellular localization of pyruvate recycling remains controversial and its physiological significance is unknown. In cultured cortical astrocytes, pyruvate formed from [U-13C]glutamate was shown to re-enter the TCA cycle after conversion to acetyl-CoA, as demonstrated by the labelling patterns in aspartate C-2 and C-3, lactate C-2, and glutamate C-4, which provides evidence for pyruvate recycling in astrocytes. This finding is in agreement with previous studies of astrocytic cultures, in which pyruvate recycling has been described from [U-13C]glutamine, in the presence of glutamate, and from [U-13C]aspartate. Pyruvate recycling in brain was studied in fasted rats receiving either an intraperitoneal or a subcutaneous injection of [1,2-13C]acetate followed by decapitation 30 min later. Extracts of cortical tissue were analysed with 13C-NMR spectroscopy and total amounts of amino acids quantified by HPLC. Plasma extracts were analysed with 1H- and 13C-NMR spectroscopy, and showed a significantly larger amount of [1,2-13C]acetate in the intraperitoneal group compared to the subcutaneous group. Furthermore, a small amount of label was detected in glucose in both groups. In the subcutaneously injected rats, [4-13C]glutamate and [2-13C]GABA were less enriched than plasma glucose, which might have been the precursor. In the intraperitoneally injected rats, however, pyruvate formation from [1,2-13C]acetate, and re-entry of this pyruvate into the TCA cycle was demonstrated by the presence of greater 13C enrichment in [4-13C]glutamate and [4-13C]glutamine compared to the subcutaneous group, probably resulting from the significantly higher [1,2-13C]acetate concentration in brain and plasma.

The human brain representation of odor identification

Odor identification (OI) tests are increasingly used clinically as biomarkers for Alzheimers disease and schizophrenia. The aim of this study was to directly compare the neuronal correlates to identified odors vs. nonidentified odors. Seventeen females with normal olfactory function underwent a functional magnetic resonance imaging (fMRI) experiment with postscanning assessment of spontaneous uncued OI. An event-related analysis was performed to compare within-subject activity to spontaneously identified vs. nonidentified odors at the whole brain level, and in anatomic and functional regions of interest (ROIs) in the medial temporal lobe (MTL). Parameter estimate values and blood oxygenated level-dependent (BOLD) signal curves for correctly identified and nonidentified odors were derived from functional ROIs in hippocampus, entorhinal, piriform, and orbitofrontal cortices. Number of activated voxels and max parameter estimate values were obtained from anatomic ROIs in the hippocampus and the entorhinal cortex. At the whole brain level the correct OI gave rise to increased activity in the left entorhinal cortex and secondary olfactory structures, including the orbitofrontal cortex. Increased activation was also observed in fusiform, primary visual, and auditory cortices, inferior frontal plus inferior temporal gyri. The anatomic MTL ROI analysis showed increased activation in the left entorhinal cortex, right hippocampus, and posterior parahippocampal gyri in correct OI. In the entorhinal cortex and hippocampus the BOLD signal increased specifically in response to identified odors and decreased for nonidentified odors. In orbitofrontal and piriform cortices both identified and nonidentified odors gave rise to an increased BOLD signal, but the response to identified odors was significantly greater than that for nonidentified odors. These results support a specific role for entorhinal cortex and hippocampus in OI, whereas piriform and orbitofrontal cortices are active in both smelling and OI. Moreover, episodic as well as semantic memory systems appeared to support OI.