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Summary The hippocampus, a structure located in the temporal lobes of the brain, is critical for the ability to recollect contextual details of past episodes. It is still debated whether the hippocampus also enables recognition memory for previously encountered context-free items. Brain imaging [1, 2] and neuropsychological patient studies [3, 4] have both individually provided conflicting answers to this question. We overcame the individual limitations of imaging and behavioral patient studies by combining them and observed a novel relationship between item memory and the hippocampus. We show that interindividual variability of hippocampal volumes in a large patient population with graded levels of hippocampal volume loss and controls correlates with context, but not item-memory performance. Nevertheless, concurrent measures of brain activity using magnetoencephalography reveal an early (350 ms) but sustained hippocampus-dependent signal that evolves from an item signal into a context memory signal. This is temporally distinct from an item-memory signal that is not hippocampus dependent. Thus, we provide evidence for a hippocampus-dependent item-memory process that initiates context retrieval without making a substantial contribution to item recognition performance. Our results reconcile contradictory evidence concerning hippocampal involvement in item memory and show that hippocampus-dependent mnemonic processes are more rapid than previously believed., Highlights ► Whether the hippocampus is needed for item as well as context memory is unclear ► We tested behavior and function in a large patient group with hippocampal atrophy ► We identified a new rapid hippocampus-dependent functional signal to familiar items ► This signal is not needed for item memory but initiates context recollection

Highlights ► Children with bilateral hippocampal damage are impaired at recalling past events. ► They are intact at imagining fictitious experiences. ► This contrasts with adult amnesic patients who are impaired at both. ► Hippocampal damage affects memory differently depending on when in life it occurs., Compared to adults, relatively little is known about autobiographical memory and the ability to imagine fictitious and future scenarios in school-aged children, despite the importance of these functions for development and subsequent independent living. Even less is understood about the effect of early hippocampal damage on children's memory and imagination abilities. To bridge this gap, we devised a novel naturalistic autobiographical memory task that enabled us to formally assess the memory for recent autobiographical experiences in healthy school-aged children. Contemporaneous with the autobiographical memories being formed, the children also imagined and described fictitious scenarios. Having established the performance of healthy school-aged children on these tasks, we proceeded to make comparisons with children (n = 21) who had experienced neonatal hypoxia/ischaemia, and consequent bilateral hippocampal damage. Our results showed that healthy children could recall autobiographical events, including spatiotemporal information and specific episodic details. By contrast, children who had experienced neonatal hypoxia/ischaemia had impaired recall, with the specific details of episodes being lost. Despite this significant memory deficit they were able to construct fictitious scenarios. This is in clear contrast to adults with hippocampal damage, who typically have impaired autobiographical memory and deficits in the construction of fictitious and future scenarios. We speculate that the paediatric patients’ relatively intact semantic memory and/or some functionality in their residual hippocampi may underpin their scene construction ability.

Convulsive status epilepticus (SE) is a common medical neurological emergency and is associated with hippocampal injury and the subsequent development of epilepsy. However, pathophysiological mechanisms that underlie injury remain unclear, and a clinically useful prognostic biomarker of at-risk patients remains elusive. We hypothesised that non-invasive quantitative multi-parametric MRI characterisation of the early time course in the lithium-pilocarpine rat model would provide insight into pathophysiological processes, and may help to develop a non-invasive prognostic marker of hippocampal injury. T(1), T(2), apparent diffusion coefficient (ADC), and cerebral blood flow (CBF) were measured before and after SE on days 0, 1, 2, 3, 7, 14 and 21. Hippocampal volume measurements were used to assess final structural outcome. MRI changes were found in the parietal cortex, hippocampus, piriform cortex, and thalamus. Each of the regions displayed time-dependent changes, and returned to baseline levels by Day 7. Hippocampal measurements peaked on Day 2, and further analysis revealed that the magnitude of these peak changes was predictive of the hippocampal volumes on Day 21. This time course is consistent with cell death and an inflammatory process. The maximal changes provide a potential clinically useful prognostic marker of final hippocampal volume.

Neurogenesis occurs at the subependymal zone (SEZ) of the adult brain. Neural progenitor cells give rise to neuroblasts, which migrate to the olfactory bulb (OB) via the rostral migratory stream (RMS). Development of methods capable of labelling and tracking these cells in vivo would be of great benefit to the understanding of neuroblast migration away from the SEZ under normal and pathological conditions. In this study, we demonstrate that endogenous neuroblasts can be labelled in vivo with an MRI contrast agent and that they can be visualised using MRI. We compared two labelling strategies: intraventricular injection of the ferumoxide Endorem, with or without the transfection agent protamine sulphate. Administration of Endorem alone resulted in its distribution outside of the ventricle and into the periventricular space after 48 h. In contrast, we observed that intraventricular injection of Endorem complexed to protamine sulphate forming the FePro complex - is restricted to the ventricular walls after 48 h. The FePro complex successfully labelled Doublecortin(+) neuroblasts in vivo up to 28 days post-injection. FePro-labelled neuroblasts in the RMS could be visualised using MRI in vivo and ex vivo on a 2.35 T MRI system, and FePro-labelled cells were identified in the OB on a 9.4 T MRI system. This study demonstrates the feasibility of in vivo imaging of endogenous neuroblast migration using MRI. (C) 2008 Elsevier Inc. All rights reserved.

The aim of this study was to identify grey matter density abnormalities in children with temporal lobe epilepsy and mesial temporal sclerosis. Magnetic resonance T1 weighted 3D datasets were obtained in children with temporal lobe epilepsy (20 left and 10 right sided, mean age 11.9 years, range 6.6-17.5) and compared to scans obtained from age-matched controls (n = 22, mean age 12.8 years, range 7.1-17.5) using voxel-based morphometry. This method detected reduced grey matter ipsilateral to the seizure focus not only in the hippocampus, but also in the lateral temporal lobe and in extra-temporal regions including the thalamus, posterior cingulate cortex and cerebellum. Bilateral differences were present in the frontal and parietal opercular cortices and lateral temporal regions. These grey matter density reductions broadly reflect the pattern of hippocampal connections and may be caused by the disruption of cortical development by the recurrent seizures, as well as by loss of functional input from the sclerotic hippocampus. (c) 2005 Elsevier Inc. All rights reserved.

Background and purpose: STAT-1 is a member of a family of proteins called signal transducers and activators of transcription (STATs), and recent studies have shown its involvement in the induction of apoptosis. There is limited information on the role of STAT-1 following stroke. In this study we use MRI measurements of cerebral perfusion and bioenergetic status to target measurements of regional STAT-1 activity. Methods: Rats were subjected to 60 or 90 min of middle cerebral artery occlusion with and without reperfusion. MRI maps of the apparent diffusion coefficient of water and cerebral blood flow were acquired throughout the study. After the ischemia or reperfusion period, the brain was excised and samples were analyzed by Western blots using anti-phospho-STAT1 and anti-Fas antibodies. Regions were selected for analysis according to their MRI characteristics. Results: Transcriptional factor STAT-1 was enhanced in the lesion core and, to a lesser extent, in the lesion periphery, following ischemia and reperfusion. This level of activity was greater than for ischemia alone. Western blots demonstrated STAT-1 phosphorylation on tyrosine 701 and not serine 727 after ischemia and 3 h of reperfusion. Enhanced expression of the apoptotic death receptor Fas was confirmed after ischemia followed by reperfusion. Conclusions: This study demonstrates that focal ischemia of the rat brain can induce STAT-1 activation, particularly following a period of reperfusion. The activation occurs not only in the lesion core, but also in the lesion periphery, as identified using MRI. STAT-1 may play an important role in the induction of cell death following stroke.

In this paper we address the assumptions about the distribution of errors made by voxel-based morphometry. Voxel-based morphometry (VBM) uses the general linear model to construct parametric statistical tests. In order for these statistics to be valid, a small number of assumptions must hold. A key assumption is that the model's error terms are normally distributed. This is usually ensured through the Central Limit Theorem by smoothing the data. However, there is increasing interest in using minimal smoothing (in order to sensitize the analysis to regional differences at a small spatial scale). The validity of such analyses is investigated. In brief, our results indicate that nonnormality in the error terms can be an issue in VBM. However, in balanced designs, provided the data are smoothed with a 4-mm FWHM kernel, nonnormality is sufficiently attenuated to render the tests valid. Unbalanced designs appear to be less robust to violations of normality: a significant number of false positives arise at a smoothing of 4 and 8 mm when comparing a single subject to a group. This is despite the fact that conventional group comparisons appear to be robust, remaining valid even with no smoothing. The implications of the results for researchers using voxel-based morphometry are discussed.

A new MRI sequence for the rapid simultaneous measurement of T2 and T2* is presented. The technique uses the multiple acquisition of spin and gradient echoes with interleaved echo planar imaging (MASAGE-IEPI). IEPI data sets are sampled during and between a pair of short and long echo time spin echoes, allowing the reconstruction of a set of images with different combinations of T2 and T2* weighting and the calculation of T2 and T2* maps. In the context of neuroimaging, these maps can provide information on cerebral hemodynamics and oxygenation status, either via the deoxyhemoglobin-based BOLD signal or by the effect of exogenous paramagnetic contrast agents. MASAGE-IEPI benefits from the inherent advantages of the IEPI approach, i.e., high time resolution and minimal image distortion, and also has good time efficiency due to the acquisition of multiple image data sets following each excitation pulse. The accuracy of the sequence for the measurement of T2 and T2* is verified on phantoms, and the technique is applied to monitor changing hemodynamics in the rat brain during episodes of hypoxia. Data for the generation of maps of T2 and T2* are acquired with a time resolution of 12 s to accurately define the rapidly changing time course. As increasing emphasis is placed on the role of T2 and T2* in the direct measurement of physiological parameters such as cerebral metabolic rate of oxygen consumption and blood vessel sizes, MASAGE-IEPI offers an efficient method for the measurement of these two important MRI parameters.

We are indebted to the KE family for their continued cooperation with our research program. We thank our collaborators at the Wellcome Department of Cognitive Neurology, Institute of Neurology, London, for assistance with the PET study and morphometric analyses, and our colleagues in the Cognitive Neuroscience Unit and Radiology and Physics Unit at the Institute of Child Health, London, for assistance with data collection and analysis. We thank Drs. Mortimer Mishkin, Marcus Pembrey, Tomas Paus, and Gabriel Leonard, for useful discussion and for comments on the manuscript.

Clinical features, magnetic resonance, and biochemical studies are reported in 7 children with pyruvate dehydrogenase (PDH) deficiency. These findings confirm the diverse clinical presentation of this condition, although neurological abnormalities are consistent features. Imaging results are also varied. Six of the children were investigated with proton magnetic resonance spectroscopy and lactate was demonstrated in brain in all patients. Regional variation in the lactate signal was observed in those patients in whom 2 regions were examined. Advances in molecular genetics have provided some explanations for the clinical variation in pyruvate dehydrogenase deficiency.

Proton magnetic resonance spectra include signals from N-acetylaspartate, creatine + phosphocreatine, and choline-containing compounds. Abnormalities in these signals can be used in the assessment of patients with intractable epilepsy. In particular, they provide a means of identifying metabolic abnormalities within the temporal lobes, detecting bilateral and diffuse pathology, and aiding lateralization of the seizure focus. The pathology demonstrated on MRS can also be related to cognitive dysfunction.

[31P]- and [1H]Nuclear magnetic resonance spectroscopy were used to study metabolism in cortical brain slices in the guinea-pig during acute exposure to pathophysiological concentrations of ammonia. Intracellular acidification, measured from the chemical shift of endogenous inorganic phosphate, was observed without any change in cellular energy status or concentrations of lactate, glutamate and glutamine. The initial acidification, which developed over a period of 9 min appeared to be heterogeneous, on the basis of a splitting of the inorganic phosphate resonance in a number of experiments, corresponding to pH changes of 0.07 and 0.27 pH units. Subsequently a homogeneous acidification, of 0.15 pH units, developed by 23 min following exposure to ammonia. Intracellular pH recovered within 6 min after discontinuation of the ammonia load. In the absence of external bicarbonate, intracellular pH was 0.12 units more acidic than in the bicarbonate buffer and ammonia caused a further acidification by 0.16 units. When glutamine synthase inhibitor, methionine sulphoximine, was added, there was a slow fall in intracellular pH. Under these conditions, subsequent addition of ammonia failed to cause acidification directly. Thus acute elevation of ammonia does not lead to a change in cerebral high-energy phosphate or lactate metabolism, but may be associated with a fall in cortical intracellular pH.

Phosphorus-31 nuclear magnetic resonance has been used to measure changes in tissue adenosine triphosphate and pH that occur during hypothermic preservation of rabbit hearts. Three potential preservation solutions were studied: the St. Thomas' Hospital no. 1 cardioplegic solution, Bretschneider's HTP solution, and a solution originated in our laboratory, CP5, which we have previously studied in the rabbit heart with functional assessment by Langendorff perfusion. After being flushed with one of these solutions, each heart was stored at 0 degrees C for 12 hours, during which time it was subjected to repeated phosphorus-31 nuclear magnetic resonance scans. It was shown that adenosine triphosphate levels decayed more slowly with CP5 than with either of the other solutions or in the control experiments. Adenosine triphosphate decay was also slower with Bretschneider's HTP than with St. Thomas' Hospital solution, but pH was somewhat better maintained with Bretschneider's HTP than with either other solution or in the control hearts, although the pH did not decrease drastically in any group. CP5 was designed to prevent cell swelling and to reduce the uptake of calcium during storage, for which reasons it contains 30 mmol/L glucose and 0.1 mmol/L calcium. The potassium content is somewhat higher and the sodium and magnesium content somewhat lower than in St. Thomas' Hospital solution, with the objective of stabilizing intracellular concentrations of these ions during storage.