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Three-dimensional (3D) multiecho balanced steady-state free precession (ME-bSSFP) has previously been demonstrated in preclinical hyperpolarized (HP)To validate a signal simulation framework for the use of sequence parameter optimization. To demonstrate the feasibility of ME-bSSFP for HPRetrospective single-center cohort study.Phantoms containing aqueous solutions of [1-The primary endpoint was the analysis of pyruvate-to-lactate conversion in PCa and healthy prostate regions of interest (ROIs) using model-free area under the curve (AUC) ratios and a one-directional kinetic model (kPearson correlation coefficients with 95% confidence intervals and paired t-tests. The level of statistical significance was set at P 0.05.Strong correlations between simulated and empirical ME-bSSFP signals were found (r 0.96). Therefore, the simulation framework was used for sequence optimization. Whole prostate metabolic HPMetabolic HP2 TECHNICAL EFFICACY: Stage 1.

Objective To develop a phantom system which can be integrated with an automated injection system, eliminating the experimental variability that arises with manual injection; for the purposes of pulse sequence testing and metric derivation in hyperpolarised 13C-MR. Methods The custom dynamic phantom was machined from Ultem and filled with a nicotinamide adenine dinucleotide and lactate dehydrogenase mixture dissolved in phosphate buffered saline. Hyperpolarised [1-13C]-pyruvate was then injected into the phantom (n = 8) via an automated syringe pump and the conversion of pyruvate to lactate monitored through a 13C imaging sequence. Results The phantom showed low coefficient of variation for the lactate to pyruvate peak signal heights (11.6%) and dynamic area-under curve ratios (11.0%). The variance for the lactate dehydrogenase enzyme rate constant (kP) was also seen to be low at 15.6%. Conclusion The dynamic phantom demonstrates high reproducibility for quantification of 13C-hyperpolarised MR-derived metrics. Establishing such a phantom is needed to facilitate development of hyperpolarsed 13C-MR pulse sequenced; and moreover, to enable multisite hyperpolarised 13C-MR clinical trials where assessment of metric variability across sites is critical. Advances in knowledge The dynamic phantom developed during the course of this study will be a useful tool in testing new pulse sequences and standardisation in future hyperpolarised work.

Rex Richards was renowned for his research in the field of nuclear magnetic resonance (NMR). Very early on, in the late 1940s, when NMR was in the domain of physicists, he foresaw that the technique might play an important role in chemistry. He embarked on a highly successful research career in which he combined the design and development of new NMR spectrometers with novel applications, initially in chemistry and subsequently in the biological sciences. One major outcome was the establishment of the Oxford Enzyme Group's NMR research programme. Another was the development of 31 P NMR spectroscopy as a non-invasive method of probing the biochemistry of intact biological tissue. Rex was an outstanding teacher and mentor. He also had highly impressive administrative skills, as recognized through successive appointments at the University of Oxford as head of the Physical Chemistry Department, then warden of Merton College and finally vice-chancellor. He was subsequently appointed director of the Leverhulme Trust and became widely respected in the arts world, as reflected by his remarkable array of committee memberships at the National and Tate Galleries.

To develop a phantom system which can be integrated with an automated injection system, eliminating the experimental variability that arises with manual injection; for the purposes of pulse sequence testing and metric derivation in hyperpolarisedThe custom dynamic phantom was machined from Ultem and filled with a nicotinamide adenine dinucleotide and lactate dehydrogenase mixture dissolved in phosphate buffered saline. Hyperpolarised [1-The phantom showed low coefficient of variation for the lactate to pyruvate peak signal heights (11.6%) and dynamic area-under curve ratios (11.0%). The variance for the lactate dehydrogenase enzyme rate constant (kP) was also seen to be low at 15.6%.The dynamic phantom demonstrates high reproducibility for quantification ofThe dynamic phantom developed during the course of this study will be a useful tool in testing new pulse sequences and standardisation in future hyperpolarised work.

Significance Thyroid hormone deficiencies are the most common preventable causes of intellectual disability. We report that mutations in the thyroid hormone receptor α1 gene (THRA) that result in intellectual disability also reduce brain size. Using human THRA mutation stem cell models, we studied the impact of THRA mutations on human brain development by combining quantitative lineage analysis, gene expression analyses, and novel assays of neuroepithelium formation. We found that THRA regulates the balance between progenitor self-renewal and neurogenesis, and thus overall brain size. Importantly, these in vitro results are consistent with in vivo evidence from magnetic resonance imaging of people with these mutations, advancing our understanding of thyroid hormone action in human brain development., Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell–cell adhesion genes. These results reveal that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

Hyperpolarised 13C MRI (HP-MRI) is a novel imaging technique that allows real-time analysis of metabolic pathways in vivo. 1 The technology to conduct HP-MRI in humans has recently become available and is starting to be clinically applied. As knowledge of molecular biology advances, it is increasingly apparent that cancer cell metabolism is related to disease outcomes, with lactate attracting specific attention. 2 Recent reviews of breast cancer screening programs have raised concerns and increased public awareness of over treatment. The scientific community needs to shift focus from improving cancer detection alone to pursuing novel methods of distinguishing aggressive breast cancers from those which will remain indolent. HP-MRI offers the opportunity to identify aggressive tumour phenotypes and help monitor/predict therapeutic response. Here we report one of the first cases of breast cancer imaged using HP-MRI alongside correlative conventional imaging, including breast MRI.

Highlights • We studied manual function in patients exposed to neonatal hypoxia-ischaemia. • Patients had preserved function in motor adaptation learning, and in speed and accuracy of handwriting. • Manual coordination was impaired on a timed pegboard task. • Motor impairment was associated with bilaterally reduced volumes of the caudate nuclei. • Early basal ganglia damage may lead to persistent deficits in fine manual control., Acute sentinel hypoxia-ischaemia in neonates can target the hippocampus, mammillary bodies, thalamus, and the basal ganglia. Our previous work with paediatric patients with a history of hypoxia-ischaemia has revealed hippocampal and diencephalic damage that impacts cognitive memory. However, the structural and functional status of other brain regions vulnerable to hypoxia-ischaemia, such as the basal ganglia, has not been investigated in these patients. Furthermore, it is not known whether there are any behavioural sequelae of such damage, especially in patients with no diagnosis of neurological disorder. Based on the established role of the basal ganglia and the thalamus in movement coordination, we studied manual motor function in 20 participants exposed to neonatal hypoxia-ischaemia, and a group of 17 healthy controls of comparable age. The patients’ handwriting speed and accuracy was within the normal range (Detailed Assessment of Speed of Handwriting), and their movement adaptation learning (Rotary Pursuit task) was comparable to the control group’s performance. However, as a group, patients showed an impairment in the Grooved Pegboard task and a trend for impairment in speed of movement while performing the Rotary Pursuit task, suggesting that some patients have subtle deficits in fine, complex hand movements. Voxel-based morphometry and volumetry showed bilateral reduction in grey matter volume of the thalamus and caudate nucleus. Reduced volumes in the caudate nucleus correlated across patients with performance on the Grooved Pegboard task. In summary, the fine movement coordination deficit affecting the hand and the wrist in patients exposed to early hypoxic-ischaemic brain injury may be related to reduced volumes of the caudate nucleus, and consistent with anecdotal parental reports of clumsiness and coordination difficulties in this cohort.

Cognitive Neuroscience and Neuropsychiatry Section, Institute of Child Health, 30 Guildford Street, London, UK Background Transposition of the great arteries (TGA) is congenital heart defect which is associated with a risk of systemic hypoxia/ischaemic (HI) brain injury in the neonatal period. Children and adolescents with corrected TGA have been reported to show motor coordination and cognitive deficits, and increased incidence of psychiatric diagnoses in follow-up. Methods We examined the ontogeny of cognitive and motor coordination deficits in relation to structural magnetic resonance Imaging (MRI) evidence of the integrity of the hippocampus and basal ganglia, by conducting a longitudinal, prospective study of groups of infants treated for TGA and age-matched healthy controls (NC). All infants were free from any neurological diagnoses. Results Voxel-Based Morphometry (VBM) analysis indicated that infants with TGA have reduced grey-matter volume in the hippocampus relative to NC. This finding is consistent with previous reports that older children with TGA have reduced hippocampal volumes. Magnetic resonance spectroscopy (MRS) was also used for the assessment of focal brain pathology in the caudate and thalamus. No evidence of pathology was revealed in either structure. The Bayley Scales of Infant Development were used to assess cognitive, fine-motor, gross-motor, expressive language and receptive language skills at two time-points (age six months and 12 months). At six months of age, the TGA group was delayed relative to NC on the gross-motor scale only. At 12 months of age, the TGA group showed significant delays on the cognitive, expressive language and fine motor scales. Conclusion We conclude that infants with corrected TGA suffer HI damage to the hippocampus during the perinatal period which has significant consequences for subsequent development within the first year of life. These data provide insight into the emergence of cognitive and motor deficits in infants with TGA.

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

Neonatal hypoxia can lead to hippocampal atrophy, which can lead, in turn, to memory impairment. To test the generalizability of this causal sequence, we examined a cohort of 41 children aged 8‐16, who, having received the arterial switch operation to correct for transposition of the great arteries, had sustained significant neonatal cyanosis but were otherwise neurodevelopmentally normal. As predicted, the cohort had significant bilateral reduction of hippocampal volumes relative to the volumes of 64 normal controls. They also had significant, yet selective, impairment of episodic memory as measured by standard tests of memory, despite relatively normal levels of intelligence, academic attainment, and verbal fluency. Across the cohort, degree of memory impairment was correlated with degree of hippocampal atrophy suggesting that even as early as neonatal life no other structure can fully compensate for hippocampal injury and its special role in serving episodic long term memory. © 2017 Wiley Periodicals, Inc.

Global anterograde amnesia is described in three patients with brain injuries that occurred in one case at birth, in another by age 4, and in the third at age 9. Magnetic resonance techniques revealed bilateral hippocampal pathology in all three cases. Remarkably, despite their pronounced amnesia for the episodes of everyday life, all three patients attended mainstream schools and attained levels of speech and language competence, literacy, and factual knowledge that are within the low average to average range. The findings provide support for the view that the episodic and semantic components of cognitive memory are partly dissociable, with only the episodic component being fully dependent on the hippocampus.

We assessed performance on selected tests of verbal memory in 48 patients who had undergone either anterior temporal lobectomy or selective amygdalo-hippocampectomy for the relief of pharmacologically intractable epilepsy. We related performance both to the side of surgical excision and to the presence or absence of abnormalities in the contralateral, unoperated, temporal lobe, as revealed by proton magnetic resonance spectroscopy (1H MRS) or T2 relaxometry. There were abnormalities on the unoperated side detected by 1H MRS in 50% of the 34 patients who successfully underwent spectroscopy, and by T2 relaxometry in 33% of the complete series of 48 patients. There was no systematic relationship between seizure outcome and the presence or absence of abnormalities on the unoperated side. Verbal memory deficits were present in patients with left-sided excision, regardless of whether there were abnormalities on the unoperated side. The patients with right-sided excision also had verbal memory deficits, but only in the group with magnetic resonance abnormalities on the contralateral (ie, left) side and only on delayed recall. The study extends previous findings on the role of the temporal lobes in memory and highlights the role of these new magnetic resonance techniques in relating cognitive processes to brain structures.

We detail the process of low-field thermal mixing (LFTM) between (1)H and (13)C nuclei in neat [1-(13)C] pyruvic acid at cryogenic temperatures (4-15 K). Using fast-field-cycling NMR, (1)H nuclei in the molecule were polarized at modest high field (2 T) and then equilibrated with (13)C nuclei by fast cycling (∼300-400 ms) to a low field (0-300 G) that activates thermal mixing. The (13)C NMR spectrum was recorded after fast cycling back to 2 T. The (13)C signal derives from (1)H polarization via LFTM, in which the polarized ('cold') proton bath contacts the unpolarised ('hot') (13)C bath at a field so low that Zeeman and dipolar interactions are similar-sized and fluctuations in the latter drive (1)H-(13)C equilibration. By varying mixing time (tmix) and field (Bmix), we determined field-dependent rates of polarization transfer (1/τ) and decay (1/T1m) during mixing. This defines conditions for effective mixing, as utilized in 'brute-force' hyperpolarization of low-γ nuclei like (13)C using Boltzmann polarization from nearby protons. For neat pyruvic acid, near-optimum mixing occurs for tmix∼ 100-300 ms and Bmix∼ 30-60 G. Three forms of frozen neat pyruvic acid were tested: two glassy samples, (one well-deoxygenated, the other O2-exposed) and one sample pre-treated by annealing (also well-deoxygenated). Both annealing and the presence of O2 are known to dramatically alter high-field longitudinal relaxation (T1) of (1)H and (13)C (up to 10(2)-10(3)-fold effects). Here, we found smaller, but still critical factors of ∼(2-5)× on both τ and T1m. Annealed, well-deoxygenated samples exhibit the longest time constants, e.g., τ∼ 30-70 ms and T1m∼ 1-20 s, each growing vs. Bmix. Mixing 'turns off' for Bmix∼100 G. That T1m≫τ is consistent with earlier success with polarization transfer from (1)H to (13)C by LFTM.

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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.

Continuous arterial spin labeling (CASL) measurements over a range of post-labeling delay (PLD) times can be interpreted to estimate cerebral blood flow (CBF) and arterial transit time (deltaa) with good spatial and temporal resolution. In this work, we present an in vivo demonstration of Hadamard-encoded continuous arterial spin labeling (H-CASL); an efficient method of imaging the inflow of short boli of labeled blood water in the brain at multiple PLD times. We present evidence that H-CASL is viable for in vivo application in the rat brain and can improve the precision of deltaa estimation in 2/3 of the imaging time required for standard multi-PLD CASL. Based on these findings, we propose that H-CASL may have application as an efficient prescan for optimization of ASL imaging parameters to improve the precision of CBF estimation.

Although observational findings linking breast milk to higher scores on cognitive tests may be confounded by factors associated with mothers' choice to breastfeed, it has been suggested that one or more constituents of breast milk facilitate cognitive development, particularly in preterms. Because cognitive scores are related to head size, we hypothesized that breast milk mediates cognitive effects by affecting brain growth. We used detailed data from a randomized feeding trial to calculate percentage of expressed maternal breast milk (%EBM) in the infant diet of 50 adolescents. MRI scans were obtained (mean age=15 y 9 mo), allowing volumes of total brain (TBV) and white and gray matter (WMV, GMV) to be calculated. In the total group, %EBM correlated significantly with verbal intelligence quotient (VIQ); in boys, with all IQ scores, TBV and WMV. VIQ was, in turn, correlated with WMV and, in boys only, additionally with TBV. No significant relationships were seen in girls or with gray matter. These data support the hypothesis that breast milk promotes brain development, particularly white matter growth. The selective effect in males accords with animal and human evidence regarding gender effects of early diet. Our data have important neurobiological and public health implications and identify areas for future mechanistic study.

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.

Arterial spin labelling (ASL) can noninvasively isolate the MR signal from arterial blood water that has flowed into the brain. In gray matter, the labelled bolus is dispersed within three main compartments during image acquisition: the intravascular compartment; intracellular tissue space; and the extracellular tissue space. Changes in the relative volumes of the extracellular and intracellular tissue space are thought to occur in many pathologic conditions such as stroke and brain tumors. Accurate measurement of the distribution of the ASL signal within these three compartments will yield better understanding of the time course of blood delivery and exchange, and may have particular application in animal models of disease to investigate the relationship between the source of the ASL signal and pathology. In this study, we sample the transverse relaxation of the ASL perfusion weighted and control images acquired with and without vascular crusher gradients at a range of postlabelling delays and tagging durations, to estimate the tricompartmental distribution of labelled water in the rat cortex. Our results provide evidence for rapid exchange of labelled blood water into the intracellular space relative to the transit time through the vascular bed, and provide a more solid foundation for cerebral blood flow quantification using ASL techniques.

To compare quantitative T2 relaxometry of cerebral white matter (WM) with qualitative assessment of conventional T2-weighted magnetic resonance (MR) images, to assess the relationship between cerebral WM T2 and region-specific apparent diffusion coefficient (ADC), and to examine WM T2 regional variation in preterm infants at term.The local ethical committee granted ethical permission for this study; informed parental consent was obtained for each infant. Sixty-two preterm infants born at less than 32 weeks gestation and nine control infants were examined at 1.5 T; T2-weighted fast spin-echo MR images, T2 relaxometry data, and diffusion-weighted MR images were acquired. Conventional T2-weighted MR images were assessed by a pediatric neuroradiologist for diffuse excessive high signal intensity (DEHSI) in WM. Regions of interest were positioned in frontal WM, central WM, and posterior WM at the level of the centrum semiovale.In preterm infants at term, T2 was longer in all WM regions than in control infants; in infants with DEHSI, T2 was longer than in infants without DEHSI and control infants, with posterior WM T2 being longer than central or frontal WM T2. In control infants, T2 was similar in all WM regions. Frontal and posterior WM ADCs were higher in preterm infants at term than in control infants.Cerebral WM T2 is an objective quantitative measurement that can easily and rapidly be obtained during clinical MR imaging in preterm infants at term.

To determine the clinical value of motor functional magnetic resonance imaging (fMRI) in the presurgical evaluation of a large group of children and adolescents with epilepsy caused by lesions close to the central sulcus., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

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.

Convulsive status epilepticus is associated with subsequent hippocampal damage and development of mesial temporal sclerosis in a subset of individuals. The lithium pilocarpine model of status epilepticus (SE) in the rat provides a model in which to investigate the molecular and pathogenic process leading to hippocampal damage. In this study, a 2-DE-based approach was used to detect proteome changes in the hippocampus, at an early stage (2 days) after SE, when increased T2 values were detectable by magnetic resonance imaging. Gel image analysis was followed by LC-MS/MS identification of protein species that differed in abundance between pilocarpine-treated and control rats. The most significantly up-regulated species in the experimental animals was identified as heat shock 27-kDa protein, in line with findings in humans and in other experimental models of epilepsy. Additional up-regulated species included dihydropyrimidinase-related protein-2, cytoskeletal proteins (alpha-tubulin and ezrin) and dihydropteridine reductase. In summary, the hippocampus of rats subject to pilocarpine-induced SE exhibits specific changes in protein abundance, which likely relate to pathogenic, neuroprotective and neurogenic responses.

The extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated allocentric spatial recall using a virtual environment in a group of patients with severe hippocampal damage (SHD), a group of patients with “moderate” hippocampal damage (MHD), and a normal control group. Through four learning blocks with feedback, participants learned the target locations of four different objects in a circular arena. Distal cues were present throughout the experiment to provide orientation. A circular boundary as well as an intra-arena landmark provided spatial reference frames. During a subsequent test phase, recall of all four objects was tested with only the boundary or the landmark being present. Patients with SHD were impaired in both phases of this task. Across groups, performance on both types of spatial recall was highly correlated with memory quotient (MQ), but not with intelligence quotient (IQ), age, or sex. However, both measures of spatial recall separated experimental groups beyond what would be expected based on MQ, a widely used measure of general memory function. Boundary-based and landmark-based spatial recall were both strongly related to bilateral hippocampal volumes, but not to volumes of the thalamus, putamen, pallidum, nucleus accumbens, or caudate nucleus. The results show that boundary-based and landmark-based allocentric spatial recall are similarly impaired in patients with SHD, that both types of recall are impaired beyond that predicted by MQ, and that recall deficits are best explained by a reduction in bilateral hippocampal volumes.SIGNIFICANCE STATEMENTIn humans, bilateral hippocampal atrophy can lead to profound impairments in episodic memory. Across species, perhaps the most well-established contribution of the hippocampus to memory is not to episodic memory generally but to allocentric spatial memory. However, the extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated spatial recall using a virtual environment in two groups of patients with hippocampal damage (moderate/severe) and a normal control group. The results showed that patients with severe hippocampal damage are impaired in learning and recalling allocentric spatial information. Furthermore, hippocampal volume reduction impaired allocentric navigation beyond what can be predicted by memory quotient as a widely used measure of general memory function.

Which specific memory functions are dependent on the hippocampus is still debated. The availability of a large cohort of patients who had sustained relatively selective hippocampal damage early in life enabled us to determine which type of mnemonic deficit showed a correlation with extent of hippocampal injury. We assessed our patient cohort on a test that provides measures of recognition and recall that are equated for difficulty and found that the patients' performance on the recall tests correlated significantly with their hippocampal volumes, whereas their performance on the equally difficult recognition tests did not and, indeed, was largely unaffected regardless of extent of hippocampal atrophy. The results provide new evidence in favor of the view that the hippocampus is essential for recall but not for recognition.

Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life.

Summary: Purpose: There is mounting evidence that a prolonged febrile seizure (PFS) can cause acute hippocampal edema although the nature of that edema remains uncertain. The principal aims of the current study were: (1) to use apparent diffusion coefficient (ADC) measurements to further characterize the hippocampal edema previously identified within 5 days of a PFS, and (2) to determine whether the age dependency of ADC in the hippocampus is different in patients when compared to a control population following a PFS. Methods: Diffusion weighted imaging was acquired in 23 children within 5 days of a PFS, and in 14 of these children a mean of 5.5 months later. Twenty-four control children were enrolled. Results: There was a reduction in ADC between the acute and follow-up investigations [mean reduction = 0.0072 mm2/s/month since PFS (95% confidence interval; 0.0001–0.014 mm2/s/month since PFS), p = 0.048] consistent with early vasogenic edema, followed by recovery in children investigated within 2 days of a PFS. In addition, the behavior of ADC with respect to age was different in patients when compared to control subjects [mean difference in slope =−0.155 mm2/s/log10 age (95% confidence interval; −0.290–0.0203 mm2/s/log10 age), p = 0.029], in that the expected age dependence was observed only in the control subjects. Conclusion: We suggest that these latter findings are most consistent with a preexisting developmental hippocampal abnormality that may predispose individuals to having a PFS.

Perinatal asphyxia occurs in approximately 1-6 per 1000 live full-term births. Different patterns of brain damage can result, though the relation of these patterns to long-term cognitive-behavioural outcome remains under investigation. The hippocampus is one brain region that can be damaged (typically not in isolation), and this site of damage has been implicated in two different long-term outcomes, cognitive memory impairment and the psychiatric disorder schizophrenia. Factors in addition to the acute episode of asphyxia likely contribute to these specific outcomes, making prediction difficult. Future studies that better document long-term cognitive-behavioural outcome, quantitatively identify patterns of brain injury over development and consider additional variables that may modulate the impact of asphyxia on cognitive and behavioural function will forward the goals of predicting long-term outcome and understanding the mechanisms by which it unfolds.

Perfusion maps, which are calculated from dynamic-susceptibility contrast (DSC)-MRI data by deconvolution of the arterial input function (AIF), are commonly used to predict tissue infarction in acute stroke. However, since the AIF is commonly measured in a major artery, there can be perfusion measurement errors associated with bolus delay/dispersion. Although methods to account for delay-related errors have been proposed, the effect of dispersion is more difficult to deal with and is usually left uncorrected. This study presents an assessment of the delay-dispersion relationship in a group of patients. Although a significant correlation was observed with one of the bolus delay definitions used, the estimation of the dispersion from the degree of delay was unreliable. Importantly, the dispersion observed in many patients was sufficient to result in substantial perfusion errors. The results are compared with previous numerical simulations, and their implications for the assessment and management of acute stroke are discussed.

A Bayesian nonlinear hierarchical random coefficients model was used in a reanalysis of a previously published longitudinal study of the extracellular direct current (DC)-potential and apparent diffusion coefficient (ADC) responses to focal ischaemia. The main purpose was to examine the data for evidence of an ADC threshold for anoxic depolarisation. A Markov chain Monte Carlo simulation approach was adopted. The Metropolis algorithm was used to generate three parallel Markov chains and thus obtain a sampled posterior probability distribution for each of the DC-potential and ADC model parameters, together with a number of derived parameters. The latter were used in a subsequent threshold analysis. The analysis provided no evidence indicating a consistent and reproducible ADC threshold for anoxic depolarisation. Copyright © 2005 John Wiley & Sons, Ltd.

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.

The neural basis of autistic spectrum disorders (ASDs) is poorly understood. Studies of mnemonic function in ASD suggest a profile of impaired episodic memory with relative preservation of semantic memory (at least in high-functioning individuals). Such a pattern is consistent with developmental hippocampal abnormality. However, imaging evidence for abnormality of the hippocampal formation in ASD is inconsistent. These inconsistencies led us to examine the memory profile of children with ASD and the relationship to structural abnormalities. A cohort of high-functioning individuals with ASD and matched controls completed a comprehensive neuropsychological memory battery and underwent magnetic resonance imaging for the purpose of voxel-based morphometric analyses. Correlations between cognitive/behavioural test scores and quantified results of brain scans were also carried out to further examine the role of the medial temporal lobe in ASD. A selective deficit in episodic memory with relative preservation of semantic memory was found. Voxel-based morphometry revealed bilateral abnormalities in several areas implicated in ASD including the hippocampal formation. A significant correlation was found between parental ratings reflecting autistic symptomatology and the measure of grey matter density in the junction area involving the amygdala, hippocampus and entorhinal cortex. The data reveal a pattern of impaired and relatively preserved mnemonic function that is consistent with a hippocampal abnormality of developmental origin. The structural imaging data highlight abnormalities in several brain regions previously implicated in ASD, including the medial temporal lobes.

Although selective vulnerability and delayed neuronal death following global ischemia have been recognized in both the human and animal brain, the underlying mechanisms of cell damage are not fully understood. In this study we investigated the time-dependent changes of the apparent diffusion coefficient (ADC) of water and cerebral blood flow (CBF) in a classic animal model of selective vulnerability and delayed neuronal death, using magnetic resonance (MR) diffusion- and perfusion-weighted imaging. CBF was monitored using the noninvasive MR arterial spin labeling method called flow-sensitive alternating inversion recovery (FAIR). Bilateral common carotid occlusion was induced for 5 min, followed by 10 hr of reperfusion in a gerbil model. The most notable finding was that the lateral portion of the striatum in the basal ganglia exhibited a prolonged and gradual ADC decrease throughout the study following reperfusion. This pattern was not exhibited within the cortex. It is suggested that regions known to exhibit so-called delayed cell death progress to infarction via a gradual process that can be monitored by MR diffusion-weighted imaging (DWI).

Multiple-slice perfusion imaging by continuous arterial spin labeling (CASL) is made possible by amplitude modulation (AM) of the labeling RF pulse, but perfusion sensitivity is reduced relative to the single-slice technique. A computer model of the Bloch equations for velocity driven adiabatic fast passage was developed to elucidate the compromised sensitivity to perfusion of the AM control technique for CASL. Calculations were performed over ranges of RF pulse amplitude, B-1; magnetic field gradient, G; phase, phi, and frequency, f, of the modulation function; velocity, v, and relaxation times, T-1 and T-2, of blood. It was found that unless f > 2 pi B-1, phi determines the performance of the AM control; excessively high B-1 or v reduces the efficiency of the AM control; and T, relaxation dominates if f is too great. In vivo, in rat brain (n = 5) at 2.35 T, the sensitivity of the AM technique to perfusion was 70% of the sensitivity of single-slice CASL.

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.

Mesial temporal sclerosis (MTS) is the most common lesion in patients who require epilepsy surgery, and approximately 50% of patients with MTS have a history of prolonged febrile convulsion (PFC) in childhood. The latter led to the hypothesis that convulsive status epilepticus, including PFC, can cause MTS. Our recently published data on children investigated within 5 days of a PFC showed that children investigated by MRI within 48 h of a PFC had large hippocampal volumes and prolongation of T2 relaxation time. Patients investigated48 h from a PFC had large hippocampal volumes and normal T2 relaxation time. These data are strongly suggestive of hippocampal oedema that is resolving within 5 days of a PFC, but do not exclude the possibility of a pre-existing hippocampal lesion. Fourteen children from the original study had follow-up investigations carried out 4-8 months after the acute investigations. Of the 14 patients, four have had further seizures. Two had short febrile convulsions, one had PFC and one had non-febrile seizures. There was a significant reduction in hippocampal volume and T2 relaxation time between the first and second investigations, and there is now no difference in hippocampal volume or T2 relaxation time in patients compared with a control population. Moreover, there is a significant increase in hippocampal volume asymmetry in patients at follow-up when compared with initial data. Five out of 14 patients had asymmetry outside the 95th percentile for control subjects and, of these, three had one hippocampal volume outside the lower 95% prediction limit for control subjects. A reduction in hippocampal volume or T2 relaxation time, into or below the normal range between the first and second scans, indicates that the earlier findings are temporary and are strongly suggestive of hippocampal oedema as the abnormality in the initial investigations. The change in hippocampal symmetry in the patient group is consistent with injury and neuronal loss associated with a PFC, especially in the three individuals who now have a single small hippocampus. However, as there is no T2 relaxation time abnormality, the hippocampi do not meet the criteria for MTS. There may be a lag period of several years between a PFC and the onset of epilepsy, and therefore some of these patients may be developing MTS. Alternatively, the asymmetry could represent return (post-acute oedema) to a pre-existing hippocampal abnormality similar to that identified in family members of patients with MTS and a history of PFC.

Two groups of adolescents, one born preterm and one with a diagnosis of developmental amnesia, were compared with age-matched normal controls on measures of hippocampal volume and memory function. Relative to control values, the preterm group values showed a mean bilateral reduction in hippocampal volume of 8–9% (ranging to 23%), whereas the developmental amnesic group values showed a reduction of 40% (ranging from 27% to 56%). Despite equivalent IQ and immediate memory scores in the two study groups, there were marked differences between them on a wide variety of verbal and visual delayed memory tasks. Consistent with their diagnosis, the developmental amnesic group was impaired relative to both other groups on nearly all delayed memory measures. The preterm group, by contrast, was significantly impaired relative to the controls on only a few memory measures, i.e., route following and prospective memory. We suggest that early hippocampal pathology leads to the disabling memory impairments associated with developmental amnesia when the volume of this structure is reduced below normal by ≈20–30% on each side. Whether this is a sufficient condition for the disorder or whether abnormality in other brain regions is also necessary remains to be determined.

The aim of this study was to determine whether partial epilepsy is associated with abnormalities in hippocampi that are not the primary seizure focus. As hippocampal T2 relaxometry is useful for identifying abnormalities that are not obvious on visual assessment of MRI, this was the method employed. Of 457 consecutive children and young adults from whom T2 relaxometry data were obtained, 96 had well characterized partial epilepsy and were enrolled, along with 27 control subjects. The patients were divided on the basis of clinical, video-EEG and visual MRI assessment into three groups: (i) those with temporal lobe epilepsy (TLE) and mesial temporal sclerosis (MTS) (MTS-TLE); (ii) lesional TLE (l-TLE); or (iii) extratemporal epilepsy (ETE). There was a significant and similar prolongation of T2 relaxation time identified in hippocampi remote from the seizure focus in all patient groups when compared with control subjects. In the non-sclerotic hippocampus of patients with MTS, T2 relaxation time was prolonged by a mean of 3.3 ms [95% confidence interval (CI), 0.8-5.9 ms; P = 0.01], patients with l-TLE had prolongation of T2 relaxation time by a mean of 4.3 ms (95% CI, 1.8-7.1 ms; P = 0.001) and those with ETE had prolongation of T2 relaxation time by a mean of 3.7 ms (95% CI, 1.6-6.6 ms; P = 0.006) compared with control subjects after adjustment for age. Unsurprisingly, in patients with MTS-TLE, T2 relaxation time in the sclerotic hippocampus was prolonged by a mean of 19 ms (95% CI = 14.6-22.4 ms; P < 0.001). The similarity in the extent of prolongation of T2 relaxation time in hippocampi that are not the primary epileptogenic focus, the wide variety of structural associations and the varied sites of epileptogenic foci, considered together, suggest that the abnormalities are likely to be caused by ongoing seizure activity rather than by underlying aetiology or site of epileptogenic focus.

Arterial spin labeling magnetic resonance methods, including flow-sensitive alternating inversion recovery (FAIR), are becoming increasingly common for the noninvasive quantification of cerebral blood flow (CBF). This report compares the FAIR method with hydrogen clearance. The latter is an established, invasive technique for CBF measurement in animals. Paired readings of CBF were obtained in gerbils to maximize the degree of spatial and temporal correspondence between methods. Flow-sensitive alternating inversion recovery (50 averages, 6.7-minute measurement time) and hydrogen clearance measurements were made concurrently. Cerebral blood flow values measured by both techniques displayed an initial decrease because of the injurious effects of electrode insertion and subsequent recovery. Mixed model regression analysis, structural equations modeling, and a simple concordance correlation coefficient analysis were performed. No evidence of a marked systematic bias in the FAIR measurements was found; mixed model regression analysis yielded relative bias estimates of 0.4 (confidence interval: 3.0, 3.9) mL · 100 g−1 · min−1 and −3.7 (−12.1, 4.7) mL · 100 g−1 · min−1 at 20 and 100 mL · 100 g−1 · min−1, respectively. The principal limitation of the FAIR technique was the magnitude of the random measurement error (imprecision), which had a standard deviation on the order of 10 mL · 100 g−1 · min−1.

Markov chain Monte Carlo simulation was used in a reanalysis of the longitudinal data obtained by Harris et al. ( J Cereb Blood Flow Metab 20:28–36) in a study of the direct current (DC) potential and apparent diffusion coefficient (ADC) responses to focal ischemia. The main purpose was to provide a formal analysis of the temporal relationship between the ADC and DC responses, to explore the possible involvement of a common latent (driving) process. A Bayesian nonlinear hierarchical random coefficients model was adopted. DC and ADC transition parameter posterior probability distributions were generated using three parallel Markov chains created using the Metropolis algorithm. Particular attention was paid to the within-subject differences between the DC and ADC time course characteristics. The results show that the DC response is biphasic, whereas the ADC exhibits monophasic behavior, and that the two DC components are each distinguishable from the ADC response in their time dependencies. The DC and ADC changes are not, therefore, driven by a common latent process. This work demonstrates a general analytical approach to the multivariate, longitudinal data-processing problem that commonly arises in stroke and other biomedical research.

Velocity-driven adiabatic fast passage (AFP) is commonly employed for perfusion imaging by continuous arterial spin labeling (CASL). The degree of inversion of protons in blood determines the sensitivity of CASL to perfusion. For this study, a computer model of the modified Bloch equations was developed to establish the optimum conditions for velocity-driven AFP. Natural variations in blood velocity over the course of the cardiac cycle were found to result in significant variations in the degree of inversion. However, the mean degree of inversion was similar to that for blood moving at a constant velocity, equal to the time-averaged mean, at peak velocities and heart rates within normal ranges. A train of RF pulses instead of a continuous RF pulse for labeling was found to result in a highly nonlinear dependence of the degree of inversion on RF duty cycle. This may have serious implications for the quantification of perfusion.

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.

New magnetic resonance techniques now provide increasingly powerful ways of identifying the structural correlates of impaired cerebral function. The aims of this article are to show how we have been using a variety of magnetic resonance techniques to identify focal pathophysiology in children with brain disease, and to describe how these findings have contributed to our understanding of impaired function in these children. An outline is given of the methods that we have chosen to use, and this is followed by their applications in a number of groups of patients. The examples that are given illustrate the importance of detecting brain abnormalities that might previously have gone undetected.

Background — MR techniques have been very powerful in providing indicators of tissue perfusion, particularly in studies of cerebral ischemia. There is considerable interest in performing absolute perfusion measurements, with the aim of improving the characterization of tissue “at risk” of stroke. However, some important caveats relating to absolute measurements need to be taken into account. The purpose of this article is to discuss some of the issues involved and the potential implications for absolute cerebral blood flow measurements in clinical use. Summary of Comment — In bolus tracking MRI, deconvolution of the concentration-time course can in theory provide accurate quantification. However, there are several important assumptions in the tracer kinetic model used, some of which may be invalid in cerebral ischemia. These can introduce significant errors in perfusion quantification. Conclusions — Although we believe that bolus tracking MRI is a powerful technique for the evaluation of perfusion in cerebral ischemia, interpretation of perfusion maps requires caution; this is particularly true when absolute quantification is attempted. Work is currently under way in a number of centers to address these problems, and with appropriate modeling they may be overcome in the future. In the interim, we believe that it is necessary for users of bolus tracking perfusion data to be aware of the current technical limitations if they are to avoid misinterpretation or overinterpretation of their findings.

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.

Efficacy of neural stem/progenitor cell (NPC) therapies after cerebral ischaemia could be better evaluated by monitoring in vivo migration and distribution of cells post-engraftment in parallel with analysis of lesion volume and functional recovery. Magnetic resonance imaging (MRI) is ideally placed to achieve this, but still poses several challenges. We show that combining the ferumoxide MRI contrast agent Endorem with protamine sulphate (FePro) improves iron oxide uptake in cells compared to Endorem alone and is non-toxic. Hence FePro complex is a better contrast agent than Endorem for monitoring NPCs. FePro complex-labelled NPCs proliferated and differentiated normally in vitro, and upon grafting into the brain 48 hours post-ischaemia they were detected in vivo by MRI. Imaging over four weeks showed the development of a confounding endogenous hypointense contrast evolution at later timepoints within the lesioned tissue. This was at least partly due to accumulation within the lesion of macrophages and endogenous iron. Neither significant NPC migration, assessed by MRI and histologically, nor a reduction in the ischaemic lesion volume was observed in NPC-grafted brains. Crucially, while MRI provides reliable information on engrafted cell location early after an ischaemic insult, pathophysiological changes to ischaemic lesions can interfere with cellular imaging at later timepoints.