Biomedical subjects

David G Gadian

Publications and source records attributed to David G Gadian.

At least 19 recordsLinked to original sources

PubMed2006

The chronic vascular and haemodynamic response after permanent bilateral common carotid occlusion in newborn and adult rats.

Vascular growth and redistribution of flow can compensate for arterial occlusion and possibly reduce the effects of hypoperfusion. As yet there is limited information on the age-dependent nature of vasculature remodelling. In this study, we have monitored the vascular and morphologic changes using magnetic resonance imaging and histology in a chronic bilateral common carotid artery occlusion (BCCAO) model in both newborn and adult rats. Acutely, cerebral blood flow (CBF) decreased immediately after BCCAO, producing a state of oligemic hypoperfusion. At 6 months after BCCAO in both adult and neonatal rats, the CBF had normalised at control values. To investigate the underlying mechanism for the return of CBF to control values, intra- and extracerebral magnetic resonance angiograms (MRAs) were acquired. As expected, signal from the common carotid arteries was present in the sham-operated rats, but was absent in the BCCAO animals. India ink angiograms demonstrated more tortuous basilar arteries in the adult rats post-BCCAO and MRAs demonstrated more extracerebral midline collaterals in the neonatal rats post-BCCAO, indicating different modes of vascular adaptation dependent on the age at onset of the insult. Both groups had collateral vessels arising from the vertebral arteries, and BCCAO was also associated with increased diameter of basilar, posterior cerebral, posterior communicating, internal carotid, middle cerebral and anterior cerebral arteries. Our study suggests that the developing and mature animals exhibit different patterns of vascular remodelling and that the BCCAO hypoperfusion model will be useful for investigating age-dependent vascular events in response to vaso-occlusive disease.

Aging↗

PubMed2006

Detecting white matter injury in sickle cell disease using voxel-based morphometry.

OBJECTIVE: Sickle cell disease (SCD) is associated with cerebrovascular disease, cerebral infarction, and cognitive dysfunction. This study aimed to detect the presence and extent of white matter abnormalities in individuals with SCD using voxel-based morphometry (VBM). METHODS: Thirty-six children and adolescents with SCD (age range, 9-24 years) and 31 controls (8-25 years) underwent magnetic resonance investigations using T1- and T2-weighted protocols. White and gray matter density maps were obtained from three-dimensional magnetic resonance imaging (MRI) data sets. Using VBM, we compared the maps between controls and SCD individuals with silent white matter infarct lesions (SCD+L; n = 16), and those without visible abnormality (SCD-L; n = 20). RESULTS: In comparison with controls, intelligence quotients (IQs) were lower in both SCD groups irrespective of presence of visible lesions. VBM showed widespread bilateral white matter abnormalities in the SCD+L group, extending beyond the regions of focal infarction in the deep anterior and posterior white matter borderzones. Bilateral white matter abnormalities were also observed in the SCD-L group, in locations similar to those in the SCD+L group. INTERPRETATION: VBM is sensitive to detection of widespread white matter injury in SCD patients in borderzones between arterial territories even in the absence of evidence of infarction. Those changes may contribute to cognitive deficits in this population.

Adolescent↗

PubMed2006

Role of fMRI in the decision-making process: epilepsy surgery for children.

Functional MRI (fMRI) is increasingly being used to evaluate children and adolescents who are candidates for surgical treatment of intractable epilepsy. It has the advantage of being noninvasive and well tolerated by young people. By identifying important functional regions within the brain, including unpredictable patterns of functional reorganization, it can aid in surgical decision-making. Here we illustrate this using a number of case studies from the pediatric epilepsy surgery program at our institution. We describe how fMRI, used in conjunction with conventional investigative methods such as neuropsychological assessment, MRI, and electrophysiology, can 1) help to improve functional outcome by enabling resective surgery that spares functional cortex, 2) guide surgical intervention by revealing when reorganization of function has occurred, and 3) show when abnormal cortex is also functionally active, and hence that surgery may not be the best option. Altogether, these roles have reduced the need for invasive procedures that can be both risky and distressing for young people with epilepsy. In our experience, fMRI has significantly contributed to the decision-making process, and improved the counseling and management of young people with intractable epilepsy.

Brain Mapping↗

PubMed2006

In vivo measurement of the longitudinal relaxation time of arterial blood (T1a) in the mouse using a pulsed arterial spin labeling approach.

A novel method for measuring the longitudinal relaxation time of arterial blood (T1a) is presented. Knowledge of T1a is essential for accurately quantifying cerebral perfusion using arterial spin labeling (ASL) techniques. The method is based on the flow-sensitive alternating inversion recovery (FAIR) pulsed ASL (PASL) approach. We modified the standard FAIR acquisition scheme by incorporating a global saturation pulse at the beginning of the recovery period. With this approach the FAIR tissue signal difference has a simple monoexponential dependence on the recovery time, with T1a as the time constant. Therefore, FAIR measurements performed over a range of recovery times can be fitted to a monoexponential recovery curve and T1a can be calculated directly. This eliminates many of the difficulties associated with the measurement of T1a. Experiments performed in vivo in the mouse at 2.35T produced a mean value of 1.51 s for T1a, consistent with previously published values.

Animals↗

PubMed2006

Bolus delay and dispersion in perfusion MRI: implications for tissue predictor models in stroke.

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.

Adolescent↗

PubMed2006

Regional variation of cerebral blood flow and arterial transit time in the normal and hypoperfused rat brain measured using continuous arterial spin labeling MRI.

Continuous arterial spin labeling (CASL) is a noninvasive magnetic resonance (MR) method for measuring cerebral perfusion. In its most widely used form, CASL incorporates a postlabeling delay to minimize the sensitivity of the technique to transit time effects, which otherwise corrupt cerebral blood flow (CBF) quantification. For this delay to work effectively, it must be longer than the longest transit time present in the system. In this work, CASL measurements were made in four coronal slices in the rat brain using a range of postlabeling delays. By doing this, direct estimation of both CBF and arterial transit time (delta(a)) was possible. These measurements were performed in the normal brain and during hypoperfusion induced by occlusion of the common carotid arteries. It was found that, in the normal rat brain, significant regional variation exists for both CBF and delta(a). Mean values of CBF and delta(a) in the selected gray matter regions of interest were 233 mL/100 g min and 266 ms, respectively, with the latter ranging from 100 to 500 ms. Therefore, use of a 500-ms postlabeling delay is suitable for any location in the normal rat brain. After common carotid artery occlusion, CBF decreased and delta(a) increased by regionally dependent amounts. In the sensory cortex, delta(a) increased to a mean value of 740 ms, significantly greater than 500 ms. These results highlight the importance of either (a) determining delta(a) as part of the CASL measurement or (b) knowing the approximate range of values delta(a) is likely to take for a given application, so that the parameters of the CASL sequence can be chosen appropriately.

Animals↗

PubMed2006

Neuroprotective effects of virally delivered HSPs in experimental stroke.

Heat shock proteins (HSPs) are molecular chaperones with essential roles in modulating the proteolytic machinery and accelerating cell repair. Heat shock protein overexpression has been observed in vivo and in vitro under stresses including heat, nutrient deprivation and ischemia. Experiments in in vivo models of stroke indicate that transgenically overexpressed or virally delivered HSPs can enhance cell survival, but cannot always reduce lesion size. This study aims to assess the effects of virally delivered HSPs in a rat middle cerebral artery occlusion model of reversible focal cerebral ischemia using noninvasive magnetic resonance imaging. Attenuated herpes simplex virus carrying HSP27, HSP70, or a LacZ control was microinjected into the striatum 3 days before ischemia. Multislice T(2)-weighted images at 24 h after ischemia indicated that lesion volume was reduced by 44% in HSP27-treated animals compared with controls (P = 0.019). No significant differences were found between HSP70-treated and control animals (P = 0.88). Immunohistochemistry and Western blots revealed that HSP27 and HSP70 expression levels were equally high in injected hemispheres, but only the former had an effect on lesion size. This is the first evidence of the efficacy of gene therapy with any viral vector expressing HSP27 in an experimental model of stroke.

Animals↗

PubMed2006

Prolonged febrile seizures are associated with hippocampal vasogenic edema and developmental changes.

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.

Age Factors↗

PubMed2005

Gradual changes in the apparent diffusion coefficient of water in selectively vulnerable brain regions following brief ischemia in the gerbil.

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).

Animals↗

PubMed2005

Understanding and optimizing the amplitude modulated control for multiple-slice continuous arterial spin labeling.

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, B1; magnetic field gradient, G; phase, phi, and frequency, f, of the modulation function; velocity, v, and relaxation times, T1 and T2, of blood. It was found that unless f>2piB1, phi determines the performance of the AM control; excessively high B1 or v reduces the efficiency of the AM control; and T1 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.

Animals↗

PubMed2005

Is anoxic depolarisation associated with an ADC threshold? A Markov chain Monte Carlo analysis.

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.

Algorithms↗

PubMed2005

Neuroprotective effects of HSP70 overexpression after cerebral ischaemia--an MRI study.

Heat shock proteins (HSPs) have been reported to increase cell survival in response to a wide range of cellular challenges. However, the role of HSP70 overexpression is still a matter of debate, with some reports showing protection and others not. In order to resolve these discrepancies and further investigate the action of these proteins in vivo, transgenic mice overexpressing HSP70 have been compared to wild-type mice in a middle cerebral artery occlusion model of permanent cerebral ischaemia. Previously, the effect of HSP70 was assessed histologically postmortem. In this report, magnetic resonance imaging (MRI) was used to assess the mice in vivo after the onset of stroke. The lesion volume, as measured at 24 h using T(2)-weighted MRI, was significantly smaller in HSP70 transgenic mice compared with wild-type mice. The smaller lesion size in HSP70 transgenic mice could not be attributed to differences in vascular anatomy or in cerebral blood flow during occlusion. Additionally, the apparent diffusion coefficient showed different spatial and temporal patterns between the groups, suggesting that the damage within the lesion may be less severe for HSP70 transgenic mice. Thus, we conclude that overexpression of HSP70 reduces the overall lesion size and may also limit the tissue damage within the lesion.

Analysis of Variance↗

PubMed2005

Extra-hippocampal grey matter density abnormalities in paediatric mesial temporal sclerosis.

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.

Adolescent↗

PubMed2005

FOXP2 and the neuroanatomy of speech and language.

That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of these remarkable faculties been found. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech.

Animals↗

PubMed2004

Direct estimation of the fiber orientation density function from diffusion-weighted MRI data using spherical deconvolution.

Diffusion-weighted magnetic resonance imaging can provide information related to the arrangement of white matter fibers. The diffusion tensor is the model most commonly used to derive the orientation of the fibers within a voxel. However, this model has been shown to fail in regions containing several fiber populations with distinct orientations. A number of alternative models have been suggested, such as multiple tensor fitting, q-space, and Q-ball imaging. However, each of these has inherent limitations. In this study, we propose a novel method for estimating the fiber orientation distribution directly from high angular resolution diffusion-weighted MR data without the need for prior assumptions regarding the number of fiber populations present. We assume that all white matter fiber bundles in the brain share identical diffusion characteristics, thus implicitly assigning any differences in diffusion anisotropy to partial volume effects. The diffusion-weighted signal attenuation measured over the surface of a sphere can then be expressed as the convolution over the sphere of a response function (the diffusion-weighted attenuation profile for a typical fiber bundle) with the fiber orientation density function (ODF). The fiber ODF (the distribution of fiber orientations within the voxel) can therefore be obtained using spherical deconvolution. The properties of the technique are demonstrated using simulations and on data acquired from a volunteer using a standard 1.5-T clinical scanner. The technique can recover the fiber ODF in regions of multiple fiber crossing and holds promise for applications such as tractography.

Algorithms↗

PubMed2003

Language fMRI abnormalities associated with FOXP2 gene mutation.

Half the members of the KE family suffer from a speech and language disorder caused by a mutation in the FOXP2 gene. We examined functional brain abnormalities associated with this mutation using two fMRI language experiments, one involving covert (silent) verb generation and the other overt (spoken) verb generation and word repetition. The unaffected family members showed a typical left-dominant distribution of activation involving Broca's area in the generation tasks and a more bilateral distribution in the repetition task, whereas the affected members showed a more posterior and more extensively bilateral pattern of activation in all tasks. Consistent with previously reported bilateral morphological abnormalities, the affected members showed significant underactivation relative to the unaffected members in Broca's area and its right homolog, as well as in other cortical language-related regions and in the putamen. Our findings suggest that the FOXP2 gene is critically involved in the development of the neural systems that mediate speech and language.

Brain Mapping↗

PubMed2003

Hippocampal abnormalities after prolonged febrile convulsion: a longitudinal MRI study.

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 investigated >48 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.

Brain Edema↗

PubMed2003

Abnormalities in hippocampi remote from the seizure focus: a T2 relaxometry study.

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.

Adolescent↗