Structural Connectivity Remote From Lesions Correlates With Somatosensory Outcome Poststroke.

Background and Purpose: Changes in connectivity of white matter fibers remote to a stroke lesion, suggestive of structural connectional diaschisis, may impact on clinical impairment and recovery after stroke. However, until recently, we have not had tract-specific techniques to map changes in white matter tracts in vivo in humans to enable investigation of potential mechanisms and clinical impact of such remote changes. Our aim was to identify and quantify white matter tracts that are affected remote from a stroke lesion and to investigate the associations between reductions in tract-specific connectivity and impaired touch discrimination function after stroke. Methods: We applied fixel-based analysis to diffusion magnetic resonance imaging data from 37 patients with stroke (right lesion =16; left lesion =21) and 26 age-matched healthy adults. Three quantitative metrics were compared between groups: fiber density; fiber-bundle cross-section; and a combined measure of both (fiber-bundle cross-section) that reflects axonal structural connectivity. Results: Compared with healthy adults, patients with stroke showed significant common fiber-bundle cross-section and fiber density reductions in 4 regions remote from focal lesions that play roles in somatosensory and spatial information processing. Structural connectivity along the somatosensory fibers of the lesioned hemisphere was correlated with contralesional hand touch function. Touch function of the ipsilesional hand was associated with connectivity of the superior longitudinal fasciculus, and, for the right-lesion group, the corpus callosum. Conclusions: Remote tract-specific reductions in axonal connectivity indicated by diffusion imaging measures are observed in the somatosensory network after stroke. These remote white matter connectivity reductions, indicative of structural connectional diaschisis, are associated with touch impairment in patients with stroke.

Correlated Resting-State Functional MRI Activity of Frontostriatal, Thalamic, Temporal, and Cerebellar Brain Regions Differentiates Stroke Survivors with High Compared to Low Depressive Symptom Scores.

Background: One in three survivors of stroke experience poststroke depression (PSD). PSD has been linked with poorer recovery of function and cognition, yet our understanding of potential mechanisms is currently limited. Alterations in resting-state functional MRI have been investigated to a limited extent. Fluctuations in low frequency signal are reported, but it is unknown if interactions are present between the level of depressive symptom score and intrinsic brain activity in varying brain regions. Objective: To investigate potential interaction effects between whole-brain resting-state activity and depressive symptoms in stroke survivors with low and high levels of depressive symptoms. Methods: A cross-sectional analysis of 63 stroke survivors who were assessed at 3 months poststroke for depression, using the Montgomery-Åsberg Depression Rating Scale (MÅDRS-SIGMA), and for brain activity using fMRI. A MÅDRS-SIGMA score of >8 was classified as high depressive symptoms. Fractional amplitude of frequency fluctuations (fALFF) data across three frequency bands (broadband, i.e., ~0.01-0.08; subbands, i.e., slow-5: ~0.01-0.027 Hz, slow-4: 0.027-0.07) was examined. Results: Of the 63 stroke survivors, 38 were classified as "low-depressive symptoms" and 25 as "high depressive symptoms." Six had a past history of depression. We found interaction effects across frequency bands in several brain regions that differentiated the two groups. The broadband analysis revealed interaction effects in the left insula and the left superior temporal lobe. The subband analysis showed contrasting fALFF response between the two groups in the left thalamus, right caudate, and left cerebellum. Across the three frequency bands, we found contrasting fALFF response in areas within the fronto-limbic-thalamic network and cerebellum. Conclusions: We provide evidence that fALFF is sensitive to changes in poststroke depressive symptom severity and implicates frontostriatal and cerebellar regions, consistent with previous studies. The use of multiband analysis could be an effective method to examine neural correlates of depression after stroke. The START-PrePARE trial is registered with the Australian New Zealand Clinical Trial Registry, number ACTRN12610000987066.

The Interleukin-1 Balance During Encephalitis Is Associated With Clinical Severity, Blood-Brain Barrier Permeability, Neuroimaging Changes, and Disease Outcome.

BACKGROUND: Encephalitis is parenchymal brain inflammation, commonly due to herpes simplex virus (HSV). Key host inflammatory mediators and their relationship to blood-brain barrier (BBB) permeability, neuroimaging changes, and disease outcome are poorly understood. METHODS: We measured levels of 38 mediators in serum (n = 78) and cerebrospinal fluid (n = 37) specimens from patients with encephalitis, including 17 with disease due to HSV infection. Outcome measures were Glasgow coma and outcome scores; CSF to serum albumin ratio, reflecting BBB permeability; and, in patients with HSV infection, magnetic resonance imaging-based temporal lobe volume. RESULTS: Serum interleukin 1 receptor antagonist (IL-1RA) levels were elevated in patients with a good outcome (P= .004). Among patients infected with HSV, the ratio of CSF IL-1ß to IL-1RA was associated with a worse outcome (P= .009); a ratio of ≥0.55 pg/mL had high specificity and sensitivity for a poor outcome (100% and 83%;P= .015). Temporal lobe volume had a negative correlation with serum IL-1RA level (P= .012) and a positive correlation with serum IL-1α level (P= .0003) and CSF IL-1ß level (P= .007). A normal coma score was associated with an elevated interleukin 10 (IL-10) level in serum specimens from HSV-infected patients (P= .007) and CSF specimens from all patients (P= .016); the IL-10 level correlated inversely with BBB permeability (P= .005). CONCLUSIONS: A proinflammatory cytokine response is associated with greater clinical severity, BBB permeability, and neuroimaging damage during encephalitis. IL-1 antagonists should be investigated as adjunctive treatment in encephalitis.

fMRI and MRS measures of neuroplasticity in the pharyngeal motor cortex.

INTRODUCTION: Paired associative stimulation (PAS), is a novel non-invasive technique where two neural substrates are employed in a temporally coordinated manner in order to modulate cortico-motor excitability within the motor cortex (M1). In swallowing, combined pharyngeal electrical and transcranial-magnetic-stimulation induced beneficial neurophysiological and behavioural effects in healthy subjects and dysphagic stroke patients. Here, we aimed to investigate the whole-brain changes in neural activation during swallowing using functional magnetic resonance imaging (fMRI) following PAS application and in parallel assess associated GABA changes with magnetic resonance spectroscopy (MRS). METHODS: Healthy adults (n=11, 38±9years old) were randomised to receive real and sham PAS to the 'stronger' motor cortex pharyngeal representation, on 2 separate visits. Following PAS, event-related fMRI was performed to assess changes in brain activation in response to water and saliva swallowing and during rest. Data were analysed (SPM8) at P<.001. MRS data were acquired using MEGA-PRESS before and after the fMRI acquisitions on both visits and GABA concentrations were measured (AMARES, jMRUI). RESULTS: Following real PAS, BOLD signal changes (group analyses) increased at the site of stimulation during water and saliva swallowing, compared to sham PAS. It is also evident that PAS induced significant increases in BOLD signal to contralateral (to stimulation) hemispheric areas that are of importance to the swallowing neural network. Following real PAS, GABA:creatine ratio showed a trend to increase contralateral to PAS. CONCLUSION: Targeted PAS applied to the human pharyngeal motor cortex induces local and remote changes in both primary and non-primary areas for water and saliva tasks. There is a possibility that changes of the inhibitory neurotransmitter, GABA, may play a role in the changes in BOLD signal. These findings provide evidence for the mechanisms underlying the beneficial effects of PAS on the brain swallowing network.

Re-wiring the brain: increased functional connectivity within primary somatosensory cortex following synchronous co-activation.

The primary somatosensory cortex shows precise topographical organisation, but can be quickly modified by alterations to sensory inputs. Temporally correlated sensory inputs to the digits can result in the merging of digit representations on the cortical surface. Underlying mechanisms driving these changes are unclear but the strengthening of intra-cortical synaptic connections via Hebbian mechanisms has been suggested. We use fMRI measures of temporal coherence to infer alterations in the relative strength of neuronal connections between digit regions 2 and 4 following 3 hours of synchronous and asynchronous co-activation. Following synchronous co-activation we find a 20% increase in temporal coherence of the fMRI signal (p=0.0004). No significant change is seen following asynchronous co-activation suggesting that temporal coincidence between the two digit inputs during co-activation is driving this coherence change. In line with previous work we also find a trend towards reduced separation of the digit representations following synchronous co-activation and significantly increased separation for the asynchronous case. Increased coherence is significantly correlated with reduced digit separation for the synchronous case. This study shows that passive synchronous stimulation to the digits strengthens the underlying cortical connections between the digit regions in only a few hours, and that this mechanism may be related to topographical re-organisation.

Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA.

There is increasing interest in the use of edited proton magnetic resonance spectroscopy for the detection of GABA in the human brain. At a recent meeting held at Cardiff University, a number of spectroscopy groups met to discuss the acquisition, analysis and interpretation of GABA-edited MR spectra. This paper aims to set out the issues discussed at this meeting, reporting areas of consensus around parameters and procedures in the field and highlighting those areas where differences remain. It is hoped that this paper can fulfill two needs, providing a summary of the current 'state-of-the-art' in the field of GABA-edited MRS at 3T using MEGA-PRESS and a basic guide to help researchers new to the field to avoid some of the pitfalls inherent in the acquisition and processing of edited MRS for GABA.

Single-session reproducibility of MR spectroscopy measures of glutathione in the mesial temporal lobe with MEGA-PRESS.

BACKGROUND AND PURPOSE: Magnetic resonance spectroscopy (MRS) measures neurochemicals in vivo. Glutathione (GSH) is a neuroprotective chemical shown to vary significantly in patients with Alzheimer's disease (AD). This work investigates the reproducibility of GSH measures in the mesial temporal lobe (MTL) to identify its potential clinical utility. METHODS: MRS data were acquired from eight healthy volunteers (31.1 ± 5.2 years; 4 male/female) using Mescher-Garwood-Point Resolved Spectroscopy (MEGA-PRESS) from the MTL in the left hemisphere across two scan sessions in the same visit. Total N-acetylaspartate (tNAA), choline (tCho), creatine (tCr), and GSH were quantified. Reproducibility of quantifications of these neurochemicals were tested using coefficient of variance (CV) between scan sessions. Reproducibility of voxel placement on the left MTL was calculated by measuring the tissue overlap and percent of hippocampus within that voxel. CV measured across different scan sessions in each individual, with a CV<15% was accepted as "good" reproducibility. Paired t-tests were carried out to establish the significant differences between the two scans across each individual with p<.05 as significant. RESULTS: TNAA (%CV = 7.2; p = .5), tCr (%CV = 7.8; p = .6) and tCho (%CV = 9.3; p = .4), and GSH (%CV = 22; p = .1). The dice coefficient that reflects the level of overlap of hippocampal tissue in the voxel was shown to be 0.8 ± 0.1. Voxel tissue composition were: Scan 1 (cerebrospinal fluid [CSF]: 5 ± 1%, white matter [WM]: 52 ± 3%, gray matter [GM]: 43 ± 3%); Scan 2 (CSF: 5 ± 1%, WM: 52 ± 4%, GM: 44 ± 4%). CONCLUSION: The data suggest measures of abundant metabolites in the MTL using the MEGA-PRESS sequence has a high reproducibility. Reproducibility of GSH in this area was poorer requiring care when interpreting measures of GSH in the MTL for clinical translational purposes.

Gray matter nulled and vascular space occupancy dependent fMRI response to visual stimulation during hypoxic hypoxia.

Two cerebral blood volume (CBV)-weighted fMRI techniques, gray matter nulled (GMN) and vascular space occupancy (VASO)-dependent techniques at spatial resolution of 2 × 2 × 5 mm(3), were compared in the study investigating functional responses in the human visual cortex to stimulation in normoxia (inspired O(2) = 21%) and mild hypoxic hypoxia (inspired O(2) = 12%). GMN and VASO signals and T(2)* were quantified in activated voxels. While the CBV-weighted signal changes in voxels activated by visual stimulation were similar in amplitude in both fMRI techniques in both oxygenation conditions, the number of activated voxels during hypoxic hypoxia was significantly reduced by 72 ± 22% in GMN fMRI and 66 ± 23% in VASO fMRI. T(2)* prolonged in GMN and VASO activated voxels in normoxia by 1.6 ± 0.5 ms and 1.7 ± 0.5 ms, respectively. In hypoxia, however, T(2)* shortened in GMN-activated voxels by 0.7 ± 0.6 ms (p < 0.001 relative to normoxia), but prolonged in VASO-activated ones by 1.1 ± 0.6 ms (p < 0.05 relative to normoxia). The data show that the hemodynamic responses to visual stimulation were not affected by hypoxic hypoxia, but T(2)* increases by both CBV-weighted fMRI techniques were smaller in activated voxels in hypoxia. The mechanisms influencing GMN fMRI signal in both oxygenation conditions were explored by simulating effects of the oxygen extraction fraction (OEF) and partial voluming with cerebral spinal fluid (CSF) and white matter in imaging voxels. It is concluded that while GMN fMRI data point to increased, rather than decreased OEF during visual stimulation in hypoxia, partial voluming by CSF is likely to affect the CBV quantification by GMN fMRI under the experimental conditions used.

Reproducibility of functional MRI localization within the human somatosensory cortex.

PURPOSE: To evaluate the effect of fMRI localization approaches and region size on the reproducibility of digit localization in the human somatosensory cortex. MATERIALS AND METHODS: Vibrotactile stimulation was applied to digits 2 and 4 producing cortical activation sites relating to each digit. Thirteen subjects were scanned twice on separate occasions in a 3 Tesla scanner using a voxel size of 2 mm. Regions of activity were thresholded to different sizes varying from 50 to 1000 voxels. Three measures of position were acquired from these regions: center of gravity (COG), center co-ordinate and peak voxel. To account for registration errors, Euclidean distance between the two digits was computed. Reproducibility was determined in terms of the 95% confidence interval for individual position in X, Y, and Z and also the distance between the two digit locations. RESULTS: Region size of 200 most significant voxels was shown to have the best reproducibility. Center co-ordinate proved to be the most precise form of localizing activity with a 95% CI of 2.1 mm, 2.6 mm, and 3.1 mm in the X, Y, and Z axes. Euclidean distance between the center co-ordinates of the two digit activation sites was shown to be a reliable means of overcoming registration errors with a 95% CI of 1.7 mm. CONCLUSION: This study shows a high level of reproducibility for fMRI localization in the somatosensory system.

A multimodal brain imaging study of repetition suppression in the human visual cortex.

Repetition suppression (RS) relates to a reduced neuronal response to a stimulus that is repeated. This phenomenon has been observed in the visual ventral stream and other sensory modalities, suggesting that it is a common feature of neuronal processing. Whilst a number of different models have been suggested to explain the underlying neural mechanisms of RS, they are difficult to test due to variety in paradigm design and the limited resolution of different measuring modalities. This study combined information from different modalities using the same paradigm across the same subjects, in an attempt to create a clearer link between fMRI, magnetoencephalography (MEG) and behaviour data, and thus better understand the underlying mechanism of neuronal RS. We used an oriented Gabor patch stimulus separated by two possible interstimulus intervals of 200 or 600 ms and two possible orientation combinations: the second patch was consistently vertical combined with the first patch which was either horizontal (DIFF) or vertical (SAME). For the 200 -ms condition only, behavioural data showed a statistically significant impairment in subjects' ability to discern the direction of tilt at the SAME condition compared to the DIFF condition; fMRI showed suppression of the BOLD response, and MEG showed suppression of the peak amplitude. A significant correlation between the suppressed BOLD and MEG signals confirm the neuronal origin of the BOLD suppression effect. Measurements from the 3 modalities suggest that neuronal RS in the visual cortex in the current orientation-driven paradigm can be best explained by an overall reduction in the size of the response of all neurons (fatigue model) or a reduction in the number of neurons responding (sharpening model).

Quantitative fMRI using hyperoxia calibration: reproducibility during a cognitive Stroop task.

Arterial spin labelling allows simultaneous measurement of both the blood-oxygenation-level-dependent (BOLD) and the cerebral blood flow (CBF) response to changes in neural activity. The addition of a hypercapnia or hyperoxia calibration allows additional quantification of changes in the cerebral metabolic rate of oxygen (CMRO(2)). In this study we test the reproducibility of measurements derived using the hyperoxia approach, during a cognitive Stroop task. A QUIPSSII sequence is used at 3 T to collect simultaneous CBF and BOLD signal during two 3 min periods of hyperoxia and an 8 min Stroop task. Hyperoxia was administered via an open system and end-tidal values were sampled via a nasal cannula; average end-tidal values of 60% were reached. This procedure is repeated to allow the reproducibility of the estimated parameters to be tested. The use of a cognitive Stroop task allows testing of the measurements in frontal and parietal regions as well as sensorimotor areas in which previous studies have been focussed. We find reduced reproducibility of the calculated parameters compared to the hypercapnia approach, thought to be attributable to lower absolute BOLD and CBF responses. In particular we do not find 'n' to have improved reproducibility compared to other parameters, as has been found in previous work using the hypercapnia approach. Across all brain areas we report a value of DeltaCMRO(2) of 12% and neurovascular coupling constant n of 2.5. Interestingly we find n to be higher in parietal and frontal areas in comparison to the primary motor cortex.

31P magnetic resonance spectroscopy study of the human visual cortex during stimulation in mild hypoxic hypoxia.

Effects of mild hypoxic hypoxia on cerebral energy state, as assessed by phosphocreatine (PCr)/γ-ATP and inorganic phosphate (P(i))/(P(i) + PCr) ratios and intracellular pH (pH(i)) in the human visual cortex, were studied using (31)P nuclear magnetic resonance spectroscopy (MRS) at 3 T. The working hypothesis that, during compromised O(2) availability obtained by hypoxic hypoxia, both cerebral energy state and pH(i) decline due to insufficient O(2) supply for energy metabolism was addressed. Under baseline hypoxic hypoxia, with blood O(2) saturation ranging from 0.95 to 0.83, neither the PCr/γ-ATP and P(i)/(P(i )+ PCr) ratios nor pH(i) was affected, thus, showing that cerebral energy metabolism was maintained. Contrary to the formulated hypothesis, visual stimulation during hypoxic hypoxia influenced neither the indicator ratios for energy state nor pH(i) in the occipital cortex. Taking these results, together with previous observations showing that cerebral blood flow responses are the same in size both in euoxia and in hypoxia at this depth (Mintun et al. in Proc Natl Acad Sci USA 98:6859-6864, 2001; Tuunanen et al. in J Cereb Blood Flow Metab 26:263-273, 2006a), it is concluded that O(2) delivery to the brain during mild hypoxic hypoxia meets the demand by the energy metabolism both under baseline and stimulated states.

Altered functional connectivity differs in stroke survivors with impaired touch sensation following left and right hemisphere lesions.

One in two survivors experience impairment in touch sensation after stroke. The nature of this impairment is likely associated with changes associated with the functional somatosensory network of the brain; however few studies have examined this. In particular, the impact of lesioned hemisphere has not been investigated. We examined resting state functional connectivity in 28 stroke survivors, 14 with left hemisphere and 14 with right hemisphere lesion, and 14 healthy controls. Contra-lesional hands showed significantly decreased touch discrimination. Whole brain functional connectivity (FC) data was extracted from four seed regions, i.e. primary (S1) and secondary (S2) somatosensory cortices in both hemispheres. Whole brain FC maps and Laterality Indices (LI) were calculated for subgroups. Inter-hemispheric FC was greater in healthy controls compared to the combined stroke cohort from the left S1 seed and bilateral S2 seeds. The left lesion subgroup showed decreased FC, relative to controls, from left ipsi-lesional S1 to contra-lesional S1 and to distributed temporal, occipital and parietal regions. In comparison, the right lesion group showed decreased connectivity from contra-lesional left S1 and bilateral S2 to ipsi-lesional parietal operculum (S2), and to occipital and temporal regions. The right lesion group also showed increased intra-hemispheric FC from ipsi-lesional right S1 to inferior parietal regions compared to controls. In comparison to the left lesion group, those with right lesion showed greater intra-hemispheric connectivity from left S1 to left parietal and occipital regions and from right S1 to right angular and parietal regions. Laterality Indices were significantly greater for stroke subgroups relative to matched controls for contra-lesional S1 (left lesion group) and contra-lesional S2 (both groups). We provide evidence of altered functional connectivity within the somatosensory network, across both hemispheres, and to other networks in stroke survivors with impaired touch sensation. Hemisphere of lesion was associated with different patterns of altered functional connectivity within the somatosensory network and with related function was associated with different patterns of altered functional connectivity within the somatosensory network and with related functional networks.

Proliferating resident microglia after focal cerebral ischaemia in mice.

Cerebral ischaemia usually results in the rapid death of neurons within the immediate territory of the affected artery. Neuronal loss is accompanied by a sequence of events, including brain oedema, blood-brain barrier (BBB) breakdown, and neuroinflammation, all of which contribute to further neuronal death. Although the role of macrophages and mononuclear phagocytes in the expansion of ischaemic injury has been widely studied, the relative contribution of these cells, either of exogenous or intrinsic central nervous system (CNS) origin is still not entirely clear. The purpose of this study, therefore, was to use different durations of transient middle cerebral artery occlusion (tMCAo) in the mouse to investigate fully post-occlusion BBB permeability and cellular changes in the brain during the 72 h post-MCAo period. This was achieved using in vivo magnetic resonance imaging (MRI) and cell labelling techniques. Our results show that BBB breakdown and formation of the primary ischaemic damage after tMCAo is not associated with significant infiltration of neutrophils, although more are observed with longer periods of MCAo. In addition, we observe very few infiltrating exogenous macrophages over a 72 h period after 30 or 60 mins of occlusion, instead a profound increase in proliferating resident microglia cells was observed. Interestingly, the more severe injury associated with 60 mins of MCAo leads to a markedly reduced proliferation of resident microglial cells, suggesting that these cells may play a protective function, possibly through phagocytosis of infiltrating neutrophils. These data further support possible beneficial actions of microglial cells in the injured brain.

Structural and physiological neurovascular changes in idiopathic Parkinson's disease and its clinical phenotypes.

Neurovascular changes are likely to interact importantly with the neurodegenerative process in idiopathic Parkinson's disease (IPD). Markers of neurovascular status (NVS) include white matter lesion (WML) burden and arterial spin labelling (ASL) measurements of cerebral blood flow (CBF) and arterial arrival time (AAT). We investigated NVS in IPD, including an analysis of IPD clinical phenotypes, by comparison with two control groups, one with a history of clinical cerebrovascular disease (CVD) (control positive, CP) and one without CVD (control negative, CN). Fifty-one patients with IPD (mean age 69.0 ± 7.7 years) (21 tremor dominant (TD), 24 postural instability and gait disorder (PIGD) and six intermediates), 18 CP (mean age 70.1 ± 8.0 years) and 34 CN subjects (mean age 67.4 ± 7.6 years) completed a 3T MRI scan protocol including T2-weighted fluid-attenuated inversion recovery (FLAIR) and ASL. IPD patients showed diffuse regions of significantly prolonged AAT, small regions of lower CBF and greater WML burden by comparison with CN subjects. TD patients showed lower WML volume by comparison with PIGD patients. These imaging data thus show altered NVS in IPD, with some evidence for IPD phenotype-specific differences.

A Feasibility Study of Quantifying Longitudinal Brain Changes in Herpes Simplex Virus (HSV) Encephalitis Using Magnetic Resonance Imaging (MRI) and Stereology.

OBJECTIVES: To assess whether it is feasible to quantify acute change in temporal lobe volume and total oedema volumes in herpes simplex virus (HSV) encephalitis as a preliminary to a trial of corticosteroid therapy. METHODS: The study analysed serially acquired magnetic resonance images (MRI), of patients with acute HSV encephalitis who had neuroimaging repeated within four weeks of the first scan. We performed volumetric measurements of the left and right temporal lobes and of cerebral oedema visible on T2 weighted Fluid Attenuated Inversion Recovery (FLAIR) images using stereology in conjunction with point counting. RESULTS: Temporal lobe volumes increased on average by 1.6% (standard deviation (SD 11%) in five patients who had not received corticosteroid therapy and decreased in two patients who had received corticosteroids by 8.5%. FLAIR hyperintensity volumes increased by 9% in patients not receiving treatment with corticosteroids and decreased by 29% in the two patients that had received corticosteroids. CONCLUSIONS: This study has shown it is feasible to quantify acute change in temporal lobe and total oedema volumes in HSV encephalitis and suggests a potential resolution of swelling in response to corticosteroid therapy. These techniques could be used as part of a randomized control trial to investigate the efficacy of corticosteroids for treating HSV encephalitis in conjunction with assessing clinical outcomes and could be of potential value in helping to predict the clinical outcomes of patients with HSV encephalitis.

A luminescent probe containing a tuftsin targeting vector coupled to a terbium complex.

Orthogonal protection strategies have been used to prepare a series of luminescent and MRI active lanthanide complexes containing a tuftsin targeting vector that are internalised by macrophage cells.

Effects of mild hypoxic hypoxia on poststimulus undershoot of blood-oxygenation-level-dependent fMRI signal in the human visual cortex.

Characteristics of the blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal poststimulus undershoot in the visual cortex were studied at varying levels of arterial blood oxygen saturation (Ysat). Undershoot with an amplitude of -0.6+/-0.2% appeared after positive BOLD response (+1.7+/-0.5%) under control conditions. Cerebral blood volume (CBV), as determined with vascular-space-occupancy-dependent fMRI, increased by 26-43% during the positive BOLD peak, but the CBV proceeded at baseline level during the BOLD poststimulus undershoot. Mild hypoxic hypoxia (Ysat ranging from 0.82 to 0.89) had no effect on the amplitude or duration of poststimulus undershoot in activated BOLD pixels. Hypoxia did not influence CBV during the BOLD poststimulus undershoot. In contrast, the positive BOLD signal at the level of all activated pixels was smaller in hypoxia than in normoxia. The present results show that the BOLD poststimulus undershoot is not influenced by curtailed oxygen availability and that, during the undershoot, CBV is not different from resting state.

Quantitative measurement of blood flow in paediatric brain tumours-a comparative study of dynamic susceptibility contrast and multi time-point arterial spin labelled MRI.

OBJECTIVE: Arterial spin-labelling (ASL) MRI uses intrinsic blood water to quantify the cerebral blood flow (CBF), removing the need for the injection of a gadolinium-based contrast agent used for conventional perfusion imaging such as dynamic susceptibility contrast (DSC). Owing to the non-invasive nature of the technique, ASL is an attractive option for use in paediatric patients. This work compared DSC and multi-timepoint ASL measures of CBF in paediatric brain tumours. METHODS: Patients (n = 23; 20 low-grade tumours and 3 high-grade tumours) had DSC and multi-timepoint ASL with and without vascular crushers (VC). VC removes the contribution from larger vessel blood flow. Mean perfusion metrics were extracted from control and T1-enhanced tumour regions of interest (ROIs): arterial arrival time (AAT) and CBF from the ASL images with and without VC, relative cerebral blood flow (rCBF), relative cerebral blood volume, delay time (DT) and mean transit time (MTT) from the DSC images. RESULTS: Significant correlations existed for: AAT and DT (r = 0.77, p = 0.0002) and CBF and rCBF (r = 0.56, p = 0.02) in control ROIs for ASL-noVC. No significant correlations existed between DSC and ASL measures in the tumour region. Significant differences between control and tumour ROI were found for MTT (p < 0.001) and rCBF (p < 0.005) measures. CONCLUSION: Significant correlations between ASL-noVC and DSC measures in the normal brain suggest that DSC is most sensitive to macrovascular blood flow. The absence of significant correlations within the tumour ROI suggests that ASL is sensitive to different physiological mechanisms compared with DSC measures. ADVANCES IN KNOWLEDGE: ASL provides information which is comparable with that of DSC in healthy tissues, but appears to reflect a different physiology in tumour tissues.

Structural and physiological MRI correlates of occult cerebrovascular disease in late-onset epilepsy.

Late-onset epilepsy (LOE), with onset after 50 years of age, is often attributed to underlying occult cerebrovascular disease. LOE is associated with a three-fold increase in subsequent stroke risk, therefore it is important to improve our understanding of pathophysiology. In this exploratory study, we aimed to determine whether established structural magnetic resonance imaging markers and novel physiological imaging markers of occult cerebrovascular disease were more common in patients with LOE than age-matched controls. Sixteen patients with LOE (mean age ± SD: 67.6 ± 6.5 years) and 15 age-matched control subjects (mean age: 65.1 ± 3.9 years) underwent a 3 T MRI scan protocol. T1-weighted images and T2-weighted fluid attenuated inversion recovery (FLAIR) images were used to determine cortical grey matter volume and white matter hyperintensity (WMH) volume respectively, whilst multiple delay time arterial spin labelling (ASL) images were collected at rest and during a hypercapnic challenge. Cerebral blood flow (CBF) and arterial arrival time (AAT) were calculated from ASL data under both normocapnic and hypercapnic conditions. Cerebrovascular reactivity was also calculated for both CBF and AAT relative to the change in end-tidal CO2. Patients with LOE were found to have significantly lower cortical volume than control subjects (33.8 ± 3.8% of intracranial volume vs. 38.0 ± 5.5%, p = 0.02) and significantly higher WMH volume (1339 ± 1408 mm3 vs. 514 ± 481 mm3, p = 0.047). Baseline whole brain AAT was found to be significantly prolonged in patients with LOE in comparison to control subjects (1539 ± 129 ms vs. 1363 ± 167 ms, p = 0.005). Voxel-based analysis showed the significant prolongation of AAT to be predominantly distributed in the frontal and temporal lobes. Voxel-based morphometry showed the lower cortical volume to be localised primarily to temporal lobes. No significant differences in CBF or cerebrovascular reactivity were found between the two groups. Baseline whole brain AAT and cortical volume differences persisted upon further analysis to take account of differences in smoking history between patients and control subjects. These findings suggest that occult cerebrovascular disease is relevant to the pathophysiology of LOE.