Voxel-Based Iterative Sensitivity (VBIS) analysis: Methods and a validation of intensity scaling for T2-weighted imaging of hippocampal sclerosis

doi:10.1016/j.neuroimage.2008.09.055

NeuroImage

Volume 44, Issue 3, 1 February 2009, Pages 812-819

https://doi.org/10.1016/j.neuroimage.2008.09.055 Get rights and content

Abstract

Abnormalities in the brain generally manifest on MRI as changes in shape (morphometry) or changes in the nature of the tissue (signal intensity). Voxel Based Morphometry (VBM) is a whole brain quantitative way of assessing morphometric changes. Voxel Based Relaxometry (VBR) directly assesses signal intensity changes in quantitative maps of T2 relaxation time, but this requires specialised multiple-echo acquisition sequences that are not usually available at clinical sites. This paper introduces and assesses an objective voxel-based statistical method for evaluation of signal intensity in groups of routinely acquired qualitative images. We call the method Voxel-Based Iterative Sensitivity (VBIS) analysis. It adaptively optimises the relative global scaling of images to maximise sensitivity to regional effects. We apply and validate the method of analysis for T2-weighted images of the human brain. To validate the method, it was directly compared with VBR by extracting T2-weighted images of a single echo from multi-echo T2 relaxometry acquisitions from a group of 24 patients with left hemisphere hippocampal sclerosis and 97 healthy controls. Expected signal abnormalities in the patients were detectable with VBIS-T2, confirming the feasibility of the technique. This opens the door to the use of a voxel-based analysis approach on the vast amount of T2-weighted image data that has been and is being acquired on MRI scanners. When a quantitative modality is not available, VBIS can be an effective way to quantify differences between groups. We expect the method could also assist quantitative analysis of other qualitative modalities such as T1-weighted MRI, SPECT and CT.

Introduction

Abnormalities in the brain generally manifest on MRI as changes in shape (morphometry) or changes in the nature of the tissue (signal intensity). Voxel Based Morphometry (VBM) (Ashburner and Friston, 2000) is a whole brain quantitative method of assessing morphometric changes in structural images. Voxel Based Relaxometry (VBR) (Pell et al., 2004) is a whole brain quantitative method of assessing signal intensity changes in T2-relaxometry maps. However, T2-relaxometry itself requires specialised multiple-echo acquisition sequences that are not usually available in clinical studies. This manuscript introduces and assesses an objective voxel-based statistical method for evaluation of signal intensity in groups of routinely acquired qualitative images. We apply and validate the method of analysis for single-echo T2-weighted images of the human brain.

T2-weighted signal depends on multiple factors such as shim, coil loading and receiver gain settings, and can vary markedly across imaging sessions and subjects. To deal with this, we developed Voxel-Based Iterative Sensitivity (VBIS) analysis, a novel adaptive approach that could in principle be applied to any qualitative imaging modality. We call the specific application of the method to T2-weighted imaging “VBIS-T2”. To assess the method, we used data acquired in a group of healthy controls and a group of patients with typical left hemisphere hippocampal sclerosis. Multi-echo T2-relaxometry had been acquired in these subjects, so we validated our method by extracting single T2-weighted image volumes from the multi-echo acquisitions. In this way, the results of VBIS-T2 could be directly compared to the results of the established VBR method.

We hypothesised that VBIS-T2 would be capable of identifying T2 signal abnormality in patients with left HS, in agreement with VBR, although VBR would likely be the more sensitive of the two techniques since it has the advantage of dealing with quantitative images. The motivation to develop VBIS-T2 was therefore not to realise a method superior to VBR, but rather to facilitate quantitative analysis of the relatively large amount of available T2-weighted imaging data, given the relative prevalence of that modality compared to T2-relaxometry.

Section snippets

Subjects

We studied 97 healthy controls (mean age 31 ± 9 (SD) years, 52 women) and, from the comprehensive epilepsy surgery program at Austin Health, 24 patients (mean age 38 ± 12 (SD) years, 11 women) with typical left hemisphere hippocampal sclerosis (HS). The study was approved by the Austin Health Human Research Ethics Committee, and conformed to the Code of Ethics of the World Medical Association (Declaration of Helsinki). All participants gave informed consent. Note that in our original VBR study (

Determining the sensitivity of the alternative analysis approaches in healthy controls

The VBIS-T2 method proved to be the most sensitive of the T2-weighted imaging approaches tested. In all methods there were no significant voxel-wise differences detected between groups at a threshold of 0.05 corrected for multiple comparisons (as one would want, given that each group consisted entirely of healthy controls). Fig. 1 shows a comparison of sensitivity between (a) Method A (global normalisation using SPM default routines) and (b) Method C (VBIS-T2). For step 4 of the VBIS method,

Discussion

We have introduced Voxel-Based Iterative Sensitivity (VBIS) analysis, a novel adaptive method of global intensity normalisation for voxel-based statistical analysis of qualitative images. We validated this objective method for T2-weighted images, demonstrating that the method is capable of detecting T2 abnormalities in expected areas in patients with hippocampal sclerosis.

Where abnormalities were detected with the VBIS-T2 method, they were mostly in similar locations to those detected by VBR.

Conclusions

This study has introduced the VBIS method, a novel approach for the quantitative evaluation of qualitative neuroimaging modalities. The method uses iteration and calculation of sensitivity maps to adaptively determine a global scaling factor that increases sensitivity in most voxels of interest. We have demonstrated that when applied to T2-weighted images, the method is capable of detecting T2 abnormalities in patients with hippocampal sclerosis. This opens the door to potential use of a

Acknowledgments

We gratefully thank Leighton R. Barnden (Department of Nuclear Medicine, The Queen Elizabeth Hospital, Woodville, South Australia) for alerting us to the need for a validated technique for quantitation of inherently qualitative imaging modalities, and for subsequent helpful discussions. We also acknowledge the support of the National Health and Medical Research Council (NH&MRC), Australia (Program Grant 400121).

References (11)

AshburnerJ. et al.
Voxel-based morphometry—the methods
NeuroImage
(2000)
GoodC.D. et al.
A voxel-based morphometric study of ageing in 465 normal adult human brains
NeuroImage
(2001)
PellG.S. et al.
Composite voxel-based analysis of volume and T2 relaxometry in temporal lobe epilepsy
NeuroImage
(2008)
PellG.S. et al.
Voxel-based relaxometry: a new approach for analysis of T2 relaxometry changes in epilepsy
NeuroImage
(2004)
AbbottD. et al.
iBrain — software for analysis and visualisation of functional MR images
NeuroImage
(2001)

There are more references available in the full text version of this article.

Cited by (18)

Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome
2018, NeuroImage: Clinical
Citation Excerpt :
TIV was included as the global covariate in the VBM statistical designs. T1wSE and T2wSE signal levels were normalised using the voxel-based iterative sensitivity (VBIS) method of Abbott et al (Abbott et al., 2009). VBIS requires an initial CFS group comparison with healthy controls for T1wSE (or T2wSE) images scaled using their whole-brain means (SPM’s ‘proportional scaling’).
We recruited 43 Chronic Fatigue Syndrome (CFS) subjects who met Fukuda criteria and 27 healthy controls and performed 3T MRI T1 and T2 weighted spin-echo (T1wSE and T2wSE) scans. T1wSE signal follows T1 relaxation rate (1/T1 relaxation time) and responds to myelin and iron (ferritin) concentrations. We performed MRI signal level group comparisons with SPM12. Spatial normalization after segmentation was performed using T2wSE scans and applied to the coregistered T1wSE scans. After global signal-level normalization of individual scans, the T1wSE group comparison detected decreased signal-levels in CFS in a brainstem region (cluster-based inference controlled for family wise error rate, P_FWE= 0.002), and increased signal-levels in large bilateral clusters in sensorimotor cortex white matter (cluster P_FWE < 0.0001). Moreover, the brainstem T1wSE values were negatively correlated with the sensorimotor values for both CFS (R² = 0.31, P = 0.00007) and healthy controls (R² = 0.34, P = 0.0009), and the regressions were co-linear. This relationship, previously unreported in either healthy controls or CFS, in view of known thalamic projection-fibre plasticity, suggests brainstem conduction deficits in CFS may stimulate the upregulation of myelin in the sensorimotor cortex to maintain brainstem – sensorimotor connectivity. VBM did not find group differences in regional grey matter or white matter volumes. We argued that increased T1wSE observed in sensorimotor WM in CFS indicates increased myelination which is a regulatory response to deficits in the brainstem although the causality cannot be tested in this study. Altered brainstem myelin may have broad consequences for cerebral function and should be a focus of future research.
Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome
2016, NeuroImage: Clinical
Citation Excerpt :
Here we report extensive results from brain MRI regressions with autonomic function (as indirectly measured by steady state BP and HR in two postures), which reveal patterns of abnormality that provide new insights into brain-body relationships in CFS and are consistent with a nerve conduction deficit in the brainstem/midbrain. In addition to grey matter (GM) and white matter (WM) volume images from voxel-based morphometry (VBM), we have utilised novel quantitative analysis of T1-weighted (T1w) and T2-weighted (T2w) spin-echo brain MRI images, after inter-subject signal-level normalisation (Abbott et al., 2009). T1w and T2w spin-echo images are ideal for cross-sectional studies because of their low-noise, high resolution and minimal distortion from the patient-induced and instrumentation-induced magnetic field inhomogeneities (Bushberg et al., 2002) that distort gradient-echo scans.
Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure (BP) and heart rate (HR). In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring. We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS. Significant CFS regressions were repeated controlling for anxiety and depression (A&D). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter. Group comparisons of CFS and NC did not find MRI differences in these locations. We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations. This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions.
Comparing voxel-based iterative sensitivity and voxel-based morphometry to detect abnormalities in T2-weighted MRI
2014, NeuroImage
Citation Excerpt :
The T2-VBM methodology is described in detail in (Diaz-de-Grenu et al., 2011) and a brief description is provided as supplementary material. The steps required by VBIS are described in (Abbott et al., 2009) and the pipeline is illustrated in Fig. 1. The VBIS approach uses two iterations to find an optimum scaling value for the T2-weighted data, and a third one to perform the final voxel-wise analysis (Fig.1).
This study aimed to test the superiority proposed by Abbott et al. (2011) of their Voxel based iterative sensitivity (VBIS) method over Voxel Based Morphometry using T2-weighted images (T2-VBM), in detecting intensity changes in Alzheimer's disease (AD). A comparison was made first in simulated intensity lesions and then in AD patients. Intensity changes were evaluated in the whole-brain with VBIS and with a simple intensity-based approach and in specific tissue classes with the conventional VBM method of using tissue probability segments. Results showed that VBIS performed well in the simulated environment though it showed no superiority in detecting the lesion compared to the much simpler VBM approach. The VBIS method, however, failed to detect any meaningful signal intensity reduction in AD patient data. Moreover, its whole brain approach was contaminated by the excess cerebrospinal fluid signal (very bright on T2-weighted scans) in areas of maximal measurable atrophy (mesial temporal lobes); this gave rise to spurious signal intensity increases in these regions in AD. The same artefact was observed for both intensity-based methods but not with the conventional VBM approach of performing statistics on grey matter segments. In conclusion, no evidence was found to indicate that VBIS offers benefits over T2-VBM in AD, nor in simulation intensity lesions. The study highlights the necessity of empirically testing voxel-based analysis techniques rather than merely claiming superiority of one method over another on theoretical grounds.
Selecting appropriate voxel-based methods for neuroimaging studies
2012, NeuroImage
We highlight a fundamental difference between voxel-based methods that interrogate signal intensity directly and those that interrogate morphometric features; we discuss how signal intensity changes might erroneously affect morphometric measures, and we provide some guidance for selection of appropriate methods to address particular hyphotheses. Our discussion is motivated by a recent application of voxel-based morphometry methods to T2-weighted images (T2-Voxel Based Morphometry; T2-VBM). In this context we discuss alternative approaches including Voxel-Based T2-Relaxometry (VBR) and Voxel Based Iterative Sensitivity analysis of T2-Weighted Images (VBIS-T2).
Automated quantitative FLAIR analysis in hippocampal sclerosis
2011, Epilepsy Research
To describe and evaluate a novel MRI post-processing technique for automated quantitative hippocampal FLAIR analysis in patients with hippocampal sclerosis (HS).
Based on a method for FLAIR analysis presented by Focke et al. (2009), T1 and coregistered FLAIR scans of individual subjects were processed together in SPM5 to conduct both a spatial and an intensity normalization of the FLAIR scans. In a further development described here, the resulting normalized FLAIR images were thresholded and weighted by a probabilistic hippocampal mask to determine the average FLAIR intensities of left and right hippocampus. The method was applied to the MRI data of 103 HS patients and 131 controls. Using a 95% confidence region calculated from the FLAIR intensities of controls as threshold, the performance in discriminating both groups was assessed.
One hundred of 103 patients and among those all 23 patients with histologically confirmed HS fell outside the 95% confidence region, amounting to 97.1% sensitivity. All but 6 controls (=95.4%) were found within the confidence region, corresponding to the expected specificity. The method could also distinguish bilateral HS and visualize signal changes after status epilepticus.
Automated FLAIR analysis is a promising tool to quantify hippocampal signal alterations, to support the detection of HS, and to monitor the temporal evolution of the disease.
Current themes in neuroimaging of epilepsy: Brain networks, dynamic phenomena, and clinical relevance
2010, Clinical Neurophysiology
Citation Excerpt :
Alternatives to VBM include tensor-based morphometry (Chung et al., 2001) in which subjects are compared in terms of a very detailed warping needed to match each brain to a template (much more detailed than VBM warping), used widely in dementia research (e.g. Hua et al., 2008); and cortical thickness mapping, in which grey matter thickness is compared across the brain surface. A technique related to VBM, voxel-based relaxometry (VBR), compares T2 signal between subjects (Abbott et al., 2009). Similar voxel-based analyses may be applied to almost any imaging modality.
Brain scanning methods were first applied in patients with epilepsy more than 30 years ago. A very substantial literature now exists in this field, which is exponentially increasing. Contemporary neuroimaging studies in epilepsy reflect new concepts in the epilepsies, as well as current methodological developments. In particular, this area is emphasising the role of networks in epileptogenicity, the existence of dynamic phenomena which can be captured by imaging, and is beginning to validate the implementation of neuroimaging in the clinic. Here, recent studies of the last 5 years are reviewed, covering the full range of neuroimaging methods with SPECT, PET and MRI in epilepsy.

View all citing articles on Scopus

View full text

Technical NoteVoxel-Based Iterative Sensitivity (VBIS) analysis: Methods and a validation of intensity scaling for T2-weighted imaging of hippocampal sclerosis

Abstract

Introduction

Section snippets

Subjects

Determining the sensitivity of the alternative analysis approaches in healthy controls

Discussion

Conclusions

Acknowledgments

NeuroImage

NeuroImage

NeuroImage

NeuroImage

iBrain — software for analysis and visualisation of functional MR images

NeuroImage

Technical Note
Voxel-Based Iterative Sensitivity (VBIS) analysis: Methods and a validation of intensity scaling for T2-weighted imaging of hippocampal sclerosis