Voxel-based Relaxometry Research Articles

Voxel-based analysis in neuroferritinopathy expands the phenotype and determines radiological correlates of disease severity

Neuroferritinopathy is an autosomal dominant adult-onset movement disorder which occurs due to mutations in the ferritin light chain gene (FTL). Extensive iron deposition and cavitation are observed post-mortem in the basal ganglia, but whether more widespread pathological changes occur, and whether they correlate with disease severity is unknown. 3D-T1w and quantitative T2 whole brain MRI scans were performed in 10 clinically symptomatic patients with the 460InsA FTL mutation and 10 age-matched controls. Voxel-based morphometry (VBM) and voxel-based relaxometry (VBR) were subsequently performed. Clinical assessment using the Unified Dystonia Rating Scale (UDRS) and Unified Huntington's Disease Rating Scale (UHDRS) was undertaken in all patients. VBM detected significant tissue changes within the substantia nigra, midbrain and dentate together with significant cerebellar atrophy in patients (FWE, p < 0.05). Iron deposition in the caudate head and cavitation in the lateral globus pallidus correlated with UDRS score (p < 0.001). There were no differences between groups with VBR. Our data show that progressive iron accumulation in the caudate nucleus, and cavitation of the globus pallidus correlate with disease severity in neuroferritinopathy. We also confirm sub-clinical cerebellar atrophy as a feature of the disease. We suggest that VBM is an effective technique to detect regions of iron deposition and cavitation, with potential wider utility to determine radiological markers of disease severity for all NBIA disorders.

Voxel-based relaxometry across the human lifespan

Voxel-based relaxometry across the human lifespan

Voxel-based Relaxometry of transverse relaxation rate with gradient echo R2(*) in patients with multiple system atrophy.

To explore the transverse relaxation rate with gradient echo R2(*) changes in patients with Parkinsonian variant of multiple system atrophy (MSA-P) with a voxel-based analysis of R2(*) map. Whole brain structural images and multi-echo T2(*) weighted image were acquired in 27 patients with probable MSA-P and 24 healthy individuals. R2(*) maps of the MSA-P were compared with the controls by voxel-based methods. Compared with the controls, MSA-P patients showed significant R2(*) decrease bilaterally in brain stem, cerebellar hemispheres, insular lobe, temporal lobes, caudate nucleus, and corpus callosum (P<0.005). R2(*) can reveal the significant brain involvements of MSA-P. The introduction of gradient echo may increase the sensitivity, although the susceptible artifact may interfere the detection efficiency of R2(*).

Voxel-based relaxometry for cases of an unresolved epilepsy diagnosis

Voxel-based relaxometry (VBR) is a technique in which a voxel-level statistical comparison of quantitative MR T2 maps is performed to identify regions with significantly elevated T2 relaxation time. Our objective was to assess the performance of single-subject VBR at 3T as a diagnostic tool for patients whose diagnosis of epilepsy or seizure focus location is uncertain. Fifty-nine patients with possible epilepsy or known epilepsy, but an unknown focus and forty-five healthy controls were studied. All subjects were scanned at 3T using a Carr-Purcell-Meiboom-Gill MR sequence. Single-subject VBR was performed at a significance level of α=0.001. Patients were classified based on whether the diagnosis of epilepsy was in question and whether there was a suspected focus. A VBR score was determined based on the presence of VBR abnormalities in any of 13 predefined regions per hemisphere. All patients exhibited significantly more median VBR abnormalities than controls (p<0.05). VBR abnormalities were seen in 69% and 89% of patients with a normal or questionably abnormal MR scan, respectively. Nineteen of the 27 patients with a suspected focus (70%) had VBR abnormalities in the suspected focus, with additional regions of involvement being elucidated. VBR also correctly predicted the seizure focus in 50% of patients whose seizure foci were confirmed based on follow-up history or clinical investigations. Single subject VBR can help identify potential seizure foci in patients whose seizure foci are uncertain.

Algebraic T2 estimation improves detection of right temporal lobe epilepsy by MR T2 relaxometry

Seizure related abnormalities may be detected with T2 relaxometry, which involves quantitative estimation of T2 values. Accounting for the partial-volume effect of cerebrospinal fluid (CSF) is important, especially for voxel-based relaxometry, VBR. With a mono-exponential decay model, this can be accomplished by including a baseline constant. An algebraic calculation, which accommodates this constant, offers improved T2 estimation speed over the commonly used non-linear fitting approach. Our objective was to compare the algebraic approach against three fitting approaches for the detection of seizure related abnormalities. We tested the performance of the four methods in the presence of noise using simulated data as well as real data acquired at 3 T with a Carr-Purcell-Meiboom-Gill sequence from 45 healthy subjects and 24 patients with confirmed right temporal lobe epilepsy. A quantitative analysis was performed on spatially normalized data by measuring T2 in various regions and with a whole brain tissue segmentation analysis. The detection rate of hippocampal T2 changes in patients was assessed by comparing the regional T2 measurements from each patient against the control data with a z-score threshold of 2.33. The algebraic method yielded high sensitivity for detection of hippocampal abnormalities in the epileptic patients in regional assessment and in follow-up single-subject VBR. This can be attributed to the relatively small variance across healthy subjects and improved precision in the presence of CSF and noise in simulation. In conclusion, the algebraic method is better than fitting based on faster calculation speed and better sensitivity for detecting seizure-related T2 changes.

Hippocampal T2 abnormalities in healthy adults

We compared hippocampal abnormalities in 42 healthy adults identified by voxel-based relaxometry (VBR) and by visual inspection. Hippocampal abnormalities were seen in 8 (19.0%) and 10 (23.8%) of subjects by VBR and visual inspection, respectively (p>0.05). Notably, 50% of the abnormalities seen by visual inspection were likely false positive. This suggests that VBR is a more specific measure and should be considered in subjects with questionable hippocampal abnormalities.

Age effects on voxel-based relaxometry used for epileptic patients

T2 voxel-based relaxometry (VBR) is a technique that allows for a quantitative, unbiased analysis of T2 relaxation time across the whole brain. Previous studies have shown that this technique is effective for clinical analysis of single patients; however, the effects of age normal age-related changes on these data were unknown. Our study was therefore designed to assess the effect of normal aging on VBR data. A linear regression with age as a predictor of T2 was run in both a (1) whole-brain voxel-based manner to determine regions which showed significant age-related change and subsequently (2) on a selection of regions-of-interest to allow for a more detailed analysis of the trends. T2 estimates showed a significant increase with age in the frontal lobe white matter and a significant decrease with age in the putamen with region-of-interest and voxel-based regressions (p<0.05). There was also a general trend for T2 to decrease in inferior temporal lobe grey matter in the voxel-based regression. Age causes changes in T2 relaxation time in healthy control subjects, with increases being observed in frontal lobe white matter and decreases in the putamen. These changes should be accounted for when interpreting single subject VBR data.

Voxel‐Based Morphometry and Voxel‐Based Relaxometry in Parkinsonian Variant of Multiple System Atrophy

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder divided into a parkinsonian (MSA-P) and a cerebellar variant. The purpose of this study was to assess regional brain atrophy and iron content using Voxel-based morphometry (VBM) and Voxel-based relaxometry (VBR) respectively, in MSA-P. Using biological parametric mapping the effect of brain atrophy was evaluated in T2 relaxation time (T2) measurements by applying analysis of covariance (ANCOVA) and correlation analysis to the VBM and VBR data. Eleven patients with MSA-P (aged 61.9 +/- 11.7 years, disease duration 5.42 +/- 2.5 years) and 11 controls were studied. In comparison to the controls the patients showed decreased gray matter in the putamen, the caudate nuclei, the thalami, the anterior cerebellar lobes, and the cerebral cortex, and white matter atrophy in the pons, midbrain, and peduncles. VBR analysis showed prolonged T2 in various cortical regions. On ANCOVA, when controlling for gray and white matter volume, these regions of prolonged T2 were shrunk. Negative correlation was demonstrated between T2 and gray and white matter volume. Diffuse brain atrophy, mainly in the motor circuitry is observed in MSA-P. Normalization for atrophy should always be performed in T2 measurements.

Harsh corporal punishment is associated with increased T2 relaxation time in dopamine-rich regions

Harsh corporal punishment (HCP) was defined as frequent parental administration of corporal punishment (CP) for discipline, with occasional use of objects such as straps, or paddles. CP is linked to increased risk for depression and substance abuse. We examine whether long-term exposure to HCP acts as sub-traumatic stressor that contributes to brain alterations, particularly in dopaminergic pathways, which may mediate their increased vulnerability to drug and alcohol abuse. Nineteen young adults who experienced early HCP but no other forms of maltreatment and twenty-three comparable controls were studied. T2 relaxation time (T2-RT) measurements were performed with an echo planar imaging TE stepping technique and T2 maps were calculated and analyzed voxel-by-voxel to locate regional T2-RT differences between groups. Previous studies indicated that T2-RT provides an indirect index of resting cerebral blood volume. Region of interest (ROI) analyses were also conducted in caudate, putamen, nucleus accumbens, anterior cingulate cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus and cerebellar hemispheres. Voxel-based relaxometry showed that HCP was associated with increased T2-RT in right caudate and putamen. ROI analyses also revealed increased T2-RT in dorsolateral prefrontal cortex, substantia nigra, thalamus and accumbens but not globus pallidus or cerebellum. There were significant associations between T2-RT measures in dopamine target regions and use of drugs and alcohol, and memory performance. Alteration in the paramagnetic or hemodynamic properties of dopaminergic cell body and projection regions were observed in subjects with HCP, and these findings may relate to their increased risk for drug and alcohol abuse.

Age-related Iron Deposition in the Basal Ganglia: Quantitative Analysis in Healthy Subjects

To determine the values of iron accumulation in the basal ganglia of healthy volunteers of different ages with R2* and raw signal intensity measurements from T1-weighted magnetic resonance (MR) images, supported by voxel-based relaxometry (VBR), and to compare them with previously reported iron concentrations found in autopsy material. The ethics committee approved the study, and the participants or their parents gave written informed consent. Eighty subjects (41 female and 39 male subjects; age range, 1-80 years) were examined at 1.5 T. For each subject, R2* values were calculated. Curves for R2* versus age were obtained for globus pallidus (GP), putamen, caudate nucleus, substantia nigra (SN), and frontal white matter (FWM). To highlight possible differences in iron concentration among the age decades, VBR was applied. Signal intensity values were estimated on T1-weighted fast low-angle shot images, and regions of interest were drawn in each nucleus. R2* values were also compared with iron concentrations reported in a postmortem study. Statistical analysis was performed (t test), and a difference with P < .05 (FDR corrected) was significant. The curves for R2* versus age showed an exponential increase with increasing age in all the basal ganglia. VBR demonstrated significant differences (P < .05, corrected) in the comparison between the 2nd and the following decades for lenticular nuclei. Good correlation coefficients were found for GP (R(2) = 0.64), putamen (R(2) = 0.51), and SN (R(2) = 0.53) when compared with findings in the postmortem study. Signal intensity curves were similar to the R2* curves. R2* measurements can be used to quantify brain iron accumulation and thus may allow better evaluation of neurodegenerative diseases associated with iron deposition.

Single-subject voxel-based relaxometry for clinical assessment of temporal lobe epilepsy

T2 relaxometry, quantitative assessment of T2 relaxation time in magnetic resonance (MR) data, typically uses manually drawn regions of interest (ROIs). This approach is limited by its subjectivity and its restricted scope of investigation. A recently developed approach called voxel-based relaxometry (VBR) provides an unbiased statistical analysis of the whole brain. Our objective was to assess the clinical utility of single-subject VBR for patients with temporal lobe epilepsy (TLE). Forty-five patients with TLE confirmed by history, EEG, and structural MRI and 25 control subjects were scanned at 3T using a modified Carr-Purcell-Meiboom-Gill MR sequence. ROIs were drawn for each patient and control subject, and measurements were made on unregistered T2 maps. VBR was performed on a single-subject basis at a significance level of alpha=0.05. Patients were grouped according to seizure focus (left mesial, right mesial, other), and whether structural MR imaging was normal or abnormal. Up to 85% of patients in the temporal lobe groups demonstrated T2 abnormalities. VBR detected abnormalities either in equal numbers or in more patients (up to 23% more) than ROI analysis for each group. The number of detected abnormalities per patient was higher using VBR (3.38 versus 2.04, p<0.05). VBR also identified abnormalities that were missed by ROI analysis. The rate of VBR detection of abnormalities was higher for patients than controls (76% versus 36%). VBR can be performed on single subjects with TLE and it detects considerably more abnormalities than ROI analysis. VBR may be a clinically useful tool for the detection of T2 abnormalities at the seizure focus and sites remote from it.

In vivo voxel-based relaxometry in amyotrophic lateral sclerosis

We applied voxel-based relaxometry (VBR) in 12 ALS patients and 12 matched healthy controls and compared the results with those of voxel-based morphometry (VBM). VBR revealed a reduced relaxation rate in the right precentral gyrus and ventral pons. Individual region of interest (ROI)-based analysis of R2 maps confirmed our VBR results. VBM depicted a reduction of white matter in the paracentral lobules and in the right middle cerebellar peduncle. Our data suggests that VBR and ROI analysis of R2 maps may have a higher sensitivity in detecting local tissue atrophy in the motor cortex and along the corticospinal tract than VBM. Larger prospective studies are necessary to evaluate the usefulness and relevance of VBR and ROI-based analysis of R2 maps in clinical practice.

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

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.

Voxel-based morphometry and voxel-based relaxometry in multiple system atrophy – A comparison between clinical subtypes and correlations with clinical parameters

Multiple system atrophy (MSA) is a neurodegenerative disease affecting basal ganglia, brainstem, cerebellum, and intermediolateral cell columns of the spinal cord. Clinically, a cerebellar (MSA-C) and a parkinsonian variant of MSA (MSA-P) are distinguished. We used voxel-based morphometry (VBM) and voxel-based relaxometry (VBR) in 48 MSA patients (32 MSA-C, 16 MSA-P) and 46 controls. In MSA-C, VBM revealed gray matter loss in cerebellum, right thalamus, both putamina and several cortical regions including insular cortex. Gray matter loss in the cerebellum and insular cortex was correlated with disease duration and severity. There was white matter loss in the brainstem, which was correlated with disease duration and severity. VBR analysis in MSA-C showed decreased relaxation rate R2 in cerebellum, pontine brainstem and cortical regions including insular cortex. In MSA-P, gray matter was reduced in cerebellum, dorsal midbrain, both putamina, and several cortical regions including insular cortex. A correlation with disease duration and severity was detected only for some small cortical areas. Direct comparison of MSA-C and MSA-P showed differences only in infratentorial brain regions where structural abnormalities were more pronounced in MSA-C than in MSA-P. In MSA-C, there was a stronger reduction of gray matter in the basal parts of the cerebellum, of white matter in the brainstem and of the relaxation rate R2 in the cerebellum and brainstem.

Composite voxel-based analysis of volume and T2 relaxometry in temporal lobe epilepsy

Voxel-based analyses of tissue characteristics such as volume and T2 are usually carried out in isolation. However, as the images are analysed in a common voxel-based framework, it is possible to directly assess the spatial relationships of abnormalities detected by each technique. We utilize this approach in well-characterized patients with unilateral temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS). TLE is associated with potentially widespread volume and T2 signal abnormalities in MRI images but the relationship between these two aspects of tissue abnormality is not well understood. Here we use a novel approach of combined univariate and multivariate voxel-wise analysis to investigate the spatial relationship of these abnormalities. We studied 19 TLE patients and compared them to 115 control subjects. Grey matter (GM) and white matter (WM) volume changes were assessed with voxel-based morphometry (VBM), and changes in T2 relaxation times were evaluated with voxel-based relaxometry (VBR). The volume and T2 changes obtained using the combined univariate approach were found in an extensive area, prominently in the ipsilateral hippocampus and amygdala (overlap of GM–VBM and VBR), and in the remaining temporal lobe (overlap of WM–VBR and VBR). Other cortical and subcortical areas showed isolated volume or T2 changes. The multivariate analysis based on the Hotelling T2 statistic, indicated a similar pattern of distributed changes across the brain but with a greater degree of statistical significance in certain areas. The composite analyses appear to identify a network of affected areas not as easily appreciated by the individual analysis of volume or T2 changes.

Voxel-based morphometry and voxel-based relaxometry in multiple system atrophy—A comparison between clinical subtypes and correlations with clinical parameters

Multiple system atrophy (MSA) is a neurodegenerative disease affecting basal ganglia, brainstem, cerebellum, and intermediolateral cell columns of the spinal cord. Clinically, a cerebellar (MSA-C) and a parkinsonian variant of MSA (MSA-P) are distinguished. We used voxel-based morphometry (VBM) and voxel-based relaxometry (VBR) in 48 MSA patients (32 MSA-C, 16 MSA-P) and 46 controls. In MSA-C, VBM revealed gray matter loss in cerebellum, right thalamus, both putamina and several cortical regions including insular cortex. Gray matter loss in the cerebellum and insular cortex was correlated with disease duration and severity. There was white matter loss in the brainstem, which was correlated with disease duration and severity. VBR analysis in MSA-C showed decreased relaxation rate R2 in cerebellum, pontine brainstem and cortical regions including insular cortex. In MSA-P, gray matter was reduced in cerebellum, dorsal midbrain, both putamina, and several cortical regions including insular cortex. A correlation with disease duration and severity was detected only for some small cortical areas. Direct comparison of MSA-C and MSA-P showed differences only in infratentorial brain regions where structural abnormalities were more pronounced in MSA-C than in MSA-P. In MSA-C, there was a stronger reduction of gray matter in the basal parts of the cerebellum, of white matter in the brainstem and of the relaxation rate R2 in the cerebellum and brainstem.

White matter abnormalities in autism detected through transverse relaxation time imaging

While neuroimaging studies have reported neurobiological abnormalities in autism, the underlying tissue abnormalities remain unclear. Quantitative transverse relaxation time (T2) imaging permits the examination of tissue abnormalities in vivo, with increased T2 largely reflecting increased tissue water. Blood flow and the presence of tissue iron may also affect T2. In this study, we used voxel-based relaxometry of the cerebrum and global averages to examine T2 abnormalities in autism. Nineteen males with autism (age: 9.2 ± 3.0 years) and 20 male controls (age: 10.7 ± 2.9 years) underwent magnetic resonance imaging at 3.0 T. Quantitative T2 maps, generated through gradient echo sampling of the free induction decay and echo, were segmented into gray matter, white matter, and cerebrospinal fluid. Average cerebral gray and white matter T2 were determined and compared between groups. To assess localized T2 differences, the quantitative T2 maps were warped to a template created for this study, smoothed, and compared using statistical parametric mapping. Patients with autism had an increase in average cerebral white matter T2, although no group differences were seen in average cerebral gray matter T2. Patients with autism also had bilateral regional T2 increases in the gray matter and associated white matter of the parietal lobes (primary sensory association areas) and occipital lobes (visual association areas) and in the white matter within the supplementary motor areas in the frontal lobes. The regional and global elevations in white matter T2 suggest abnormalities of white matter tissue water content in autism, which may represent a neurobiological basis for the aberrant cortical connectivity hypothesized to underlie the disorder.

Voxel-based analysis of multiple-system atrophy of cerebellar type: complementary results by combining voxel-based morphometry and voxel-based relaxometry

Voxel-based relaxometry (VBR) is a novel morphometric method that analyses the relaxation rate R2 derived from multi-echo T2-weighted images on a voxel-by-voxel basis. We used VBR to study the brain morphology of 14 patients suffering from multiple-system atrophy of cerebellar type (MSA-C) and compared the results with those obtained by voxel-based morphometry (VBM) of T1-weighted images. VBR analysis revealed reduction of relaxation rate R2 in the cerebellum and brainstem reflecting infratentorial brain atrophy. The affected regions largely corresponded to those regions in which VBM showed reductions of grey and white matter. In addition, R2 was increased in the putamen, a region in which VBM did not show abnormalities. Our data show that the combination of VBR and VBM provided convergent and complimentary information about the brain morphology of MSA-C.

Voxel-based relaxometry: a new approach for analysis of T2 relaxometry changes in epilepsy

The measurement of the T2 relaxation time (T2 relaxometry) had been established as a reliable tool for the assessment of certain conditions such as temporal lobe epilepsy. The standard procedure for analysis of T2 data uses manually drawn regions of interest (ROIs). This approach is limited by its subjective nature and its restricted scope of investigation within selected regions of the brain. In this study, we introduce a voxel-based analysis approach termed voxel-based relaxometry (VBR). Tissue signal changes were assessed in 19 patients with hippocampal sclerosis (HS) and in 38 healthy controls using (i) conventional ROI-based analysis with several bilateral ROIs and also (ii) the VBR method in which the T2 maps are warped to a stereotactic space, smoothed and statistically compared. Conventional ROI analysis identified the expected T2 increase in the sclerotic hippocampus in all HS patients. Furthermore, 13 of the 19 patients displayed a T2 increase in at least one of the other ROIs. The VBR analysis showed a similar pattern of statistically significant areas of increased T2 within the sclerotic hippocampus. In addition, extrahippocampal areas of increased T2 were apparent including the anterior temporal lobe white matter and the parahippocampal gyrus. The results of the VBR analysis are in agreement with the conventional ROI analysis. The VBR analysis has the advantage of providing an even-handed assessment of T2 differences through the brain. We recommend VBR as an alternative means of relaxometry data analysis that provides an objective assessment of differences between subjects.