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1.  Altered brain morphometry in carpal tunnel syndrome is associated with median nerve pathology☆☆☆ 
NeuroImage : Clinical  2013;2:313-319.
Objective
Carpal tunnel syndrome (CTS) is a common median nerve entrapment neuropathy characterized by pain, paresthesias, diminished peripheral nerve conduction velocity (NCV) and maladaptive functional brain neuroplasticity. We evaluated structural reorganization in brain gray matter (GM) and white matter (WM) and whether such plasticity is linked to altered median nerve function in CTS.
Methods
We performed NCV testing, T1-weighted structural MRI, and diffusion tensor imaging (DTI) in 28 CTS and 28 age-matched healthy controls (HC). Voxel-based morphometry (VBM) contrasted regional GM volume for CTS versus HC. Significant clusters were correlated with clinical metrics and served as seeds to define associated WM tracts using DTI data and probabilistic tractography. Within these WM tracts, fractional anisotropy (FA), axial (AD) and radial (RD) diffusivity were evaluated for group differences and correlations with clinical metrics.
Results
For CTS subjects, GM volume was significantly reduced in contralesional S1 (hand-area), pulvinar and frontal pole. GM volume in contralesional S1 correlated with median NCV. NCV was also correlated with RD and was negatively correlated with FA within U-fiber cortico-cortical association tracts identified from the contralesional S1 VBM seed.
Conclusions
Our study identified clear morphometric changes in the CTS brain. This central morphometric change is likely secondary to peripheral nerve pathology and altered somatosensory afference. Enhanced axonal coherence and myelination within cortico-cortical tracts connecting primary somatosensory and motor areas may accompany peripheral nerve deafferentation. As structural plasticity was correlated with NCV and not symptomatology, the former may be a better determinant of appropriate clinical intervention for CTS, including surgery.
Highlights
► CTS demonstrated reduced GM volume in S1, pulvinar, and frontal pole. ► GM volume in S1 was significantly correlated with median nerve conduction velocity. ► Median nerve velocity was linked to WM microstructure in tracts connected to S1.
doi:10.1016/j.nicl.2013.02.001
PMCID: PMC3689649  PMID: 23799199
CTS, carpal tunnel syndrome; NCV, nerve conduction velocity; GM, gray matter; WM, white matter; DTI, diffusion tensor imaging; VBM, voxel-based morphometry; FA, fractional anisotropy; AD, axial diffusivity; RD, radial diffusivity; S1, primary somatosensory cortex; M1, primary motor cortex; Nerve conduction velocity (NCV); Diffusion tensor imaging (DTI); Voxel-based morphometry (VBM); Fractional anisotropy (FA); Axial diffusivity (AD); Radial diffusivity (RD)
2.  Altered brain morphometry in carpal tunnel syndrome is associated with median nerve pathology 
NeuroImage : clinical  2013;2:313-319.
Objective
Carpal tunnel syndrome (CTS) is a common median nerve entrapment neuropathy characterized by pain, paresthesias, diminished peripheral nerve conduction velocity (NCV) and maladaptive functional brain neuroplasticity. We evaluated structural reorganization in brain gray (GM) and white (WM) matter and whether such plasticity is linked to altered median nerve function in CTS.
Methods
We performed NCV testing, T1-weighted structural MRI, and diffusion tensor imaging (DTI) in 28 CTS and 28 age-matched healthy controls (HC). Voxel-based morphometry (VBM) contrasted regional GM volume for CTS versus HC. Significant clusters were correlated with clinical metrics and served as seeds to define associated WM tracts using DTI data and probabilistic tractography. Within these WM tracts, fractional anisotropy (FA), axial (AD) and radial (RD) diffusivity were evaluated for group differences and correlations with clinical metrics.
Results
For CTS subjects, GM volume was significantly reduced in contralesional S1 (hand-area), pulvinar and frontal pole. GM volume in contralesional S1 correlated with median NCV. NCV was also correlated with RD and was negatively correlated with FA within U-fiber cortico-cortical association tracts identified from the contralesional S1 VBM seed.
Conclusions
Our study identified clear morphometric changes in the CTS brain. This central morphometric change is likely secondary to peripheral nerve pathology and altered somatosensory afference. Enhanced axonal coherence and myelination within cortico-cortical tracts connecting primary somatosensory and motor areas may accompany peripheral nerve deafferentation. As structural plasticity was correlated with NCV and not symptomatology, the former may be a better determinant of appropriate clinical intervention for CTS, including surgery.
doi:10.1016/j.nicl.2013.02.001
PMCID: PMC3689649  PMID: 23799199
nerve conduction velocity (NCV); diffusion tensor imaging (DTI); voxel-based morphometry (VBM); fractional anisotropy (FA); axial diffusivity (AD); radial diffusivity (RD)
3.  Extrahippocampal gray matter loss and hippocampal deafferentation in patients with temporal lobe epilepsy 
Epilepsia  2010;51(4):519-528.
Summary
Purpose
Medial temporal epilepsy (MTLE) is associated with extrahippocampal brain atrophy. The mechanisms underlying brain damage in MTLE are unknown. Seizures may lead to neuronal damage, but another possible explanation is deafferentation from loss of hippocampal connections. This study aimed to investigate the relationship between hippocampal deafferentation and brain atrophy in MTLE.
Methods
Three different MRI studies were performed involving 23 patients with unilateral MTLE (8 left and 15 right) and 34 healthy controls: (1) voxel-based morphometry (VBM), (2) diffusion tensor imaging (DTI) and (3) probabilistic tractography (PT). VBM was employed to define differences in regional gray matter volume (GMV) between controls and patients. Voxel-wise analyses of DTI evaluated differences in fractional anisotropy (FA), mean diffusivity (MD) and hippocampal PT. Z-scores were computed for regions-of-interest (ROI) GMV and perihippocampal FA and MD (to quantify hippocampal fiber integrity). The relationship between hippocampal deafferentation and regional GMV was investigated through the association between ROI Z scores and hippocampal fiber integrity.
Results
Patients with MTLE exhibited a significant reduction in GMV and FA in perihippocampal and limbic areas. There was a decrease in hippocampal PT in patients with MTLE in limbic areas. A significant relationship between loss of hippocampal connections and regional GMV atrophy was found involving the putamen, pallidum, middle and inferior temporal areas, amygdala and ceberellar hemisphere.
Discussion
There is a relationship between hippocampal disconnection and regional brain atrophy in MTLE. These results indicate that hippocampal deafferentation plays a contributory role in extrahippocampal brain damage in MTLE.
doi:10.1111/j.1528-1167.2009.02506.x
PMCID: PMC2855766  PMID: 20163442
Temporal lobe epilepsy; Atrophy; Neural network; Magnetic resonance imaging
4.  Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy 
Neurology  2011;76(1):34-40.
Objective:
The aim of this study was to determine if there were focal cortical abnormalities in juvenile myoclonic epilepsy (JME) using neuropsychological investigations and MRI.
Methods:
Twenty-eight patients with JME and a large sample of healthy controls were assessed using a series of neuropsychological tests as well as structural and diffusion tensor MRI (DTI). DTI measures assessed fractional anisotropy (FA) within a white matter skeleton.
Results:
Neuropsychological testing indicated subtle dysfunctions in verbal fluency, comprehension, and expression, as well as nonverbal memory and mental flexibility. Utilizing whole-brain voxel-based morphometry for gray matter MRI data and tract-based spatial statistics for white matter diffusion MRI data, we found reductions in gray matter volume (GMV) in the supplementary motor area and posterior cingulate cortex and reductions in FA in underlying white matter of the corpus callosum. Supplementary motor area FA predicted scores in word naming tasks and expression scores. Posterior cingulate cortex GMV and FA predicted cognitive inhibition scores on the mental flexibility task.
Conclusions:
The neuropsychological, structural, and tractography results implicate mesial frontal cortex, especially the supplementary motor area, and posterior cingulate cortex in JME.
doi:10.1212/WNL.0b013e318203e93d
PMCID: PMC3030222  PMID: 21205693
5.  COGNITIVE PROCESSING SPEED AND THE STRUCTURE OF WHITE MATTER PATHWAYS: CONVERGENT EVIDENCE FROM NORMAL VARIATION AND LESION STUDIES 
NeuroImage  2008;42(2):1032-1044.
We investigated the relation between cognitive processing speed and structural properties of white matter pathways via convergent imaging studies in healthy and brain-injured groups. Voxel-based morphometry (VBM) was applied to diffusion tensor imaging data from thirty-nine young healthy subjects in order to investigate the relation between processing speed, as assessed with the Digit-Symbol subtest from WAIS-III, and fractional anisotropy, an index of microstructural organization of white matter. Digit-Symbol performance was positively correlated with fractional anisotropy of white matter in the parietal and temporal lobes bilaterally and in the left middle frontal gyrus. Fiber tractography indicated that these regions are consistent with the trajectories of the superior and inferior longitudinal fasciculi. In a second investigation, we assessed the effect of white matter damage on processing speed using voxel-based lesion symptom mapping (VLSM) analysis of data from seventy-two patients with left hemisphere strokes. Lesions in left parietal white matter, together with cortical lesions in supramarginal and angular gyri were associated with impaired performance. These findings suggest that cognitive processing speed, as assessed by the Digit-Symbol test, is closely related to the structural integrity of white matter tracts associated with parietal and temporal cortices and left middle frontal gyrus. Further, fiber tractography applied to VBM results and the patient findings suggest that the superior longitudinal fasciculus, a major tract subserving fronto-parietal integration, makes a prominent contribution to processing speed.
doi:10.1016/j.neuroimage.2008.03.057
PMCID: PMC2630965  PMID: 18602840
Cognitive processing speed; diffusion tensor imaging; individual differences; magnetic resonance imaging; neural pathways; neuropsychology
6.  Atrophy of spared grey matter tissue predicts poorer motor recovery and rehabilitation response in chronic stroke 
Background and Purpose
Although the motor deficit following stroke is clearly due to the structural brain damage that has been sustained, this relationship is attenuated from the acute to chronic phases. We investigated the possibility that motor impairment and response to Constraint-Induced Movement therapy (CI therapy) in chronic stroke patients may relate more strongly to the structural integrity of brain structures remote from the lesion than to measures of overt tissue damage.
Methods
Voxel-based morphometry (VBM) analysis was performed on MRI scans from 80 chronic stroke patients to investigate whether variations in grey matter density were correlated with extent of residual motor impairment or with CI therapy-induced motor recovery.
Results
Decreased grey matter density in non-infarcted motor regions was significantly correlated with magnitude of residual motor deficit. In addition, reduced grey matter density in multiple remote brain regions predicted a lesser extent of motor improvement from CI therapy.
Conclusions
Atrophy in seemingly healthy parts of the brain that are distant from the infarct accounts for at least a portion of the sustained motor deficit in chronic stroke.
doi:10.1161/STROKEAHA.111.633255
PMCID: PMC3265680  PMID: 22096036
Stroke; rehabilitation; grey matter; morphometry; CI therapy; motor; lesion
7.  Structural brain abnormalities in cervical dystonia 
BMC Neuroscience  2013;14:123.
Background
Idiopathic cervical dystonia is characterized by involuntary spasms, tremors or jerks. It is not restricted to a disturbance in the basal ganglia system because non-conventional voxel-based MRI morphometry (VBM) and diffusion tensor imaging (DTI) have detected numerous regional changes in the brains of patients.
In this study scans of 24 patients with cervical dystonia and 24 age-and sex-matched controls were analysed using VBM, DTI and magnetization transfer imaging (MTI) using a voxel-based approach and a region-of-interest analysis. Results were correlated with UDRS, TWSTRS and disease duration.
Results
We found structural alterations in the basal ganglia; thalamus; motor cortex; premotor cortex; frontal, temporal and parietal cortices; visual system; cerebellum and brainstem of the patients with dystonia.
Conclusions
Cervical dystonia is a multisystem disease involving several networks such as the motor, sensory and visual systems.
doi:10.1186/1471-2202-14-123
PMCID: PMC3852757  PMID: 24131497
Visual system; Basal ganglia; Dorsolateral prefrontal cortex
8.  Microstructure Abnormalities in Adolescents with Internet Addiction Disorder 
PLoS ONE  2011;6(6):e20708.
Background
Recent studies suggest that internet addiction disorder (IAD) is associated with structural abnormalities in brain gray matter. However, few studies have investigated the effects of internet addiction on the microstructural integrity of major neuronal fiber pathways, and almost no studies have assessed the microstructural changes with the duration of internet addiction.
Methodology/Principal Findings
We investigated the morphology of the brain in adolescents with IAD (N = 18) using an optimized voxel-based morphometry (VBM) technique, and studied the white matter fractional anisotropy (FA) changes using the diffusion tensor imaging (DTI) method, linking these brain structural measures to the duration of IAD. We provided evidences demonstrating the multiple structural changes of the brain in IAD subjects. VBM results indicated the decreased gray matter volume in the bilateral dorsolateral prefrontal cortex (DLPFC), the supplementary motor area (SMA), the orbitofrontal cortex (OFC), the cerebellum and the left rostral ACC (rACC). DTI analysis revealed the enhanced FA value of the left posterior limb of the internal capsule (PLIC) and reduced FA value in the white matter within the right parahippocampal gyrus (PHG). Gray matter volumes of the DLPFC, rACC, SMA, and white matter FA changes of the PLIC were significantly correlated with the duration of internet addiction in the adolescents with IAD.
Conclusions
Our results suggested that long-term internet addiction would result in brain structural alterations, which probably contributed to chronic dysfunction in subjects with IAD. The current study may shed further light on the potential brain effects of IAD.
doi:10.1371/journal.pone.0020708
PMCID: PMC3108989  PMID: 21677775
9.  Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging 
Molecular Psychiatry  2010;15(8):823-830.
Neuroimaging studies have found evidence of altered brain structure and function in schizophrenia, but have had complex findings regarding the localization of abnormality. We applied multimodal imaging (voxel-based morphometry (VBM), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) combined with tractography) to 32 chronic schizophrenic patients and matched healthy controls. At a conservative threshold of P=0.01 corrected, structural and functional imaging revealed overlapping regions of abnormality in the medial frontal cortex. DTI found that white matter abnormality predominated in the anterior corpus callosum, and analysis of the anatomical connectivity of representative seed regions again implicated fibres projecting to the medial frontal cortex. There was also evidence of convergent abnormality in the dorsolateral prefrontal cortex, although here the laterality was less consistent across techniques. The medial frontal region identified by these three imaging techniques corresponds to the anterior midline node of the default mode network, a brain system which is believed to support internally directed thought, a state of watchfulness, and/or the maintenance of one's sense of self, and which is of considerable current interest in neuropsychiatric disorders.
doi:10.1038/mp.2009.146
PMCID: PMC2927029  PMID: 20065955
schizophrenia; voxel-based morphometry; fMRI; diffusion tensor imaging; default mode network; anterior cingulate cortex
10.  Voxel-based Morphometry of Brain MRI in Normal Aging and Alzheimer’s Disease 
Aging and Disease  2012;4(1):29-37.
Voxel-based morphometry (VBM) using structural brain MRI has been widely used for assessment of normal aging and Alzheimer’s disease (AD). VBM of MRI data comprises segmentation into gray matter, white matter, and cerebrospinal fluid partitions, anatomical standardization of all the images to the same stereotactic space using linear affine transformation and further non-linear warping, smoothing, and finally performing a statistical analysis. Two techniques for VBM are commonly used, optimized VBM using statistical parametric mapping (SPM) 2 or SPM5 with non-linear warping based on discrete cosine transforms and SPM8 plus non-linear warping based on diffeomorphic anatomical registration using exponentiated Lie algebra (DARTEL). In normal aging, most cortical regions prominently in frontal and insular areas have been reported to show age-related gray matter atrophy. In contrast, specific structures such as amygdala, hippocampus, and thalamus have been reported to be preserved in normal aging. On the other hand, VBM studies have demonstrated progression of atrophy mapping upstream to Braak’s stages of neurofibrillary tangle deposition in AD. The earliest atrophy takes place in medial temporal structures. Stand-alone VBM software using SPM8 plus DARTEL running on Windows has been newly developed as an adjunct to the clinical assessment of AD. This software provides a Z-score map as a consequence of comparison of a patient’s MRI with a normal database.
PMCID: PMC3570139  PMID: 23423504
Neuroradiology; MRI; voxel-based morphometry; aging; Alzheimer’s disease
11.  Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder 
Background
Previous magnetic resonance imaging (MRI) studies in young patients with bipolar disorder indicated the presence of grey matter concentration changes as well as microstructural alterations in white matter in various neocortical areas and the corpus callosum. Whether these structural changes are also present in elderly patients with bipolar disorder with long-lasting clinical evolution remains unclear.
Methods
We performed a prospective MRI study of consecutive elderly, euthymic patients with bipolar disorder and healthy, elderly controls. We conducted a voxel-based morphometry (VBM) analysis and a tract-based spatial statistics (TBSS) analysis to assess fractional anisotropy and longitudinal, radial and mean diffusivity derived by diffusion tensor imaging (DTI).
Results
We included 19 patients with bipolar disorder and 47 controls in our study. Fractional anisotropy was the most sensitive DTI marker and decreased significantly in the ventral part of the corpus callosum in patients with bipolar disorder. Longitudinal, radial and mean diffusivity showed no significant between-group differences. Grey matter concentration was reduced in patients with bipolar disorder in the right anterior insula, head of the caudate nucleus, nucleus accumbens, ventral putamen and frontal orbital cortex. Conversely, there was no grey matter concentration or fractional anisotropy increase in any brain region in patients with bipolar disorder compared with controls.
Limitations
The major limitation of our study is the small number of patients with bipolar disorder.
Conclusion
Our data document the concomitant presence of grey matter concentration decreases in the anterior limbic areas and the reduced fibre tract coherence in the corpus callosum of elderly patients with long-lasting bipolar disorder.
doi:10.1503/jpn.100140
PMCID: PMC3201993  PMID: 21284917
12.  Multi-parametric neuroimaging evaluation of cerebrotendinous xanthomatosis and its correlation with neuropsychological presentations 
BMC Neurology  2010;10:59.
Background
Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder. Recent studies show that brain damage in CTX patients extends beyond the abnormalities observed on conventional magnetic resonance imaging (MRI). We studied the MRI and 99 mTc-ethyl cysteinate dimer single photon emission computed tomography (SPECT) findings of CTX patients and made a correlation with the neuropsychological presentations.
Methods
Diffusion tensor imaging (DTI) and 3D T1-weighted images of five CTX patients were compared with 15 age-matched controls. Voxel-based morphometry (VBM) was use to delineate gray matter (GM) and white matter (WM) volume loss. Fractional anisotropy (FA), mean diffusivity (MD), and eigenvalues derived from DTI were used to detect WM changes and correlate with neuropsychological results. SPECT functional studies were used to correlate with GM changes.
Results
Cognitive results showed that aside from moderate mental retardation, the patient group performed worse in all cognitive domains. Despite the extensive GM atrophy pattern, the cerebellum, peri-Sylvian regions and parietal-occipital regions were correlated with SPECT results. WM atrophy located in the peri-dentate and left cerebral peduncle areas corresponded with changes in diffusion measures, while axial and radial diffusivity suggested both demyelinating and axonal changes. Changes in FA and MD were preceded by VBM in the corpus callosum and corona radiata. Cognitive results correlated with FA changes.
Conclusion
In CTX, GM atrophy affected the perfusion patterns. Changes in WM included atrophy, and axonal changes with demyelination. Disconnection of major fiber tracts among different cortical regions may contribute to cognitive impairment.
doi:10.1186/1471-2377-10-59
PMCID: PMC2909944  PMID: 20602799
13.  The development of corpus callosum microstructure and associations with bimanual task performance in healthy adolescents 
NeuroImage  2007;39(4):1918-1925.
Cross-sectional and longitudinal volumetric studies suggest that the corpus callosum (CC) continues to mature structurally from infancy to adulthood. Diffusion tensor imaging (DTI) provides in vivo information about the directional organization of white matter microstructure and shows potential for elucidating even more subtle brain changes during adolescent development. We used DTI to examine CC microstructure in healthy right-handed adolescents (n = 92, ages 9–23 years) and correlated the imaging data with motor task performance. The primary DTI variable was fractional anisotropy (FA), which reflects the degree of white matter’s directional organization. Participants completed an alternating finger tapping test to assess interhemispheric transfer and motor speed. Task performance was significantly correlated with age. Analyses of variance indicated that 9–11 year-olds generally performed worse than each of the older groups. Males outperformed females. Significant positive correlations between age and FA were observed in the splenium of the CC, which interconnects posterior cortical regions. Analyses of variance indicated that individuals older than 18 years had significantly higher FA than 9–11 year-olds. FA levels in the genu and splenium correlated significantly with task performance. Regression analyses indicated that bimanual coordination was significantly predicted by age, gender, and splenium FA. Decreases in alternating finger tapping time and increases in FA likely reflect increased myelination in the CC and more efficient neuronal signal transmission. These findings expand upon existing neuroimaging reports of CC development by showing associations between bimanual coordination and white matter microstructural organization in an adolescent sample.
doi:10.1016/j.neuroimage.2007.10.018
PMCID: PMC2408381  PMID: 18060810
14.  Diffusion tensor imaging and voxel based morphometry study in amyotrophic lateral sclerosis: relationships with motor disability 
The aim of this study was to investigate the extent of cortical and subcortical lesions in amyotrophic lateral sclerosis (ALS) using, in combination, voxel based diffusion tensor imaging (DTI) and voxel based morphometry (VBM). We included 15 patients with definite or probable ALS and 25 healthy volunteers. Patients were assessed using the revised ALS Functional Rating Scale (ALSFRS‐R). In patients, reduced fractional anisotropy was found in bilateral corticospinal tracts, the left insula/ventrolateral premotor cortex, the right parietal cortex and the thalamus, which correlated with the ALSFRS‐R. Increased mean diffusivity (MD) was found bilaterally in the motor cortex, the ventrolateral premotor cortex/insula, the hippocampal formations and the right superior temporal gyrus, which did not correlate with the ALSFRS‐R. VBM analysis showed no changes in white matter but widespread volume decreases in grey matter in several regions exhibiting MD abnormalities. In ALS patients, our results show that subcortical lesions extend beyond the corticospinal tract and are clinically relevant.
doi:10.1136/jnnp.2006.101758
PMCID: PMC2117724  PMID: 17635981
15.  Voxel-based morphometry (VBM) studies in schizophrenia—can white matter changes be reliably detected with VBM? 
Psychiatry Research  2011;193(2):65-70.
Voxel-Based Morphometry (VBM) is a hypothesis-free, whole-brain, voxel-by-voxel analytic method that attempts to compare imaging data between populations. Schizophrenia studies have utilized this method to localize differences in Diffusion Tensor Imaging (DTI) derived Fractional Anisotropy (FA), a measure of white matter integrity, between patients and healthy controls. The number of publications has grown, although it is unclear how reliable and reproducible this method is, given the subtle white matter abnormalities expected in schizophrenia. Here we analyze and combine results from 23 studies published to date that use VBM to study schizophrenia in order to evaluate the reproducibility of this method in DTI analysis. Coordinates of each region reported in DTI VBM studies published thus far in schizophrenia were plotted onto a Montreal Neurological Institute atlas, and their anatomical locations were recorded. Results indicated that the reductions of FA in patients with schizophrenia were scattered across the brain. Moreover, even the most consistently reported regions were reported independently in less than 35% of the papers studied. Other instances of reduced FA were replicated at an even lower rate. Our findings demonstrate striking inconsistency, with none of the regions reported in much more than a third of the published papers. Poor replication rate suggests that the application of VBM to DTI data may not be the optimal way for studying the subtle microstructural abnormalities that are being hypothesized in schizophrenia.
doi:10.1016/j.pscychresns.2011.01.009
PMCID: PMC3382976  PMID: 21684124
Diffusion tensor imaging; meta-analysis; chronic schizophrenia; first-episode schizophrenia; fractional anisotropy
16.  White matter abnormalities in Methcathinone abusers with an extrapyramidal syndrome 
Brain : a journal of neurology  2010;133(0 12):3676-3684.
Summary
We examined white matter abnormalities in patients with a distinctive extrapyramidal syndrome due to intravenous methcathinone (ephedrone) abuse. We performed diffusion tensor imaging in ten patients and fifteen age-matched controls to assess white matter structure across the whole brain. Diffuse significant decreases in white matter fractional anisotropy, a diffusion tensor imaging metric which reflects microstructural integrity, occurred in the patients compared with controls. In addition, we identified two foci of severe white matter abnormality underlying the right ventral premotor cortex and the medial frontal cortex, two cortical regions involved in higher-level executive control of motor function. Paths connecting different cortical regions with the globus pallidus, the nucleus previously shown to be abnormal on structural imaging in these patients, were generated using probabilistic tractography. The fractional anisotropy within all these tracts was lower in the patient group than controls. Finally, we tested for a relationship between white matter integrity and clinical outcome. We identified a region within the left corticospinal tract in which lower fractional anisotropy was associated with greater functional deficit but this region did not show reduced fractional anisotropy in the overall patient group compared to controls. These patients have widespread white matter damage with greatest severity of damage underlying executive motor areas.
doi:10.1093/brain/awq281
PMCID: PMC3677802  PMID: 21036949
Extrapyramidal syndrome; Methcathinone; Manganese toxicity; diffusion imaging; white matter tracts
17.  Comparison between brain CT and MRI for voxel-based morphometry of Alzheimer's disease 
Brain and Behavior  2013;3(4):487-493.
The voxel-based morphometry (VBM) technique using brain magnetic resonance imaging (MRI) objectively maps gray matter loss on a voxel-by-voxel basis after anatomic standardization. In patients with Alzheimer's disease (AD), reductions of gray matter volume, mainly in the medial temporal structures, have been reported; however, inhomogeneity and geometric distortion of the field intensity hampers the reproducibility of MRI. In the present study, we developed a novel computed tomography (CT)-based VBM method and used this technique to detect volume loss in AD patients as compared with normal controls. The results were compared with MRI-based VBM using the same subjects. Pittsburgh Compound B (11C-PIB) positron emission tomography (PET)/CT was performed and two experts in neuro-nuclear medicine judged whether regional amyloid β load was consistent with a diagnosis of AD. Before the injection of 11C-PIB, high-quality CT scans were obtained using the same PET/CT equipment. MRI was performed within a mean interval of 25.1 ± 8.2 days before the PET/CT scan. Using statistical parametric mapping 8 (SPM8), the extracted gray matter images from CT and MRI were spatially normalized using a gray matter template and smoothed using a Gaussian kernel. Group comparisons were performed using SPM8 between five 11C-PIB-positive patients with probable AD and seven 11C-PIB-negative age-matched controls with normal cognition. Gray matter volumes in the bilateral medial temporal areas were reduced in the AD group as compared with the cognitively normal group in both CT-based VBM (in the left; P < 0.0001, cluster size 2776 and in the right; P < 0.0001, cluster size 630) and MRI-based VBM (in the left; P < 0.0001, cluster size 381 and in the right, P < 0.0001, cluster size 421). This newly developed CT-based VBM technique can detect significant atrophy in the entorhinal cortex in probable AD patients as previously reported using MRI-based VBM. However, CT-VBM was more sensitive and revealed larger areas of significant atrophy than MR-VBM.
doi:10.1002/brb3.146
PMCID: PMC3869687  PMID: 24381817
Alzheimer's disease; CT; PIB; VBM
18.  White matter structural connectivity is associated with sensorimotor function in stroke survivors☆ 
NeuroImage : Clinical  2013;2:767-781.
Purpose
Diffusion tensor imaging (DTI) provides functionally relevant information about white matter structure. Local anatomical connectivity information combined with fractional anisotropy (FA) and mean diffusivity (MD) may predict functional outcomes in stroke survivors. Imaging methods for predicting functional outcomes in stroke survivors are not well established. This work uses DTI to objectively assess the effects of a stroke lesion on white matter structure and sensorimotor function.
Methods
A voxel-based approach is introduced to assess a stroke lesion's global impact on motor function. Anatomical T1-weighted and diffusion tensor images of the brain were acquired for nineteen subjects (10 post-stroke and 9 age-matched controls). A manually selected volume of interest was used to alleviate the effects of stroke lesions on image registration. Images from all subjects were registered to the images of the control subject that was anatomically closest to Talairach space. Each subject's transformed image was uniformly seeded for DTI tractography. Each seed was inversely transformed into the individual subject space, where DTI tractography was conducted and then the results were transformed back to the reference space. A voxel-wise connectivity matrix was constructed from the fibers, which was then used to calculate the number of directly and indirectly connected neighbors of each voxel. A novel voxel-wise indirect structural connectivity (VISC) index was computed as the average number of direct connections to a voxel's indirect neighbors. Voxel-based analyses (VBA) were performed to compare VISC, FA, and MD for the detection of lesion-induced changes in sensorimotor function. For each voxel, a t-value was computed from the differences between each stroke brain and the 9 controls. A series of linear regressions was performed between Fugl-Meyer (FM) assessment scores of sensorimotor impairment and each DTI metric's log number of voxels that differed from the control group.
Results
Correlation between the logarithm of the number of significant voxels in the ipsilesional hemisphere and total Fugl-Meyer score was moderate for MD (R2 = 0.512), and greater for VISC (R2 = 0.796) and FA (R2 = 0.674). The slopes of FA (p = 0.0036), VISC (p = 0.0005), and MD (p = 0.0199) versus the total FM score were significant. However, these correlations were driven by the upper extremity motor component of the FM score (VISC: R2 = 0.879) with little influence of the lower extremity motor component (FA: R2 = 0.177).
Conclusion
The results suggest that a voxel-wise metric based on DTI tractography can predict upper extremity sensorimotor function of stroke survivors, and that supraspinal intraconnectivity may have a less dominant role in lower extremity function.
Highlights
•An intrinsic voxel-based structural connectivity metric is proposed.•The metric enhances the impact of stroke lesions on the distant voxels.•Whole-brain extralesional anatomical connectivity predicts functional outcome.•Functional impact of a lesion is determined by residual anatomical connectivity.•Connectivity to the posterior parietal cortex is a key to sensorimotor function.
doi:10.1016/j.nicl.2013.05.009
PMCID: PMC3777792  PMID: 24179827
DTI, diffusion tensor imaging; FA, fractional anisotropy; FOV, field of view; FM, Fugl-Meyer; LDV, log difference volume; LE, lower extremity; MD, mean diffusivity; TE, echo time; TFIRE, Tactful Functional Imaging Research Environment; TR, repetition time; UE, upper extremity; VISC, voxel-wise indirect structural connectivity; Voxel-wise structural connectivity; Tractography; Diffusion tensor imaging; Stroke; Sensorimotor function; Lesion analysis
19.  Microstructural Status of Ipsilesional and Contralesional Corticospinal Tract Correlates with Motor Skill in Chronic Stroke Patients 
Human brain mapping  2009;30(11):3461-3474.
Greater loss in structural integrity of the ipsilesional corticospinal tract (CST) is associated with poorer motor outcome in hemiparetic stroke patients. Animal models of stroke have demonstrated that structural remodeling of white matter in the ipsilesional and contralesional hemispheres is associated with improved motor recovery. Accordingly, motor recovery in stroke patients may relate to the relative strength of CST degeneration and remodeling. This study examined the relationship between microstructural status of brain white matter tracts, indexed by the fractional anisotropy (FA) metric derived from diffusion tensor imaging (DTI) data, and motor skill of the stroke-affected hand in chronic stroke patients. Voxelwise analysis revealed that motor skill significantly and positively correlated with FA of the ipsilesional and contralesional CST in the patients. Additional voxelwise analyses showed that patients with poorer motor skill had reduced FA of bilateral CST compared to normal control subjects whereas patients with better motor skill had elevated FA of bilateral CST compared to controls. These findings were confirmed using a DTI-tractography method applied to the CST in both hemispheres. The results of this study suggest that the level of motor skill recovery achieved in hemiparetic stroke patients relates to microstructural status of the CST in both the ipsilesional and contralesional hemispheres, which may reflect the net effect of degeneration and remodeling of bilateral CST.
doi:10.1002/hbm.20770
PMCID: PMC2780023  PMID: 19370766
diffusion tensor imaging; anisotropy; stroke recovery; hemiparesis; tractography; white matter
20.  Integrity of white matter in the corpus callosum correlates with bimanual co-ordination skills 
NeuroImage  2007;36(Suppl 2):T16-T21.
Variation in brain structure may reflect variation in functional properties of specific brain systems. Structural variation may therefore reflect variation in behavioural performance. Here, we use diffusion-weighted magnetic resonance imaging to show that variation in white matter integrity in a specific region in the body of the corpus callosum is associated with variation in performance of a bimanual co-ordination task. When the callosal region showing this association is used as a seed for probabilistic tractography, inter-hemispheric pathways are generated to the supplementary motor area and caudal cingulate motor area. This provides further evidence for the role of medial wall motor areas in bimanual co-ordination and supports the idea that variation in brain structure reflects inter-individual differences in skilled performance.
doi:10.1016/j.neuroimage.2007.03.041
PMCID: PMC3119816  PMID: 17499163
21.  Diffusion tensor imaging and voxel based morphometry study in early progressive supranuclear palsy 
Background
A comprehensive characterisation of grey and white matter changes in progressive supranuclear palsy (PSP), the second most common extrapyramidal syndrome after Parkinson disease, is still not available.
Objective
To evaluate grey and white matter changes in mild PSP patients by voxel based morphometry (VBM) and diffusion tensor imaging (DTI), respectively.
Methods
14 mild PSP patients and 14 healthy controls entered the study and underwent a clinical and neuropsychological evaluation according with a standardised assessment. Each subject had a structural magnetic resonance imaging (MRI) study. Processing analysis of MRI data was carried out according to optimised VBM and fractional anisotropy was determined.
Results
Compared with the controls, in PSP patients VBM analysis showed a significant clusters of reduced grey matter in premotor cortex, frontal operculum, anterior insula, hippocampus, and parahippocampal gyrus, bilaterally. With regard to subcortical brain regions, the pulvinar, dorsomedial and anterior nuclei of the thalamus, and superior and inferior culliculum were affected bilaterally. A bilateral decrease in fractional anisotropy in superior longitudinal fasciculus, anterior part of corpus callosum, arcuate fascicolus, posterior thalamic radiations, and internal capsule, probably involving the cortico‐bulbar tracts, was present in PSP patients.
Conclusions
These data provide evidence for both grey and white matter degeneration in PSP from the early disease stage. These structural changes suggest that atrophy of cortical and subcortical structures and neurodegeneration of specific fibre tracts contribute to neurological deficits in PSP.
doi:10.1136/jnnp.2005.075713
PMCID: PMC2077489  PMID: 16306152
progressive supranuclear palsy; magnetic resonance imaging; voxel based morphometry; diffusion tensor imaging
22.  3D Fiber Tractography with Susceptibility Tensor Imaging 
NeuroImage  2011;59(2):1290-1298.
Gradient-echo MRI has revealed anisotropic magnetic susceptibility in the brain white matter. This magnetic susceptibility anisotropy can be measured and characterized with susceptibility tensor imaging (STI). In this study, a method of fiber tractography based on STI is proposed and demonstrated in the mouse brain. STI experiments of perfusion-fixed mouse brains were conducted at 7.0 T. The magnetic susceptibility tensor was calculated for each voxel with regularization and decomposed into its eigensystem. The major eigenvector is found to be aligned with the underlying fiber orientation. Following the orientation of the major eigenvector, we are able to map distinctive fiber pathways in 3D. As a comparison, diffusion tensor imaging (DTI) and DTI fiber tractography were also conducted on the same specimens. The relationship between STI and DTI fiber tracts was explored with similarities and differences identified. It is anticipated that the proposed method of STI tractography may provide a new way to study white matter fiber architecture. As STI tractography is based on physical principles that are fundamentally different from DTI, it may also be valuable for the ongoing validation of DTI tractography.
doi:10.1016/j.neuroimage.2011.07.096
PMCID: PMC3235503  PMID: 21867759
susceptibility tensor imaging; tractography; magnetic susceptibility anisotropy; phase imaging; diffusion tensor imaging
23.  Bilateral Brain Regions Associated with Naming in Older Adults 
Brain and language  2010;113(3):113-123.
To determine structural brain correlates of naming abilities in older adults, we tested 24 individuals aged 56 to 79 on two confrontation-naming tests (the Boston Naming Test (BNT) and the Action Naming Test (ANT)), then collected from these individuals structural Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI) data. Overall, several regions showed that greater gray and white matter volume/integrity measures were associated with better task performance. Left peri-Sylvian language regions and their right-hemisphere counterparts, plus left mid-frontal gyrus correlated with accuracy and/or negatively with response time (RT) on the naming tests. Fractional anisotropy maps derived from DTI showed robust positive correlations with ANT accuracy bilaterally in the temporal lobe and in right middle frontal lobe, as well as negative correlations with BNT RT, bilaterally, in the white matter within middle and inferior temporal lobes. We conclude that those older adults with relatively better naming skills can rely on right-hemisphere peri-Sylvian and mid-frontal regions and pathways, in conjunction with left-hemisphere peri-Sylvian and mid-frontal regions, to achieve their success.
doi:10.1016/j.bandl.2010.03.001
PMCID: PMC2975055  PMID: 20399492
24.  Neuroanatomical Correlates of Developmental Dyscalculia: Combined Evidence from Morphometry and Tractography 
Poor mathematical abilities adversely affect academic and career opportunities. The neuroanatomical basis of developmental dyscalculia (DD), a specific learning deficit with prevalence rates exceeding 5%, is poorly understood. We used structural MRI and diffusion tensor imaging (DTI) to examine macro- and micro-structural impairments in 7- to 9-year-old children with DD, compared to a group of typically developing (TD) children matched on age, gender, intelligence, reading abilities and working memory capacity. Voxel-based morphometry (VBM) revealed reduced grey matter (GM) bilaterally in superior parietal lobule, intra-parietal sulcus, fusiform gyrus, parahippocampal gyrus and right anterior temporal cortex in children with DD. VBM analysis also showed reduced white matter (WM) volume in right temporal-parietal cortex. DTI revealed reduced fractional anisotropy (FA) in this WM region, pointing to significant right hemisphere micro-structural impairments. Furthermore, FA in this region was correlated with numerical operations but not verbal mathematical reasoning or word reading. Atlas-based tract mapping identified the inferior longitudinal fasciculus, inferior fronto-occipital fasciculus and caudal forceps major as key pathways impaired in DD. DTI tractography suggests that long-range WM projection fibers linking the right fusiform gyrus with temporal-parietal WM are a specific source of vulnerability in DD. Network and classification analysis suggest that DD in children may be characterized by multiple dysfunctional circuits arising from a core WM deficit. Our findings link GM and WM abnormalities in children with DD and they point to macro- and micro-structural abnormalities in right hemisphere temporal-parietal WM, and pathways associated with it, as key neuroanatomical correlates of DD.
doi:10.3389/neuro.09.051.2009
PMCID: PMC2796911  PMID: 20046827
mathematical disability; white matter; grey matter; diffusion tensor imaging; voxel-based morphometry; development
25.  Primary Dystonia: Conceptualizing the Disorder Through a Structural Brain Imaging Lens 
Tremor and Other Hyperkinetic Movements  2013;3:tre-03-152-3638-4.
Background
Dystonia is a hyperkinetic movement disorder characterized by involuntary, repetitive twisting movements. The anatomical structures and pathways implicated in its pathogenesis and their relationships to the neurophysiological paradigms of abnormal surround inhibition, maladaptive plasticity, and impaired sensorimotor integration remain unclear.
Objective
We review the use of high-resolution structural brain imaging using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) techniques for evaluating brain changes in primary torsion dystonia and their relationships to the pathophysiology of this disorder.
Methods
A PubMed search was conducted to identify relevant literature.
Results
VBM and DTI studies produced somewhat conflicting results across different forms of primary dystonia and reported increases, decreases, or both in gray matter volume and white matter integrity. However, despite the discrepancies, these studies are consistent in revealing brain abnormalities in dystonia that extend beyond the basal ganglia and involve the sensorimotor cortex and cerebellum.
Discussion
Although limited to date, structural magnetic resonance imaging (MRI) studies combined with functional brain imaging and neurophysiological modalities begin to establish structural-functional relationships at different levels of the abnormal basal ganglia, cortical, and cerebellar networks and provide clues into the pathophysiological mechanisms that underlie primary dystonia. Cross-disciplinary studies are needed for further investigations of the interplay between structural-functional brain abnormalities and environmental and genetic risk factors in dystonia patients.
PMCID: PMC3629863  PMID: 23610744
Primary dystonia; voxel-based morphometry; diffusion tensor imaging; MRI

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