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1.  Regional changes in thalamic shape and volume with increasing age 
Neuroimage  2012;63(3):1134-1142.
The thalamus undergoes significant volume loss and microstructural change with increasing age. Alterations in thalamo-cortical connectivity may contribute to the decline in cognitive ability associated with aging. The aim of this study was to assess changes in thalamic shape and in the volume and diffusivity of thalamic regions parcellated by their connectivity to specific cortical regions in order to test the hypothesis age related thalamic change primarily affects thalamic nuclei connecting to the frontal cortex.
Using structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), we assessed thalamic volume and diffusivity in 86 healthy volunteers, median (range) age 44 (20–74) years. Regional thalamic micro and macro structural changes were assessed by segmenting the thalamus based on connectivity to the frontal, parietal, temporal and occipital cortices and determining the volumes and mean diffusivity of the thalamic projections.
Linear regression analysis was performed to test the relationship between increasing age and (i) normalised thalamic volume, (ii) whole thalamus diffusion measures, (iii) mean diffusivity (MD) of the thalamo-cortical projections, and (iv) volumes of the thalamo-cortical projections. We also assessed thalamic shape change using vertex analysis.
We observed a significant reduction in the volume and a significant increase in MD of the whole thalamus with increasing age. The volume of the thalamo-frontal projections decreased significantly with increasing age, however there was no significant relationship between the volumes of the thalamo-cortical projections to the parietal, temporal, and occipital cortex and age. Thalamic shape analysis showed that the greatest shape change was in the anterior thalamus, incorporating regions containing the anterior nucleus, the ventroanterior nucleus and the dorsomedial nucleus. To explore these results further we studied two additional groups of subjects (a younger and an older aged group, n = 20), which showed that the volume of the thalamo-frontal projections was correlated to executive functions scores, as assessed by the Stroop test. These data suggest that atrophy of the frontal thalamo-cortical unit may explain, at least in part, disorders of attention, working memory and executive function associated with increasing age.
doi:10.1016/j.neuroimage.2012.07.043
PMCID: PMC3507623  PMID: 22846656
Healthy aging; Thalamus; Thalamo-cortical connectivity; Diffusion tensor imaging; Vertex analysis
2.  Diffusion Tensor Imaging of Post Mortem Multiple Sclerosis Brain 
NeuroImage  2006;35(2):467-477.
Magnetic resonance imaging (MRI) is being used to probe the central nervous system (CNS) of patients with multiple sclerosis (MS), a chronic demyelinating disease. Conventional T2-weighted MRI (cMRI) largely fails to predict the degree of patients' disability. This shortcoming may be due to poor specificity of cMRI for clinically relevant pathology. Diffusion tensor imaging (DTI) has shown promise to be more specific for MS pathology. In this study we investigated the association between histological indices of myelin content, axonal count and gliosis, and two measures of DTI (mean diffusivity [MD] and fractional anisotropy [FA]), in unfixed post mortem MS brain using a 1.5-T MR system. Both MD and FA were significantly lower in post mortem MS brain compared to published data acquired in vivo. However, the differences of MD and FA described in vivo between white matter lesions (WMLs) and normal-appearing white matter (NAWM) were retained in this study of post mortem brain: average MD in WMLs was 0.35×10−3 mm2/s (SD, 0.09) versus 0.22 (0.04) in NAWM; FA was 0.22 (0.06) in WMLs versus 0.38 (0.13) in NAWM. Correlations were detected between myelin content (Trmyelin) and (i) FA (r=−0.79, p<0.001), (ii) MD (r=0.68, p<0.001), and (iii) axonal count (r=−0.81, p<0.001). Multiple regression suggested that these correlations largely explain the apparent association of axonal count with (i) FA (r=0.70, p<0.001) and (ii) MD (r=−0.66, p<0.001). In conclusion, this study suggests that FA and MD are affected by myelin content and – to a lesser degree – axonal count in post mortem MS brain.
doi:10.1016/j.neuroimage.2006.12.010
PMCID: PMC1892244  PMID: 17258908
3.  Diffusion tensor imaging of post mortem multiple sclerosis brain 
Neuroimage  2007;35(2):467-477.
Magnetic resonance imaging (MRI) is being used to probe the central nervous system (CNS) of patients with multiple sclerosis (MS), a chronic demyelinating disease. Conventional T2-weighted MRI (cMRI) largely fails to predict the degree of patients' disability. This shortcoming may be due to poor specificity of cMRI for clinically relevant pathology. Diffusion tensor imaging (DTI) has shown promise to be more specific for MS pathology. In this study we investigated the association between histological indices of myelin content, axonal count and gliosis, and two measures of DTI (mean diffusivity [MD] and fractional anisotropy [FA]), in unfixed post mortem MS brain using a 1.5-T MR system. Both MD and FA were significantly lower in post mortem MS brain compared to published data acquired in vivo. However, the differences of MD and FA described in vivo between white matter lesions (WMLs) and normal-appearing white matter (NAWM) were retained in this study of post mortem brain: average MD in WMLs was 0.35 × 10− 3 mm2/s (SD, 0.09) versus 0.22 (0.04) in NAWM; FA was 0.22 (0.06) in WMLs versus 0.38 (0.13) in NAWM. Correlations were detected between myelin content (Trmyelin) and (i) FA (r = − 0.79, p < 0.001), (ii) MD (r = 0.68, p < 0.001), and (iii) axonal count (r = − 0.81, p < 0.001). Multiple regression suggested that these correlations largely explain the apparent association of axonal count with (i) FA (r = 0.70, p < 0.001) and (ii) MD (r = − 0.66, p < 0.001). In conclusion, this study suggests that FA and MD are affected by myelin content and – to a lesser degree – axonal count in post mortem MS brain.
doi:10.1016/j.neuroimage.2006.12.010
PMCID: PMC1892244  PMID: 17258908
4.  Development of Cerebral Fiber Pathways in Cats revealed by Diffusion Spectrum Imaging 
NeuroImage  2009;49(2):1231-1240.
Examination of the three-dimensional axonal pathways in the developing brain is key to understanding the formation of cerebral connectivity. By tracing fiber pathways throughout the entire brain, diffusion tractography provides information that cannot be achieved by conventional anatomical MR imaging or histology. However, standard diffusion tractography (based on diffusion tensor imaging, or DTI) tends to terminate in brain areas with low water diffusivity, indexed by low diffusion fractional anisotropy (FA), which can be caused by crossing fibers as well as fibers with less myelin. For this reason, DTI tractography is not effective for delineating the structural changes that occur in the developing brain, where the process of myelination is incomplete, and where crossing fibers exist in greater numbers than in the adult brain. Unlike DTI, diffusion spectrum imaging (DSI) can define multiple directions of water diffusivity; as such, diffusion tractography based on DSI provides marked flexibility for delineation of fiber tracts in areas where the fiber architecture is complex and multidirectional, even in areas of low FA. In this study, we showed that FA values were lower in the white matter of newborn (postnatal day 0; P0) cat brains than in the white matter of infant (P35) and juvenile (P100) cat brains. These results correlated well with histological myelin stains of the white matter: the newborn kitten brain has much less myelin than that found in cat brains at later stages of development. Using DSI tractography, we successfully identified structural changes in thalamo-cortical and cortico-cortical association tracts in cat brains from one stage of development to another. In newborns, the main body of the thalamo-cortical tract was smooth, and fibers branching from it were almost straight, while the main body became more complex and branching fibers became curved reflecting gyrification in the older cats. Cortico-cortical tracts in the temporal lobe were smooth in newborns, and they formed a sharper angle in the later stages of development. The cingulum bundle and superior longitudinal fasciculus became more visible with time. Within the first month after birth, structural changes occurred in these tracts that coincided with the formation of the gyri. These results show that DSI tractography has the potential for mapping morphological changes in low FA areas associated with growth and development. The technique may also be applicable to the study of other forms of brain plasticity, including future studies in vivo.
doi:10.1016/j.neuroimage.2009.09.002
PMCID: PMC2789885  PMID: 19747553
Diffusion Spectrum Imaging; Tractography; Development; Thalamo-cortical tracts; Cat
5.  A robust method for investigating thalamic white matter tracts after traumatic brain injury 
Neuroimage  2012;63(2):779-788.
Damage to the structural connections of the thalamus is a frequent feature of traumatic brain injury (TBI) and can be a key factor in determining clinical outcome. Until recently it has been difficult to quantify the extent of this damage in vivo. Diffusion tensor imaging (DTI) provides a validated method to investigate traumatic axonal injury, and can be applied to quantify damage to thalamic connections. DTI can also be used to assess white matter tract structure using tractography, and this technique has been used to study thalamo-cortical connections in the healthy brain. However, the presence of white matter injury can cause failure of tractography algorithms. Here, we report a method for investigating thalamo-cortical connectivity that bypasses the need for individual tractography. We first created a template for a number of thalamo-cortical connections using probabilistic tractography performed in ten healthy subjects. This template for investigating white matter structure was validated by comparison with individual tractography in the same group, as well as in an independent control group (N = 11). We also evaluated two methods of masking tract location using the tract skeleton generated by tract based spatial statistics, and a cerebrospinal fluid mask. Voxel-wise estimates of fractional anisotropy derived from the template were more strongly correlated with individual tractography when both types of masking were used. The tract templates were then used to sample DTI measures from a group of TBI patients (N = 22), with direct comparison performed against probabilistic tractography in individual patients. Probabilistic tractography often failed to produce anatomically plausible tracts in TBI patients. Importantly, we show that this problem increases as tracts become more damaged, and leads to underestimation of the amount of traumatic axonal injury. In contrast, the tract template can be used in these cases, allowing a more accurate assessment of white matter damage. In summary, we propose a method suitable for assessing specific thalamo-cortical white matter connections after TBI that is robust to the presence of varying amounts of traumatic axonal injury, as well as highlighting the potential problems of applying tractography algorithms in patient populations.
Highlights
► TBI produces significant damage to thalamo-cortical white matter connections. ► This damage disrupts probabilistic tractography in patients. ► The error associated with patient tractography increases with tract damage. ► A template approach allows more accurate estimation of tract damage after TBI.
doi:10.1016/j.neuroimage.2012.07.016
PMCID: PMC3471070  PMID: 22813952
TH, thalamus; ACCR, right anterior cingulate cortex; ACCL, left anterior cingulate cortex; IFGR, right inferior frontal gyrus; IFGL, left inferior frontal gyrus; SFGR, right superior frontal gyrus; SFGL, left superior frontal gyrus; SPLR, right superior parietal lobe; SPLL, left superior parietal lobe; STGR, right superior temporal gyrus; STGL, left superior temporal lobe; Diffusion tensor imaging; Tractography; Thalamus; Traumatic axonal injury
6.  Impaired thalamocortical connectivity in autism spectrum disorder: a study of functional and anatomical connectivity 
Brain  2013;136(6):1942-1955.
The thalamus plays crucial roles in the development and mature functioning of numerous sensorimotor, cognitive and attentional circuits. Currently limited evidence suggests that autism spectrum disorder may be associated with thalamic abnormalities, potentially related to sociocommunicative and other impairments in this disorder. We used functional connectivity magnetic resonance imaging and diffusion tensor imaging probabilistic tractography to study the functional and anatomical integrity of thalamo-cortical connectivity in children and adolescents with autism spectrum disorder and matched typically developing children. For connectivity with five cortical seeds (prefontal, parieto-occipital, motor, somatosensory and temporal), we found evidence of both anatomical and functional underconnectivity. The only exception was functional connectivity with the temporal lobe, which was increased in the autism spectrum disorders group, especially in the right hemisphere. However, this effect was robust only in partial correlation analyses (partialling out time series from other cortical seeds), whereas findings from total correlation analyses suggest that temporo-thalamic overconnectivity in the autism group was only relative to the underconnectivity found for other cortical seeds. We also found evidence of microstructural compromise within the thalamic motor parcel, associated with compromise in tracts between thalamus and motor cortex, suggesting that the thalamus may play a role in motor abnormalities reported in previous autism studies. More generally, a number of correlations of diffusion tensor imaging and functional connectivity magnetic resonance imaging measures with diagnostic and neuropsychological scores indicate involvement of abnormal thalamocortical connectivity in sociocommunicative and cognitive impairments in autism spectrum disorder.
doi:10.1093/brain/awt079
PMCID: PMC3673456  PMID: 23739917
autism; thalamus; connectivity; functional MRI; diffusion tensor imaging
7.  Thalamo-striato-cortical determinants to fatigue in multiple sclerosis 
Brain and Behavior  2013;3(6):715-728.
Background
The aim was to explore the thalamo-striato-cortical theory of central fatigue in multiple sclerosis (MS) patients with self-reported fatigue. If the theory correctly predicted fatigue based on disruptions of the thalamo-striato-cortical network, we expected altered brain activation in this network in MS participants while performing a complex cognitive task that challenged fatigue.
Methods
MS participants with self-reported fatigue were examined by functional magnetic resonance imaging (fMRI) during the performance of a complex working memory task. In this task, cognitive effort was challenged by a parametric design, which modeled the cerebral responses at increasing cognitive demands. In order to explore the theory of central fatigue in MS we also analyzed the cerebral responses by adding perceived fatigue scores as covariates in the analysis and by calculating the functional connectivity between regions in the thalamo-striatocortical network. The main findings were that MS participants elicited altered brain responses in the thalamo-striato-cortical network, and that brain activation in the left posterior parietal cortex and the right substantia nigra was positively correlated to perceived fatigue ratings. MS participants had stronger cortical-to-cortical and subcortical-to-subcortical connections, whereas they had weaker cortical-to-subcortical connections.
Conclusions
The findings of the present study indicate that the thalamo-striato-cortical network is involved in the pathophysiology of fatigue in MS, and provide support for the theory of central fatigue. However, due to the limited number of participants and the somewhat heterogeneous sample of MS participants, these results have to be regarded as tentative, though they might serve as a basis for future studies.
doi:10.1002/brb3.181
PMCID: PMC3868176  PMID: 24363974
Basal ganglia; functional magnetic resonance imaging; parietal cortex; substantia nigra; working memory
8.  Pyramidal tract mapping by diffusion tensor magnetic resonance imaging in multiple sclerosis: improving correlations with disability 
Background: Current magnetic resonance imaging (MRI) outcome measures such as T2 lesion load correlate poorly with disability in multiple sclerosis. Diffusion tensor imaging (DTI) of the brain can provide unique information regarding the orientation and integrity of white matter tracts in vivo.
Objective: To use this information to map the pyramidal tracts of patients with multiple sclerosis, investigate the relation between burden of disease in the tracts and disability, and compare this with more global magnetic resonance estimates of disease burden.
Methods: 25 patients with relapsing-remitting multiple sclerosis and 17 healthy volunteers were studied with DTI. An algorithm was used that automatically produced anatomically plausible maps of white matter tracts. The integrity of the pyramidal tracts was assessed using relative anisotropy and a novel measure (Lt) derived from the compounded relative anisotropy along the tracts. The methods were compared with both traditional and more recent techniques for measuring disease burden in multiple sclerosis (T2 lesion load and "whole brain" diffusion histograms).
Results: Relative anisotropy and Lt were significantly lower in patients than controls (p < 0.05). Pyramidal tract Lt in the patients correlated significantly with both expanded disability status scale (r = -0.48, p < 0.05), and to a greater degree, the pyramidal Kurtzke functional system score (KFS-p) (r = -0.75, p < 0.0001). T2 lesion load and diffusion histogram parameters did not correlate with disability.
Conclusions: Tract mapping using DTI is feasible and may increase the specificity of MRI in multiple sclerosis by matching appropriate tracts with specific clinical scoring systems. These techniques may be applicable to a wide range of neurological conditions.
doi:10.1136/jnnp.74.2.203
PMCID: PMC1738288  PMID: 12531950
9.  Cerebello-Thalamo-Cortical Connectivity Regulates Penetrance in Dystonia 
Dystonia is a brain disorder characterized by sustained involuntary muscle contractions. It is typically inherited as an autosomal dominant trait with incomplete penetrance. While lacking clear degenerative neuropathology, primary dystonia is thought to involve microstructural and functional changes in neuronal circuitry. In the current study, we used magnetic resonance (MR) diffusion tensor imaging (DTI) and probabilistic tractography to identify the specific circuit abnormalities that underlie clinical penetrance in carriers of genetic mutations for this disorder. This approach revealed reduced integrity of cerebello-thalamo-cortical (CbTC) fiber tracts, likely developmental in origin, in both manifesting and clinically non-manifesting dystonia mutation carriers. In these subjects, reductions in cerebello-thalamic connectivity correlated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Non-manifesting mutation carriers were distinguished by an additional area of fiber tract disruption situated distally along the thalamo-cortical segment of the pathway, in tandem with the proximal cerebellar outflow abnormality. In individual gene carriers, clinical penetrance was determined by the difference in connectivity measured at these two sites. Overall, these findings point to a novel mechanism to explain differences in clinical expression in carriers of genes for brain disease.
doi:10.1523/JNEUROSCI.2300-09.2009
PMCID: PMC2745646  PMID: 19657027
dystonia; connectivity; imaging; genetics; development; cerebral blood flow
10.  Widespread grey matter pathology dominates the longitudinal cerebral MRI and clinical landscape of amyotrophic lateral sclerosis 
Brain  2014;137(9):2546-2555.
Menke/Koerner et al. use structural MRI to explore the extent of longitudinal changes in cerebral pathology in amyotrophic lateral sclerosis, and their relationship to clinical features. A characteristic white matter tract pathological signature is seen cross-sectionally, while cortical involvement dominates longitudinally. This has implications for the development of biomarkers for diagnosis versus therapeutic monitoring.
Diagnosis, stratification and monitoring of disease progression in amyotrophic lateral sclerosis currently rely on clinical history and examination. The phenotypic heterogeneity of amyotrophic lateral sclerosis, including extramotor cognitive impairments is now well recognized. Candidate biomarkers have shown variable sensitivity and specificity, and studies have been mainly undertaken only cross-sectionally. Sixty patients with sporadic amyotrophic lateral sclerosis (without a family history of amyotrophic lateral sclerosis or dementia) underwent baseline multimodal magnetic resonance imaging at 3 T. Grey matter pathology was identified through analysis of T1-weighted images using voxel-based morphometry. White matter pathology was assessed using tract-based spatial statistics analysis of indices derived from diffusion tensor imaging. Cross-sectional analyses included group comparison with a group of healthy controls (n = 36) and correlations with clinical features, including regional disability, clinical upper motor neuron signs and cognitive impairment. Patients were offered 6-monthly follow-up MRI, and the last available scan was used for a separate longitudinal analysis (n = 27). In cross-sectional study, the core signature of white matter pathology was confirmed within the corticospinal tract and callosal body, and linked strongly to clinical upper motor neuron burden, but also to limb disability subscore and progression rate. Localized grey matter abnormalities were detected in a topographically appropriate region of the left motor cortex in relation to bulbar disability, and in Broca’s area and its homologue in relation to verbal fluency. Longitudinal analysis revealed progressive and widespread changes in the grey matter, notably including the basal ganglia. In contrast there was limited white matter pathology progression, in keeping with a previously unrecognized limited change in individual clinical upper motor neuron scores, despite advancing disability. Although a consistent core white matter pathology was found cross-sectionally, grey matter pathology was dominant longitudinally, and included progression in clinically silent areas such as the basal ganglia, believed to reflect their wider cortical connectivity. Such changes were significant across a range of apparently sporadic patients rather than being a genotype-specific effect. It is also suggested that the upper motor neuron lesion in amyotrophic lateral sclerosis may be relatively constant during the established symptomatic period. These findings have implications for the development of effective diagnostic versus therapeutic monitoring magnetic resonance imaging biomarkers. Amyotrophic lateral sclerosis may be characterized initially by a predominantly white matter tract pathological signature, evolving as a widespread cortical network degeneration.
doi:10.1093/brain/awu162
PMCID: PMC4132644  PMID: 24951638
motor neuron disease; biomarker; magnetic resonance imaging; voxel-based morphometry; diffusion tensor imaging
11.  Abnormal thalamocortical structural and functional connectivity in juvenile myoclonic epilepsy 
Brain  2012;135(12):3635-3644.
Juvenile myoclonic epilepsy is the most common idiopathic generalized epilepsy, characterized by frequent myoclonic jerks, generalized tonic-clonic seizures and, less commonly, absences. Neuropsychological and, less consistently, anatomical studies have indicated frontal lobe dysfunction in the disease. Given its presumed thalamo–cortical basis, we investigated thalamo–cortical structural connectivity, as measured by diffusion tensor imaging, in a cohort of 28 participants with juvenile myoclonic epilepsy and detected changes in an anterior thalamo–cortical bundle compared with healthy control subjects. We then investigated task-modulated functional connectivity from the anterior thalamic region identified using functional magnetic resonance imaging in a task consistently shown to be impaired in this group, phonemic verbal fluency. We demonstrate an alteration in task-modulated connectivity in a region of frontal cortex directly connected to the thalamus via the same anatomical bundle, and overlapping with the supplementary motor area. Further, we show that the degree of abnormal connectivity is related to disease severity in those with active seizures. By integrating methods examining structural and effective interregional connectivity, these results provide convincing evidence for abnormalities in a specific thalamo–cortical circuit, with reduced structural and task-induced functional connectivity, which may underlie the functional abnormalities in this idiopathic epilepsy.
doi:10.1093/brain/aws296
PMCID: PMC3525058  PMID: 23250883
juvenile myoclonic epilepsy; connectivity; functional MRI; diffusion MRI
12.  Multiple Sclerosis Normal-Appearing White Matter: Pathology-Imaging Correlations 
Annals of neurology  2011;70(5):764-773.
Objective
To determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis (MS) brains.
Methods
Brain tissues were obtained through a rapid post-mortem protocol that included in situ MRI. Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) Regions that were abnormal on all images (“T2T1MTR lesions”); (2) NAWM regions with slightly-abnormal MTR located close to white matter lesions (“sa-WM Close”); (3) NAWM regions with slightly-abnormal MTR located far from lesions (“sa-WM Far”); and (4) NAWM regions with normal MTR (“NAWM”).
Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins and blood vessels.
Results
Forty-eight ROIs from four secondary progressive MS brains were analyzed. Sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged MHCII(+) microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in non-lesional WM were correlated with activated microglia, but not with axonal or myelin integrity.
Interpretation
The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.
doi:10.1002/ana.22521
PMCID: PMC3241216  PMID: 22162059
13.  Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease 
Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in over 30% of these patients. While post-mortem pathology studies and in vivo magnetic resonance imaging (MRI) demonstrate that the hippocampus is targeted in MS, the neuropathology underlying hippocampal dysfunction remains unknown. Furthermore, there are no treatments available to date to effectively prevent neurodegeneration and associated cognitive dysfunction in MS. We have recently demonstrated that the hippocampus is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. The objective of this study was to assess whether a candidate treatment (testosterone) could prevent hippocampal synaptic dysfunction and underlying pathology when administered in either a preventative or a therapeutic (post-disease induction) manner. Electrophysiological studies revealed impairments in basal excitatory synaptic transmission that involved both AMPA receptor-mediated changes in synaptic currents, and faster decay rates of NMDA receptor-mediated currents in mice with EAE. Neuropathology revealed atrophy of the pyramidal and dendritic layers of hippocampal cornu ammonis 1 (CA1), decreased pre (Synapsin-1) and post (postsynaptic density 95; PSD-95) synaptic staining, diffuse demyelination, and microglial activation. Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as pre- and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in excitatory postsynaptic potentials are significantly correlated to changes in postsynaptic protein levels and suggest that PSD-95 is a neuropathological substrate to impaired synaptic transmission in the hippocampus during EAE. This is the first report demonstrating that testosterone is a viable therapeutic treatment option that can restore both hippocampal function and disease-associated pathology that occur during autoimmune disease.
doi:10.1523/JNEUROSCI.2796-12.2012
PMCID: PMC3571760  PMID: 22956822
hippocampus; synaptic transmission; testosterone; PSD-95; experimental autoimmune encephalomyelitis; Multiple Sclerosis
14.  Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. 
BMJ : British Medical Journal  1990;300(6725):631-634.
OBJECTIVE--To compare the abnormalities shown by magnetic resonance imaging of the brain in three clinically distinct groups of patients with multiple sclerosis, and to correlate the extent of abnormality with the degree of clinical disability in the three groups. DESIGN--All patients underwent magnetic resonance imaging and full neurological examination, and their disability was scored according to the expanded Kurtzke disability state scale. SETTING--National Hospital for Nervous Diseases (Multiple Sclerosis NMR Research Group). PATIENTS--Three groups of patients with confirmed multiple sclerosis were studied: 12 patients with minimal disability despite a long (greater than 10 years) duration of illness (benign multiple sclerosis), 16 who had developed progressive disability after a relapsing and remitting course (secondary progressive multiple sclerosis), and 13 who had had progressive disability from the onset of the disease (primary progressive multiple sclerosis). MAIN OUTCOME MEASURES--Number and size of lesions in 17 anatomically defined sites; total lesion load, estimated with an arbitrary scoring system weighted for the size of lesions; and disability score. RESULTS--Magnetic resonance imaging showed that all 41 patients had abnormalities. These were extensive in the groups with secondary progressive and benign disease compared with the group with primary progressive disease. The lesions in the patients with secondary progressive disease were larger and more confluent than those in the two other groups (p = 0.007). Most lesions (85%) in the patients with primary progressive disease were under 5 mm in diameter; this percentage was higher than that in the two other groups (p = 0.032). Consequently the patients with primary progressive disease had the lowest mean lesion load (36.7); that in the patients with benign disease was 52.7 and that in the patients with secondary progressive disease 64.6 (p = 0.05). No correlation existed between disability and total lesion load. The distribution of brain lesions and of detectable lesions of the spinal cord, and the frequency of cortical atrophy, were similar in all groups. CONCLUSIONS--No relation was found between the degree of clinical disability and the extent of abnormality shown by magnetic resonance imaging: patients with clinically benign disease often had extensive abnormalities and those with primary progressive disease had surprisingly few lesions. Though magnetic resonance imaging increases knowledge of the disease process in multiple sclerosis and is invaluable in diagnosis, it is not helpful in predicting disability in individual patients.
Images
PMCID: PMC1662448  PMID: 2138923
15.  Impaired small-world efficiency in structural cortical networks in multiple sclerosis associated with white matter lesion load 
Brain  2009;132(12):3366-3379.
White matter tracts, which play a crucial role in the coordination of information flow between different regions of grey matter, are particularly vulnerable to multiple sclerosis. Many studies have shown that the white matter lesions in multiple sclerosis are associated with focal abnormalities of grey matter, but little is known about the alterations in the coordinated patterns of cortical morphology among regions in the disease. Here, we used cortical thickness measurements from structural magnetic resonance imaging to investigate the relationship between the white matter lesion load and the topological efficiency of structural cortical networks in multiple sclerosis. Network efficiency was defined using a ‘small-world’ network model that quantifies the effectiveness of information transfer within brain networks. In this study, we first classified patients (n = 330) into six subgroups according to their total white matter lesion loads, and identified structural brain networks for each multiple sclerosis group by thresholding the corresponding inter-regional cortical thickness correlation matrix, followed by a network efficiency analysis with graph theoretical approaches. The structural cortical networks in multiple sclerosis demonstrated efficient small-world architecture regardless of the lesion load, an organization that maximizes the information processing at a relatively low wiring cost. However, we found that the overall small-world network efficiency in multiple sclerosis was significantly disrupted in a manner proportional to the extent of total white matter lesions. Moreover, regional efficiency was also significantly decreased in specific brain regions, including the insula and precentral gyrus as well as regions of prefrontal and temporal association cortices. Finally, we showed that the lesions also altered many cortical thickness correlations in the frontal, temporal and parietal lobes. Our results suggest that the white matter lesions in multiple sclerosis might be associated with aberrant neuronal connectivity among widely distributed brain regions, and provide structural (morphological) evidence for the notion of multiple sclerosis as a disconnection syndrome.
doi:10.1093/brain/awp089
PMCID: PMC2792366  PMID: 19439423
cortical thickness; connectivity; MRI; multiple sclerosis; small-world networks
16.  The effects of hemorrhagic parenchymal infarction on the establishment of sensori-motor structural and functional connectivity in early infancy 
Neuroradiology  2014;56(11):985-994.
Introduction
The objective of the study was to characterize alterations of structural and functional connectivity within the developing sensori-motor system in infants with focal perinatal brain injury and at high risk of cerebral palsy.
Methods
Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data were used to study the developing functional and structural connectivity framework in six infants born prematurely at term equivalent age. This was first characterised in three infants without focal pathology, which was then compared to that derived from three infants with unilateral haemorrhagic parenchymal infarction and a subsequent focal periventricular white matter lesion who developed later haemiparesis.
Results
Functional responses to passive hand movement were in the contralateral perirolandic cortex, regardless of focal pathology. In infants with unilateral periventricular injury, afferent thalamo-cortical tracts appeared to have developed compensatory trajectories which circumvented areas of damage. In contrast, efferent corticospinal tracts showed marked asymmetry at term equivalent age following focal brain injury. Sensori-motor network analysis suggested that inter-hemispheric functional connectivity is largely preserved despite pathology and that impairment may be associated with adverse neurodevelopmental outcome.
Conclusion
Following focal perinatal brain injury, altered structural and functional connectivity is already present and can be characterized with MRI at term equivalent age. The results of this small case series suggest that these techniques may provide valuable new information about prognosis and the pathophysiology underlying cerebral palsy.
Electronic supplementary material
The online version of this article (doi:10.1007/s00234-014-1412-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00234-014-1412-5
PMCID: PMC4210651  PMID: 25119253
Neonatal; Focal brain lesion; fMRI; Diffusion MRI; Connectivity
17.  7 Tesla Magnetic Resonance Imaging to Detect Cortical Pathology in Multiple Sclerosis 
PLoS ONE  2014;9(10):e108863.
Background
Neocortical lesions (NLs) are an important pathological component of multiple sclerosis (MS), but their visualization by magnetic resonance imaging (MRI) remains challenging.
Objectives
We aimed at assessing the sensitivity of multi echo gradient echo (ME-GRE) T2*-weighted MRI at 7.0 Tesla in depicting NLs compared to myelin and iron staining.
Methods
Samples from two MS patients were imaged post mortem using a whole body 7T MRI scanner with a 24-channel receive-only array. Isotropic 200 micron resolution images with varying T2* weighting were reconstructed from the ME-GRE data and converted into R2* maps. Immunohistochemical staining for myelin (proteolipid protein, PLP) and diaminobenzidine-enhanced Turnbull blue staining for iron were performed.
Results
Prospective and retrospective sensitivities of MRI for the detection of NLs were 48% and 67% respectively. We observed MRI maps detecting only a small portion of 20 subpial NLs extending over large cortical areas on PLP stainings. No MRI signal changes suggestive of iron accumulation in NLs were observed. Conversely, R2* maps indicated iron loss in NLs, which was confirmed by histological quantification.
Conclusions
High-resolution post mortem imaging using R2* and magnitude maps permits detection of focal NLs. However, disclosing extensive subpial demyelination with MRI remains challenging.
doi:10.1371/journal.pone.0108863
PMCID: PMC4193749  PMID: 25303286
18.  Quantitative Magnetic Resonance Imaging of Cortical Multiple Sclerosis Pathology 
Although significant improvements have been made regarding the visualization and characterization of cortical multiple sclerosis (MS) lesions using magnetic resonance imaging (MRI), cortical lesions (CL) continue to be under-detected in vivo, and we have a limited understanding of the causes of GM pathology. The objective of this study was to characterize the MRI signature of CLs to help interpret the changes seen in vivo and elucidate the factors limiting their visualization. A quantitative 3D high-resolution (350 μm isotropic) MRI study at 3 Tesla of a fixed post mortem cerebral hemisphere from a patient with MS is presented in combination with matched immunohistochemistry. Type III subpial lesions are characterized by an increase in T1, T2 and M0, and a decrease in MTR in comparison to the normal appearing cortex (NAC). All quantitative MR parameters were associated with cortical GM myelin content, while T1 showed the strongest correlation. The histogram analysis showed extensive overlap between CL and NAC for all MR parameters and myelin content. This is due to the poor contrast in myelin content between CL and NAC in comparison to the variability in myelo-architecture throughout the healthy cortex. This latter comparison is highlighted by the representation of T1 times on cortical surfaces at several laminar depths.
doi:10.1155/2012/742018
PMCID: PMC3506905  PMID: 23213531
19.  Combining tractography and cortical measures to test system-specific hypotheses in multiple sclerosis 
The objective was to test three motor system-specific hypotheses in multiple sclerosis patients: (i) corticospinal tract and primary motor cortex imaging measures differ between multiple sclerosis patients and controls; (ii) in patients, these measures correlate with disability; (iii) in patients, corticospinal tract measures correlate with measures of the ipsilateral primary motor cortex.
Eleven multiple sclerosis patients with a history of hemiparesis attributable to a lesion within the contralateral corticospinal tract, and 12 controls were studied. We used two advanced imaging techniques: (i) diffusion-based probabilistic tractography, to obtain connectivity and fractional anisotropy of the corticospinal tract; and (ii) FreeSurfer, to measure volume, thickness, surface area, and curvature of precentral and paracentral cortices. Differences in these measures between patients and controls, and relationships between each other and to clinical scores, were investigated.
Patients showed lower corticospinal tract fractional anisotropy and smaller volume and surface area of the precentral gyrus than controls. In patients, corticospinal tract connectivity and paracentral cortical volume, surface area, and curvature were lower with increasing disability; lower connectivity of the affected corticospinal tract was associated with greater surface area of the ipsilateral paracentral cortex.
Corticospinal tract connectivity and new measures of the primary motor cortex, such as surface area and curvature, reflect the underlying white and grey matter damage that contributes to disability. The correlation between lower connectivity of the affected corticospinal tract and greater surface area of the ipsilateral paracentral cortex suggests the possibility of cortical adaptation. Combining tractography and cortical measures is a useful approach in testing hypotheses which are specific to clinically relevant functional systems in multiple sclerosis, and can be applied to other neurological diseases.
doi:10.1177/1352458510362440
PMCID: PMC2925387  PMID: 20215478
atrophy; MRI; relapsing–remitting multiple sclerosis
20.  Independent Sources of Spontaneous BOLD Fluctuation Along the Visual Pathway 
Brain topography  2013;26(4):10.1007/s10548-013-0290-1.
In resting-state functional magnetic resonance imaging (fMRI) experiments, correlation analysis can be used to identify clusters of cortical regions that may be functionally connected. Although such functional connectivity is often assumed to reflect cortico-cortical connections, a potential confound is the contribution of subcortical brain regions, many of which have strong anatomical connectivity to cortical regions and may also enable cortico-cortical interactions through trans-thalamic pathways. To investigate this, we performed resting state fMRI of the human visual system, including cortical regions and subcortical nuclei of the pulvinar and lateral geniculate. Regression analysis was used to investigate the dependence of the measured inter-regional correlations upon afferents from specific retinal, thalamic and cortical regions as well as systemic global signal fluctuation. A high level of interhemispheric correlation (cc = 0.95) was found in the visual cortex that could not be explained by activity in the subcortical nuclei investigated; in addition a relatively low level of inter-hemispheric correlation (cc = 0.39–0.42) was found in vision-related thalamic nuclei that could not be explained by direct anatomical connections or their cortical inputs. These findings suggest that spontaneous fMRI signal correlations within the human visual system originate from a mixture of independent signal sources that may be transmitted through thalamo-cortical, cortico-thalamic, and cortico-cortical connections either trans-callosal or trans-thalamic in origin. Our findings thus call for more cautious interpretation of resting state functional connectivity in terms of any single type of anatomical connectivity.
doi:10.1007/s10548-013-0290-1
PMCID: PMC3815538  PMID: 23660870
Resting state fMRI; Human visual system; Brain connectivity; Correlation analysis; Callosal pathway; Thalamic pathway
21.  In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI 
Neurology  2009;73(12):941-948.
Objective:
We used ultra-high field MRI to visualize cortical lesion types described by neuropathology in 16 patients with multiple sclerosis (MS) compared with 8 age-matched controls; to characterize the contrast properties of cortical lesions including T2*, T2, T1, and phase images; and to investigate the relationship between cortical lesion types and clinical data.
Methods:
We collected, on a 7-T scanner, 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE) images (0.33 × 033 × 1 mm3), and a 3-dimensional magnetization-prepared rapid gradient echo.
Results:
Overall, 199 cortical lesions were detected in patients on both FLASH-T2* and T2-TSE scans. Seven-tesla MRI allowed for characterization of cortical plaques into type I (leukocortical), type II (intracortical), and type III/IV (subpial extending partly or completely through the cortical width) lesions as described histopathologically. Types III and IV were the most frequent type of cortical plaques (50.2%), followed by type I (36.2%) and type II (13.6%) lesions. Each lesion type was more frequent in secondary progressive than in relapsing–remitting MS. This difference, however, was significant only for type III/IV lesions. T2*-weighted images showed the highest, while phase images showed the lowest, contrast-to-noise ratio for all cortical lesion types. In patients, the number of type III/IV lesions was associated with greater disability (p < 0.02 by Spearman test) and older age (p < 0.04 by Spearman test).
Conclusions:
Seven-tesla MRI detected different histologic cortical lesion types in our small multiple sclerosis (MS) sample, suggesting, if validated in a larger population, that it may prove a valuable tool to assess the contribution of cortical MS pathology to clinical disability.
GLOSSARY
= analysis of variance;
= background noise;
= contrast-to-noise ratio;
= double-inversion recovery;
= Expanded Disability Status Scale;
= fluid-attenuated inversion recovery;
= fast low-angle shot;
= gray matter;
= magnetization-prepared rapid gradient echo;
= magnetic resonance;
= multiple sclerosis;
= normal-appearing cortical gray matter;
= radiofrequency;
= region of interest;
= relapsing–remitting multiple sclerosis;
= signal-to-noise ratio;
= secondary progressive multiple sclerosis;
= time of acquisition;
= echo time;
= repetition time;
= turbo spin-echo;
= white matter.
doi:10.1212/WNL.0b013e3181b64bf7
PMCID: PMC2754332  PMID: 19641168
22.  White matter involvement in sporadic Creutzfeldt-Jakob disease 
Brain  2014;137(12):3339-3354.
Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P = 0.002), axial (P = 0.0003) and radial (P = 0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P < 0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P = 0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white matter abnormality either on T2-weighted or diffusion-weighted images. Widespread reduction in white matter mean diffusivity, however, was apparent visibly on the quantitative attenuation coefficient maps compared to healthy control subjects. Neuropathological analysis showed diffuse astrocytic gliosis and activated microglia in the white matter, rare prion deposition and subtle subcortical microvacuolization, and patchy foci of demyelination with no evident white matter axonal degeneration. Decreased mean diffusivity on attenuation coefficient maps might be associated with astrocytic gliosis. We show for the first time significant global reduced mean diffusivity within the white matter in sporadic Creutzfeldt-Jakob disease, suggesting possible primary involvement of the white matter, rather than changes secondary to neuronal degeneration/loss.
Sporadic Creutzfeldt-Jakob disease (sCJD) is considered primarily a disease of grey matter. However, Caverzasi et al. now show a global decrease in mean diffusivity in white matter. The changes appear to be associated with reactive astrocytic gliosis and activated microglia, and suggest primary involvement of the white matter in sCJD.
doi:10.1093/brain/awu298
PMCID: PMC4240303  PMID: 25367029
DTI; CJD; mean diffusivity; gliosis; microglia
23.  Microstructural differences in the thalamus and thalamic radiations in the congenitally deaf 
Neuroimage  2014;100(100):347-357.
There is evidence of both crossmodal and intermodal plasticity in the deaf brain. Here, we investigated whether sub-cortical plasticity, specifically of the thalamus, contributed to this reorganisation. We contrasted diffusion weighted magnetic resonance imaging data from 13 congenitally deaf and 13 hearing participants, all of whom had learnt British Sign Language after 10 years of age. Connectivity based segmentation of the thalamus revealed changes to mean and radial diffusivity in occipital and frontal regions, which may be linked to enhanced peripheral visual acuity, and differences in how visual attention is deployed in the deaf group. Using probabilistic tractography, tracts were traced between the thalamus and its cortical targets, and microstructural measurements were extracted from these tracts. Group differences were found in microstructural measurements of occipital, frontal, somatosensory, motor and parietal thalamo-cortical tracts. Our findings suggest that there is sub-cortical plasticity in the deaf brain, and that white matter alterations can be found throughout the deaf brain, rather than being restricted to, or focussed in the auditory cortex.
Highlights
•Diffusion weighted MRI data was acquired from congenitally deaf and hearing groups.•Mean and radial diffusivity is altered in the thalamus of congenitally deaf people.•Diffusivity in white matter thalamo-cortical radiations is altered in deafness.
doi:10.1016/j.neuroimage.2014.05.077
PMCID: PMC4148523  PMID: 24907483
Diffusion weighted MRI; Deafness; Thalamus; Neuroplasticity
24.  The radial diffusivity and magnetization transfer pool size ratio are sensitive markers for demyelination in a rat model of type III multiple sclerosis (MS) lesions 
NeuroImage  2013;74:298-305.
Determining biophysical sensitivity and specificity of quantitative magnetic resonance imaging is essential to develop effective imaging metrics of neurodegeneration. Among these metrics apparent pool size ratio (PSR) from quantitative magnetization transfer (qMT) imaging and radial diffusivity (RD) from diffusion tensor imaging (DTI) are both known to relate to histological measure of myelin density and integrity. However their relative sensitivities towards quantitative myelin detection are unknown. In this study, we correlated high-resolution quantitative magnetic resonance imaging measures of subvoxel tissue structures with corresponding quantitative myelin histology in a lipopolysacharide (LPS) mediated animal model of MS. Specifically, we acquired quantitative magnetization transfer (qMT) and diffusion tensor imaging (DTI) metrics (on the same tissue sample) in an animal model system of type III oligodendrogliopathy which lacked prominent lymphocytic infiltration, a system that had not been previously examined with quantitative MRI. We find that the qMT measured apparent pool size ratio (PSR) showed the strongest correlation with a histological measure of myelin content. DTI measured RD showed the next strongest correlation, and other DTI and relaxation parameters (such as the longitudinal relaxation rate (R1f) or fractional anisotropy (FA)) showed considerably weaker correlations with myelin content.
doi:10.1016/j.neuroimage.2013.02.034
PMCID: PMC3995162  PMID: 23481461
Quantitative magnetization transfer (qMT); Diffusion Tensor Imaging (DTI); 9.4T; White matter; Myelin; demyelination; lippopolysaccharide (LPS); Rat brain; Multiple Sclerosis (MS)
25.  DTI detects water diffusion abnormalities in the thalamus that correlate with an extremity pain episode in a patient with multiple sclerosis☆ 
NeuroImage : Clinical  2013;2:258-262.
Background
Various types of multiple sclerosis (MS) related pain have been discussed. One concept is that deafferentation secondary to lesions in the spino-thalamo-cortical network can cause central pain. However, this hypothesis is somehow limited by a lack of a robust association between pain episodes and sites of lesion location.
Objective
We tested the hypothesis that temporary tissue alterations in the thalamus that are not detectable by conventional magnetic resonance imaging (T1w, FLAIR) can potentially explain a focal, paroxysmal central pain episode of a patient with MS. For microstructural tissue assessment we employed ten longitudinal diffusion tensor imaging (DTI) examinations.
Results
We could demonstrate an abnormal, unilateral temporary increase of the fractional anisotropy (FA) in the thalamus contralateral to the affected body side. Before the pain episode and after pain relief the FA reached completely normal values as seen in identically investigated age and gender matched 100 healthy control subjects.
Conclusion
These findings suggest that: i.) frequently applied and quantitatively evaluated DTI could be used as a sensitive imaging technique for detection of pathological processes associated with MS not detectable with conventional imaging strategies, ii.) temporary pathological processes in the “normal-appearing” thalamus may explain waxing and waning symptoms like episodes of central pain, and iii.) cross-sectional case examinations on (MS) patients with central pain should be performed to investigate how often thalamic alterations occur together with central pain.
Highlights
► Illustration of robustness of quantitative assessment of thalamus microstructure by DTI ► “Normal-appearing” thalamus may explain central pain in multiple sclerosis. ► Suggestion of deep gray matter assessment by DTI in multiple sclerosis
doi:10.1016/j.nicl.2013.01.008
PMCID: PMC3778262  PMID: 24179780

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