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White Matter Abnormalities in Pediatric Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a prevalent and often severely disabling illness with onset generally in childhood or adolescence. Although white matter deficits have been implicated in the neurobiology of OCD, few studies have been conducted in pediatric patients when the brain is still developing and have examined their functional correlates. In this study, 23 pediatric OCD patients and 23 healthy volunteers, between the ages of 9 and 17 years, matched for sex, age, handedness, and IQ, received a diffusion tensor imaging exam on a 3T GE system and a brief neuropsychological battery tapping executive functions. Patient symptom severity was assessed using the Childrens Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Patients with OCD exhibited significantly greater fractional anisotropy compared to matched controls in the left dorsal cingulum bundle, splenium of the corpus callosum, right corticospinal tract, and left inferior fronto-occipital fasciculus. There were no regions of significantly lower fractional anisotropy in patients compared to controls. Higher fractional anisotropy in the splenium was significantly correlated with greater obsession severity on the CY-BOCS in the subgroup of psychotropic drug-naïve patients. Among patients, there was a significant association between greater fractional anisotropy in the dorsal cingulum bundle and better performance on measures of response inhibition and cognitive control. The overall findings suggest a pattern of greater directional coherence of white matter tracts in OCD very early in the course of illness, which may serve a compensatory mechanism, at least for response inhibition functions typically subserved by the cingulum bundle.

Thalamocortical Connectivity Correlates with Phenotypic Variability in Dystonia

Dystonia is a brain disorder characterized by abnormal involuntary movements without defining neuropathological changes. The disease is often inherited as an autosomal-dominant trait with incomplete penetrance. Individuals with dystonia, whether inherited or sporadic, exhibit striking phenotypic variability, with marked differences in the somatic distribution and severity of clinical manifestations. In the current study, we used magnetic resonance diffusion tensor imaging to identify microstructural changes associated with specific limb manifestations. Functional MRI was used to localize specific limb regions within the somatosensory cortex. Microstructural integrity was preserved when assessed in subrolandic white matter regions somatotopically related to the clinically involved limbs, but was reduced in regions linked to clinically uninvolved (asymptomatic) body areas. Clinical manifestations were greatest in subjects with relatively intact microstructure in somatotopically relevant white matter regions. Tractography revealed significant phenotype-related differences in the visualized thalamocortical tracts while corticostriatal and corticospinal pathways did not differ between groups. Cerebellothalamic microstructural abnormalities were also seen in the dystonia subjects, but these changes were associated with genotype, rather than with phenotypic variation. The findings suggest that the thalamocortical motor system is a major determinant of dystonia phenotype. This pathway may represent a novel therapeutic target for individuals with refractory limb dystonia.

Independent component analysis of resting state activity in pediatric obsessive-compulsive disorder.

Obsessive‐compulsive disorder (OCD) is an often severely disabling illness with onset generally in childhood or adolescence. Little is known, however, regarding the pattern of brain resting state activity in OCD early in the course of illness. We therefore examined differences in brain resting state activity in patients with pediatric OCD compared with healthy volunteers and their clinical correlates. Twenty‐three pediatric OCD patients and 23 healthy volunteers (age range 9–17), matched for sex, age, handedness, and IQ completed a resting state functional magnetic resonance imaging exam at 3T. Patients completed the Childrens Yale Brown Obsessive Scale. Data were decomposed into 36 functional networks using spatial group independent component analysis (ICA) and logistic regression was used to identify the components that yielded maximum group separation. Using ICA we identified three components that maximally separated the groups: a middle frontal/dorsal anterior cingulate network, an anterior/posterior cingulate network, and a visual network yielding an overall group classification of 76.1% (sensitivity = 78.3% and specificity = 73.9%). Independent component expression scores were significantly higher in patients compared with healthy volunteers in the middle frontal/dorsal anterior cingulate and the anterior/posterior cingulate networks, but lower in patients within the visual network. Higher expression scores in the anterior/posterior cingulate network correlated with greater severity of compulsions among patients. These findings implicate resting state fMRI abnormalities within the cingulate cortex and related control regions in the pathogenesis and phenomenology of OCD early in the course of the disorder and prior to extensive pharmacologic intervention. Hum Brain Mapp 35:5306–5315, 2014.

Parkinson's disease-related network topographies characterized with resting state functional MRI.

Spatial covariance mapping can be used to identify and measure the activity of disease‐related functional brain networks. While this approach has been widely used in the analysis of cerebral blood flow and metabolic PET scans, it is not clear whether it can be reliably applied to resting state functional MRI (rs‐fMRI) data. In this study, we present a novel method based on independent component analysis (ICA) to characterize specific network topographies associated with Parkinsons disease (PD). Using rs‐fMRI data from PD and healthy subjects, we used ICA with bootstrap resampling to identify a PD‐related pattern that reliably discriminated the two groups. This topography, termed rs‐MRI PD‐related pattern (fPDRP), was similar to previously characterized disease‐related patterns identified using metabolic PET imaging. Following pattern identification, we validated the fPDRP by computing its expression in rs‐fMRI testing data on a prospective case basis. Indeed, significant increases in fPDRP expression were found in separate sets of PD and control subjects. In addition to providing a similar degree of group separation as PET, fPDRP values correlated with motor disability and declined toward normal with levodopa administration. Finally, we used this approach in conjunction with neuropsychological performance measures to identify a separate PD cognition‐related pattern in the patients. This pattern, termed rs‐fMRI PD cognition‐related pattern (fPDCP), was topographically similar to its PET‐derived counterpart. Subject scores for the fPDCP correlated with executive function in both training and testing data. These findings suggest that ICA can be used in conjunction with bootstrap resampling to identify and validate stable disease‐related network topographies in rs‐fMRI. Hum Brain Mapp 38:617–630, 2017.

Regional Brain Metabolism in a Murine Systemic Lupus Erythematosus Model

Systemic lupus erythematosus (SLE) is characterized by multiorgan inflammation, neuropsychiatric disorders (NPSLE), and anti-nuclear antibodies. We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis. DNRAb + mice exhibit memory impairment or altered fear response, depending on whether the antibody penetrates the hippocampus or amygdala. Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach. In DNRAb + mice, metabolism declined at the site of BBB breach in the first 2 weeks and increased over the next 2 weeks. In contrast, DNRAb — mice exhibited metabolic increases in these regions over the 4 weeks after the insult. Memory impairment was present in DNRAb + animals with hippocampal BBB breach and altered fear conditioning in DNRAb + mice with amygdala BBB breach. In DNRAb + mice, we observed an inverse relationship between neuron number and regional metabolism, while a positive correlation was observed in DNRAb — mice. These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects.

Early registration of diffusion tensor images for group tractography of dystonia patients.

To make a group comparison of diffusion tensor imaging (DTI) results of dystonia patients and controls to reveal occult pathology. We propose using an early registration method that produces sharper group images and enables us to do group tractography.

18FDG-microPET and MR DTI findings in Tor1a+/- heterozygous knock-out mice.

TorsinA is an important protein in brain development, and plays a role in the regulation of neurite outgrowth and synaptic function. Patients with the most common form of genetic dystonia carry a mutation (DYT1) in one copy of the Tor1a gene, a 3-bp deletion, causing removal of a single glutamic acid from torsinA. Previous imaging studies have shown that abnormal cerebellar metabolism and damaged cerebello-thalamo-cortical pathway contribute to the pathophysiology of DYT1 dystonia. However, how a mutation in one copy of the Tor1a gene causes these abnormalities is not known. We studied Tor1a heterozygous knock-out mice in vivo with FDG-PET and ex vivo with diffusion tensor imaging. We found metabolic abnormalities in cerebellum, caudate-putamen, globus pallidus, sensorimotor cortex and subthalamic nucleus. We also found that FA was increased in caudate-putamen, sensorimotor cortex and brainstem. We compared our findings with a previous imaging study of the Tor1a knock-in mice. Our study suggested that having only one normal copy of Tor1a gene may be responsible for the metabolic abnormalities observed; having a copy of mutant Tor1a, on the other hand, may be responsible for white matter pathway damages seen in DYT1 dystonia subjects.

White matter changes in primary dystonia determined by 2D distribution analysis of diffusion tensor images

To determine brain tissue affected by dystonia by making group comparison of parameter‐based diffusion tensor imaging (DTI) distributions of patients with control subjects. A 2D distribution analysis of mean diffusivity and fractional anisotropy index was used for modeling brain tissues according to the inherent diffusion characteristics.

Disruption of network for visual perception of natural motion in primary dystonia

In healthy subjects, brain activation in motor regions is greater during the visual perception of “natural” target motion, which complies with the two‐thirds power law, than of “unnatural” motion, which does not. It is unknown whether motion perception is normally mediated by a specific network that can be altered in the setting of disease. We used block‐design functional magnetic resonance imaging and covariance analysis to identify normal network topographies activated in response to “natural” versus “unnatural” motion. A visual motion perception‐related pattern (VPRP) was identified in 12 healthy subjects, characterized by covarying activation responses in the inferior parietal lobule, frontal operculum, lateral occipitotemporal cortex, amygdala, and cerebellum (Crus I). Selective VPRP activation during “natural” motion was confirmed in 12 testing scans from healthy subjects. Consistent network activation was not seen, however, in 29 patients with dystonia, a neurodevelopmental disorder in which motion perception pathways may be involved. Using diffusion tractography, we evaluated the integrity of anatomical connections between the major VPRP nodes. Indeed, fiber counts in these pathways were substantially reduced in the dystonia subjects. In aggregate, the findings associate normal motion perception with a discrete brain network which can be disrupted under pathological conditions.

FV2. Cognition-related Parkinson’s disease pattern with functional MRI: Validation and clinical correlates

Background Parkinson’s disease and related cognitive deficits have been associated with specific functional topographies termed functional PD-related pattern (fPDRP) and PD cognition-related pattern (fPDCP) ( Vo et al., 2017 ). Using multivariate analysis in resting-state functional MRI data this novel approach discriminated normal controls from PD patients based on their pattern expression and was associated with the severity of clinical measures. Aim We aim to investigate whether the functional PDCP topography is reproducible across different PD populations and whether fPDCP expression values can discriminate PD patients with and without mild cognitive impairment. Method Rs-fMRI scans from 22 PD patients in the on-state and 13 matched control subjects were analyzed using independent component analysis in conjunction with bootstrap resampling to identify a fPDCP topography in an independent cohort of PD patients from Berlin (Charite). Neuropsychological testing results were assessed and correlated with pattern expression. For further validation, subject scores for the fPDCP BERLIN pattern were computed in an independent group of 21 PD patients from North Shore (NS), USA. Subject scores and temporal dynamics were estimated for prospective cases with dual regression using the spatial maps generated from the Berlin derivation set and z-scored with regard to the normal control group. Results The fPDCP Berlin topography resembled the original fPDCP NS network topography ( Fig. 1 ). Subjects scores for the different fPDCP topographies from Berlin and North Shore were closely correlated in the Berlin sample (r = 0.67; p  Fig. 2 ). fPDCP expression was significantly elevated in patients with MCI compared to their cognitively unimpaired counterparts in the NS cohort (p Fig. 2 ). Conclusions These findings suggest that fPDCP represents a stable disease related network topography across independent patient populations. This and the ability to discriminate PD patients with mild cognitive impairment indicate that fPDCP could be used as non-invasive imaging biomarker for cognitive dysfunction in PD patients.