Myelination- and immune-mediated MR-based brain network correlates.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by inflammatory and neurodegenerative processes. Despite demyelination being a hallmark of the disease, how it relates to neurodegeneration has still not been completely unraveled, and research is still ongoing into how these processes can be tracked non-invasively. Magnetic resonance imaging (MRI) derived brain network characteristics, which closely mirror disease processes and relate to functional impairment, recently became important variables for characterizing immune-mediated neurodegeneration; however, their histopathological basis remains unclear. METHODS: In order to determine the MRI-derived correlates of myelin dynamics and to test if brain network characteristics derived from diffusion tensor imaging reflect microstructural tissue reorganization, we took advantage of the cuprizone model of general demyelination in mice and performed longitudinal histological and imaging analyses with behavioral tests. By introducing cuprizone into the diet, we induced targeted and consistent demyelination of oligodendrocytes, over a period of 5 weeks. Subsequent myelin synthesis was enabled by reintroduction of normal food. RESULTS: Using specific immune-histological markers, we demonstrated that 2 weeks of cuprizone diet induced a 52% reduction of myelin content in the corpus callosum (CC) and a 35% reduction in the neocortex. An extended cuprizone diet increased myelin loss in the CC, while remyelination commenced in the neocortex. These histologically determined dynamics were reflected by MRI measurements from diffusion tensor imaging. Demyelination was associated with decreased fractional anisotropy (FA) values and increased modularity and clustering at the network level. MRI-derived modularization of the brain network and FA reduction in key anatomical regions, including the hippocampus, thalamus, and analyzed cortical areas, were closely related to impaired memory function and anxiety-like behavior. CONCLUSION: Network-specific remyelination, shown by histology and MRI metrics, determined amelioration of functional performance and neuropsychiatric symptoms. Taken together, we illustrate the histological basis for the MRI-driven network responses to demyelination, where increased modularity leads to evolving damage and abnormal behavior in MS. Quantitative information about in vivo myelination processes is mirrored by diffusion-based imaging of microstructural integrity and network characteristics.

Resolving the cognitive clinico-radiological paradox - Microstructural degeneration of fronto-striatal-thalamic loops in early active multiple sclerosis.

BACKGROUND: Associations between cognitive impairment (CI) and both global and regional brain volumes can be weak in early multiple sclerosis (MS), a dilemma known as cognitive clinico-radiological paradox. We hypothesized that white-matter (WM) integrity within fronto-striatal-thalamic networks may be a sensitive marker for impaired performance in speed-dependent tasks, typical for early MS. METHODS: Twenty-seven patients with early active relapsing-remitting MS (RRMS) received comprehensive neuropsychological assessment and underwent structural and diffusion-weighted brain magnetic resonance imaging (MRI). Global and regional brain volumes were obtained using FreeSurfer software. Fractional anisotropy (FA) was computed from diffusion tensor images to assess microstructural alterations within three anatomically predefined fronto-striatal-thalamic loops known to be relevant for speed-dependent attention and executive functions. RESULTS: Overall cognitive performance (Spearman's ρ = .51) and performance in the domains processing speed (ρ = .44) and executive functions (ρ = .41) were correlated with patients' mean FA within the right dorsolateral-prefrontal loop. In addition, overall cognitive performance correlated with mean FA within the right lateral orbitofrontal loop (ρ = .39) - but only before controlling for WM lesion count. In contrast, regional volumes of grey-matter structures within these fronto-striatal-thalamic loops (including the thalamus) were not significantly related to CI. The total brain volume was associated with performance in the domain verbal memory (ρ = .43) only. CONCLUSIONS: Microstructural degeneration within specific fronto-striatal-thalamic WM networks, previously characterized as crucial for task-monitoring, better accounts for speed-dependent CI in patients with early active RRMS than global or regional brain volumes. Our findings may advance our understanding of the neural substrates underlying CI characteristic for early RRMS.

Impairment of frequency-specific responses associated with altered electrical activity patterns in auditory thalamus following focal and general demyelination.

Multiple sclerosis is characterized by intermingled episodes of de- and remyelination and the occurrence of white- and grey-matter damage. To mimic the randomly distributed pathophysiological brain lesions observed in MS, we assessed the impact of focal white and grey matter demyelination on thalamic function by directing targeted lysolecithin-induced lesions to the capsula interna (CI), the auditory cortex (A1), or the ventral medial geniculate nucleus (vMGN) in mice. Pathophysiological consequences were compared with those of cuprizone treatment at different stages of demyelination and remyelination. Combining single unit recordings and auditory stimulation in freely behaving mice revealed changes in auditory response profile and electrical activity pattern in the thalamus, depending on the region of the initial insult and the state of remyelination. Cuprizone-induced general demyelination significantly diminished vMGN neuronal activity and frequency-specific responses. Targeted lysolecithin-induced lesions directed either to A1 or to vMGN revealed a permanent impairment of frequency-specific responses, an increase in latency of auditory responses and a reduction in occurrence of burst firing in vMGN neurons. These findings indicate that demyelination of grey matter areas in the thalamocortical system permanently affects vMGN frequency specificity and the prevalence of bursting in the auditory thalamus.

Amygdala enlargement and emotional responses in (autoimmune) temporal lobe epilepsy.

Temporal lobe epilepsy with amygdala enlargement (TLE-AE) is increasingly recognized as a distinct adult electroclinical syndrome. However, functional consequences of morphological alterations of the amygdala in TLE-AE are poorly understood. Here, two emotional stimulation designs were employed to investigate subjective emotional rating and skin conductance responses in a sample of treatment-naïve patients with suspected or confirmed autoimmune TLE-AE (n = 12) in comparison to a healthy control group (n = 16). A subgroup of patients completed follow-up measurements after treatment. As compared to healthy controls, patients with suspected or confirmed autoimmune TLE-AE showed markedly attenuated skin conductance responses and arousal ratings, especially pronounced for anxiety-inducing stimuli. The degree of right amygdala enlargement was significantly correlated with the degree of autonomic arousal attenuation. Furthermore, a decline of amygdala enlargement following prompt aggressive immunotherapy in one patient suffering from severe confirmed autoimmune TLE-AE with a very recent clinical onset was accompanied by a significant improvement of autonomic responses. Findings suggest dual impairments of autonomic and cognitive discrimination of stimulus arousal as hallmarks of emotional processing in TLE-AE. Emotional responses might, at least partially, recover after successful treatment, as implied by first single case data.

Diagnostic Value of Diffusion Tensor Imaging and Positron Emission Tomography in Early Stages of Frontotemporal Dementia.

BACKGROUND: Due to suboptimal sensitivity and specificity of structural and molecular neuroimaging tools, the diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging. OBJECTIVE: Investigation of the sensitivity of diffusion tensor imaging (DTI) and fluorodeoxyglucose positron emission tomography (FDG-PET) to detect cerebral alterations in early stages of bvFTD despite inconspicuous conventional MRI. METHODS: Thirty patients with early stages of bvFTD underwent a detailed neuropsychological examination, cerebral 3T MRI with DTI analysis, and FDG-PET. After 12 months of follow-up, all patients finally fulfilled the diagnosis of bvFTD. Individual FDG-PET data analyses showed that 20 patients exhibited a "typical" pattern for bvFTD with bifrontal and/or temporal hypometabolism (bvFTD/PET+), and that 10 patients showed a "non-typical"/normal pattern (bvFTD/PET-). DTI data were compared with 42 healthy controls in an individual and voxel-based group analysis. To examine the clinical relevance of the findings, associations between pathologically altered voxels of DTI or FDG-PET results and behavioral symptoms were estimated by linear regression analyses. RESULTS: DTI voxel-based group analyses revealed microstructural degeneration in bifrontal and bitemporal areas in bvFTD/PET+ and bvFTD/PET- groups. However, when comparing the sensitivity of individual DTI data analysis with FDG-PET, DTI appeared to be less sensitive. Neuropsychological symptoms were considerably related to neurodegeneration within frontotemporal areas identified by DTI and FDG-PET. CONCLUSION: DTI seems to be an interesting tool for detection of functionally relevant neurodegenerative alterations in early stages of bvFTD, even in bvFTD/PET- patients. However, at a single subject level, it seems to be less sensitive than FDG-PET. Thus, improvement of individual DTI analysis is necessary.

Association of grey matter changes with stability and flexibility of prediction in akinetic-rigid Parkinson's disease.

Parkinson's disease (PD), which is caused by degeneration of dopaminergic neurons in the midbrain, results in a heterogeneous clinical picture including cognitive decline. Since the phasic signal of dopamine neurons is proposed to guide learning by signifying mismatches between subjects' expectations and external events, we here investigated whether akinetic-rigid PD patients without mild cognitive impairment exhibit difficulties in dealing with either relevant (requiring flexibility) or irrelevant (requiring stability) prediction errors. Following our previous study on flexibility and stability in prediction (Trempler et al. J Cogn Neurosci 29(2):298-309, 2017), we then assessed whether deficits would correspond with specific structural alterations in dopaminergic regions as well as in inferior frontal cortex, medial prefrontal cortex, and the hippocampus. Twenty-one healthy controls and twenty-one akinetic-rigid PD patients on and off medication performed a task which required to serially predict upcoming items. Switches between predictable sequences had to be indicated via button press, whereas sequence omissions had to be ignored. Independent of the disease, midbrain volume was related to a general response bias to unexpected events, whereas right putamen volume correlated with the ability to discriminate between relevant and irrelevant prediction errors. However, patients compared with healthy participants showed deficits in stabilisation against irrelevant prediction errors, associated with thickness of right inferior frontal gyrus and left medial prefrontal cortex. Flexible updating due to relevant prediction errors was also affected in patients compared with controls and associated with right hippocampus volume. Dopaminergic medication influenced behavioural performance across, but not within the patients. Our exploratory study warrants further research on deficient prediction error processing and its structural correlates as a core of cognitive symptoms occurring already in early stages of the disease.

Cortex Parcellation Associated Whole White Matter Parcellation in Individual Subjects.

The investigation of specific white matter areas is a growing field in neurological research and is typically achieved through the use of atlases. However, the definition of anatomically based regions remains challenging for the white matter and thus hinders region-specific analysis in individual subjects. In this article, we focus on creating a whole white matter parcellation method for individual subjects where these areas can be associated to cortex regions. This is done by combining cortex parcellation and fiber tracking data. By tracking fibers out of each cortex region and labeling the fibers according to their origin, we populate a candidate image. We then derive the white matter parcellation by classifying each white matter voxel according to the distribution of labels in the corresponding voxel from the candidate image. The parcellation of the white matter with the presented method is highly reliable and is not as dependent on registration as with white matter atlases. This method allows for the parcellation of the whole white matter into individual cortex region associated areas and, therefore, associates white matter alterations to cortex regions. In addition, we compare the results from the presented method to existing atlases. The areas generated by the presented method are not as sharply defined as the areas in most existing atlases; however, they are computed directly in the DWI space of the subject and, therefore, do not suffer from distortion caused by registration. The presented approach might be a promising tool for clinical and basic research to investigate modalities or system specific micro structural alterations of white matter areas in a quantitative manner.

Evidence for early, non-lesional cerebellar damage in patients with multiple sclerosis: DTI measures correlate with disability, atrophy, and disease duration.

BACKGROUND: Common symptoms of multiple sclerosis (MS) such as gait ataxia, poor coordination of the hands, and intention tremor are usually the result of dysfunctionality in the cerebellum. Magnetic resonance imaging (MRI) has frequently failed to detect cerebellar damage in the form of inflammatory lesions in patients presenting with symptoms of cerebellar dysfunction. OBJECTIVE: To detect microstructural cerebellar tissue alterations in early MS patients with a "normal appearing" cerebellum using diffusion tensor imaging (DTI). METHODS: A total of 68 patients with relapsing-remitting MS (RRMS) and without cerebellar lesions and 26 age-matched healthy controls were admitted to high-resolution MRI and DTI to assess microstructure and volume of the cerebellar white matter (CBWM). RESULTS: We found cerebellar fractional anisotropy (FA) and CBWM volume reductions in the group of 68 patients. Interestingly, a subgroup of these patients that was derived by including only patients with early and mild MS (N=23, median age 30 years, median Expanded Disability Status Scale =1.5, median duration 28 months) showed already cerebellar FA but no CBWM volume reductions. FA reductions were correlated with disability, atrophy, and disease duration. CONCLUSION: "Normal appearing" cerebellar white matter can be damaged in a very early stage of RRMS. DTI seems to be a sensitive tool for detecting this hidden cerebellar damage.

Early and Degressive Putamen Atrophy in Multiple Sclerosis.

Putamen atrophy and its long-term progress during disease course were recently shown in patients with multiple sclerosis (MS). Here we investigated retrospectively the time point of atrophy onset in patients with relapsing-remitting MS (RRMS). 68 patients with RRMS and 26 healthy controls (HC) were admitted to 3T MRI in a cross-sectional study. We quantitatively analyzed the putamen volume of individual patients in relation to disease duration by correcting for age and intracranial volume (ICV). Patient's relative putamen volume (RPV), expressed in percent of ICV, was significantly reduced compared to HC. Based on the correlation between RPV and age, we computed the age-corrected RPV deviation (ΔRPV) from HC. Patients showed significantly negative ΔRPV. Interestingly, the age-corrected ΔRPV depended logarithmically on disease duration: Directly after first symptom manifestation, patients already showed a reduced RPV followed by a further degressive volumetric decline. This means that atrophy progression was stronger in the first than in later years of disease. Putamen atrophy starts directly after initial symptom manifestation or even years before, and progresses in a degressive manner. Due to its important role in neurological functions, early detection of putamen atrophy seems necessary. High-resolution structural MRI allows monitoring of disease course.