White matter alterations in glaucoma and monocular blindness differ outside the visual system.

The degree to which glaucoma has effects in the brain beyond the eye and the visual pathways is unclear. To clarify this, we investigated white matter microstructure (WMM) in 37 tracts of patients with glaucoma, monocular blindness, and controls. We used brainlife.io for reproducibility. White matter tracts were subdivided into seven categories ranging from those primarily involved in vision (the visual white matter) to those primarily involved in cognition and motor control. In the vision tracts, WMM was decreased as measured by fractional anisotropy in both glaucoma and monocular blind subjects compared to controls, suggesting neurodegeneration due to reduced sensory inputs. A test-retest approach was used to validate these results. The pattern of results was different in monocular blind subjects, where WMM properties increased outside the visual white matter as compared to controls. This pattern of results suggests that whereas in the monocular blind loss of visual input might promote white matter reorganization outside of the early visual system, such reorganization might be reduced or absent in glaucoma. The results provide indirect evidence that in glaucoma unknown factors might limit the reorganization as seen in other patient groups following visual loss.

Intra- and interscanner variability of magnetic resonance imaging based volumetry in multiple sclerosis.

Brain volumetric measurements in multiple sclerosis (MS) reflect not only disease-specific processes but also other sources of variability. The latter has to be considered especially in multicenter and longitudinal studies. Here, we compare data generated by three different 3-Tesla magnetic resonance scanners (Philips Achieva; Siemens Verio; GE Signa MR750). We scanned two patients diagnosed with relapsing remitting MS six times per scanner within three weeks (T1w and FLAIR, 3D). We assessed T2-hyperintense lesions by an automated lesion segmentation tool and determined volumes of grey matter (GM), white matter (WM) and whole brain (GM+WM) from the lesion-filled T1-weighted images using voxel-based morphometry (SPM8/VBM8) and SIENAX (FSL). We measured cortical thickness using FreeSurfer from both, lesion-filled and original T1-weighted images. We quantified brain volume changes with SIENA. In both patients, we found significant differences in total lesion volume, global brain tissue volumes and cortical thickness measures between the scanners. Morphometric measures varied remarkably between repeated scans at each scanner, independent of the brain imaging software tool used. We conclude that for cross-sectional multicenter studies, the effect of different scanners has to be taken into account. For longitudinal monocentric studies, the expected effect size should exceed the size of false positive findings observed in this study. Assuming a physiological loss of brain volume of about 0.3% per year in healthy adult subjects (Good et al., 2001), which may double in MS (De Stefano et al., 2010; De Stefano et al., 2015), with current tools reliable estimation of brain atrophy in individual patients is only possible over periods of several years.

Neurodegeneration beyond the primary visual pathways in a population with a high incidence of normal-pressure glaucoma.

PURPOSE: Glaucoma is the most common age-related neurodegenerative eye disease in western society. It is an insidious disease that, when untreated or detected too late, leads inevitably to blindness. An outstanding issue is whether glaucoma should be considered exclusively an eye disease or also a brain disease. To further examine it, we used Diffusion Tensor Imaging (DTI) to study white matter integrity in a Japanese glaucoma population. This population has a very high incidence of normal-pressure glaucoma, in which optic nerve damage occurs in the absence of the elevated eye pressure that characterises the more common form of glaucoma. METHODS: We performed DTI in 30 participants with normal-pressure glaucoma and 21 age-matched healthy controls. We used voxel-wise tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of the white matter of the brain between patients and control group. Whole-brain and region of interest-based analyses served to find associations between diffusion indices and clinical measures of glaucomatous damage. RESULTS: Fractional Anisotropy was significantly lower in glaucoma patients in a cluster in the right occipital lobe (p < 0.05; family-wise error-corrected) comprising fibres of both the optic radiation and the forceps major. Additional analysis confirmed bilateral involvement of the optic radiations and forceps major and additionally revealed damage to the corpus callosum and parietal lobe (p < 0.09; family-wise error-corrected). The region of interest-based analysis revealed a positive association between Fractional Anisotropy of the optic radiation and optic nerve damage. CONCLUSIONS: In this specific population, glaucoma is associated with lower Fractional Anisotropy in the optic radiations, forceps major and corpus callosum. We interpret these reductions as evidence for white matter degeneration in these loci. In particular, the degeneration of the corpus callosum suggests the presence of neurodegeneration of the brain beyond what can be explained on the basis of propagated retinal and pre-geniculate damage. We discuss how this finding links to the emerging view that a brain component that is independent from the eye damage plays a role in the aetiology of glaucoma.

Mindful attention to breath regulates emotions via increased amygdala-prefrontal cortex connectivity.

Mindfulness practice is beneficial for emotion regulation; however, the neural mechanisms underlying this effect are poorly understood. The current study focuses on effects of attention-to-breath (ATB) as a basic mindfulness practice on aversive emotions at behavioral and brain levels. A key finding across different emotion regulation strategies is the modulation of amygdala and prefrontal activity. It is unclear how ATB relevant brain areas in the prefrontal cortex integrate with amygdala activation during emotional stimulation. We proposed that, during emotional stimulation, ATB down-regulates activation in the amygdala and increases its integration with prefrontal regions. To address this hypothesis, 26 healthy controls were trained in mindfulness-based attention-to-breath meditation for two weeks and then stimulated with aversive pictures during both attention-to-breath and passive viewing while undergoing fMRI. Data were controlled for breathing frequency. Results indicate that (1) ATB was effective in regulating aversive emotions. (2) Left dorso-medial prefrontal cortex was associated with ATB in general. (3) A fronto-parietal network was additionally recruited during emotional stimulation. (4) ATB down regulated amygdala activation and increased amygdala-prefrontal integration, with such increased integration being associated with mindfulness ability. Results suggest amygdala-dorsal prefrontal cortex integration as a potential neural pathway of emotion regulation by mindfulness practice.

Visual imagery and functional connectivity in blindness: a single-case study.

We present a case report on visual brain plasticity after total blindness acquired in adulthood. SH lost her sight when she was 27. Despite having been totally blind for 43 years, she reported to strongly rely on her vivid visual imagery. Three-Tesla magnetic resonance imaging (MRI) of SH and age-matched controls was performed. The MRI sequence included anatomical MRI, resting-state functional MRI, and task-related functional MRI where SH was instructed to imagine colours, faces, and motion. Compared to controls, voxel-based analysis revealed white matter loss along SH's visual pathway as well as grey matter atrophy in the calcarine sulci. Yet we demonstrated activation in visual areas, including V1, using functional MRI. Of the four identified visual resting-state networks, none showed alterations in spatial extent; hence, SH's preserved visual imagery seems to be mediated by intrinsic brain networks of normal extent. Time courses of two of these networks showed increased correlation with that of the inferior posterior default mode network, which may reflect adaptive changes supporting SH's strong internal visual representations. Overall, our findings demonstrate that conscious visual experience is possible even after years of absence of extrinsic input.

Mindfulness is associated with intrinsic functional connectivity between default mode and salience networks.

Mindfulness is attention to present moment experience without judgment. Mindfulness practice is associated with brain activity in areas overlapping with the default mode, salience, and central executive networks (DMN, SN, CEN). We hypothesized that intrinsic functional connectivity (iFC; i.e., synchronized ongoing activity) across these networks is associated with mindfulness scores. After 2 weeks of daily 20 min attention to breath training, healthy participants were assessed by mindfulness questionnaires and resting-state functional MRI. Independent component analysis (ICA) of imaging data revealed networks of interest, whose activity time series defined inter-network intrinsic functional connectivity (inter-iFC) by temporal correlation. Inter-iFC between subnetworks of the DMN and SN-and inter-iFC between subnetworks of the SN and left CEN at trend-was correlated with mindfulness scores. Additional control analyses about visual networks' inter-iFC support the specificity of our findings. Results provide evidence that mindfulness is associated with iFC between DMN and SN. Data suggest that ongoing interactions among central intrinsic brain networks link with the ability to attend to current experience without judgment.

Atrophy and structural variability of the upper cervical cord in early multiple sclerosis.

BACKGROUND: Despite agreement about spinal cord atrophy in progressive forms of multiple sclerosis (MS), data on clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) are conflicting. OBJECTIVE: To determine the onset of spinal cord atrophy in the disease course of MS. METHODS: Structural brain magnetic resonance imaging (MRI) was acquired from 267 patients with CIS (85) or RRMS (182) and 64 healthy controls (HCs). The upper cervical cord cross-sectional area (UCCA) was determined at the level of C2/C3 by a segmentation tool and adjusted for focal MS lesions. The coefficient of variation (CV) was calculated from all measurements between C2/C3 and 13 mm above as a measure of structural variability. RESULTS: Compared to HCs (76.1±6.9 mm(2)), UCCA was significantly reduced in CIS patients (73.5±5.8 mm(2), p=0.018) and RRMS patients (72.4±7.0 mm(2), p<0.001). Structural variability was higher in patients than in HCs, particularly but not exclusively in case of focal lesions (mean CV HCs/patients without/with lesions: 2.13%/2.55%/3.32%, all p-values<0.007). UCCA and CV correlated with Expanded Disability Status Scale (EDSS) scores (r =-0.131/0.192, p=0.044/<0.001) and disease duration (r=-0.134/0.300, p=0.039/< 0.001). CV additionally correlated with hand and arm function (r=0.180, p=0.014). CONCLUSION: In MS, cervical cord atrophy already occurs in CIS. In early stages, structural variability may be a more meaningful marker of spinal cord pathology than atrophy.

Spinal cord atrophy in early Huntington's disease.

Despite evidence for spinal cord involvement, it remains unclear whether spinal cord atrophy exists in early Huntington's disease. We studied magnetic resonance images, covering both brain and upper cervical cord, in two cohorts of Huntington's patients and in one cohort of Alzheimer's patients. All cohorts included healthy controls comparable with regard to age and gender. We found significant spinal cord atrophy in both cohorts of Huntington's patients but not in the cohort of Alzheimer's patients. Furthermore, spinal cord atrophy correlated with motor symptoms indicating that spinal cord atrophy occurs in the clinical stages and does not result from abnormal development.

Brain size and white matter content of cerebrospinal tracts determine the upper cervical cord area: evidence from structural brain MRI.

INTRODUCTION: Measurement of the upper cervical cord area (UCCA) from brain MRI may be an effective way to quantify spinal cord involvement in neurological disorders such as multiple sclerosis. However, knowledge on the determinants of UCCA in healthy controls (HCs) is limited. METHODS: In two cohorts of 133 and 285 HCs, we studied the influence of different demographic, body-related, and brain-related parameters on UCCA by simple and partial correlation analyses as well as by voxel-based morphometry (VBM) across both cerebral gray matter (GM) and white matter (WM). RESULTS: First, we confirmed the known but moderate effect of age on UCCA in the older cohort. Second, we studied the correlation of UCCA with sex, body height, and total intracranial volume (TIV). TIV was the only variable that correlated significantly with UCCA after correction for the other variables. Third, we studied the correlation of UCCA with brain-related parameters. Brain volume correlated stronger with UCCA than TIV. Both volumes of the brain tissue compartments GM and WM correlated with UCCA significantly. WM volume explained variance of UCCA after correction for GM volume, whilst the opposite was not observed. Correspondingly, VBM did not yield any brain region, whose GM content correlated significantly with UCCA, whilst cerebral WM content of cerebrospinal tracts strongly correlated with UCCA. This latter effect increased along a craniocaudal gradient. CONCLUSION: UCCA is mainly determined by brain volume as well as by WM content of cerebrospinal tracts.

White-matter lesions drive deep gray-matter atrophy in early multiple sclerosis: support from structural MRI.

BACKGROUND: In MS, the relationship between lesions within cerebral white matter (WM) and atrophy within deep gray matter (GM) is unclear. OBJECTIVE: To investigate the spatial relationship between WM lesions and deep GM atrophy. METHODS: We performed a cross-sectional structural magnetic resonance imaging (MRI) study (3 Tesla) in 249 patients with clinically-isolated syndrome or relapsing-remitting MS (Expanded Disability Status Scale score: median, 1.0; range, 0-4) and in 49 healthy controls. Preprocessing of T1-weighted and fluid-attenuated T2-weighted images resulted in normalized GM images and WM lesion probability maps. We performed two voxel-wise analyses: 1. We localized GM atrophy and confirmed that it is most pronounced within deep GM; 2. We searched for a spatial relationship between WM lesions and deep GM atrophy; to this end we analyzed WM lesion probability maps by voxel-wise multiple regression, including four variables derived from maxima of regional deep GM atrophy (caudate and pulvinar, each left and right). RESULTS: Atrophy of each deep GM region was explained by ipsilateral WM lesion probability, in the area most densely connected to the respective deep GM region. CONCLUSION: We demonstrated that WM lesions and deep GM atrophy are spatially related. Our results are best compatible with the hypothesis that WM lesions contribute to deep GM atrophy through axonal pathology.

Automated morphometry of the visual pathway in primary open-angle glaucoma.

PURPOSE: To establish whether primary open-angle glaucoma (POAG) is associated with a change in volume of the visual pathway structures between the eyes and the visual cortex. METHODS: To answer this question, magnetic resonance imaging (MRI) was used in combination with automated segmentation and voxel-based morphometry (VBM). Eight patients with POAG and 12 age-matched control subjects participated in the study. Only POAG patients with bilateral glaucomatous visual field loss were admitted to the study. The scotoma in both eyes had to include the paracentral region and had to, at least partially, overlap. All participants underwent high-resolution, T(1)-weighted, 3-T MRI scanning[b]. Subsequently, VBM was used to determine the volume of the optic nerves, the optic chiasm, the optic tracts, the lateral geniculate nuclei (LGN), and the optic radiations. Analysis of covariance was used to compare these volumes in the POAG and control groups. The main outcome parameter of the measurement was the volume of visual pathway structures. RESULTS: Compared with the controls, subjects with glaucoma showed reduced volume (P < 0.005) of all structures along the visual pathway, including the optic nerves, the optic chiasm, the optic tracts, the LGN, and the optic radiations. CONCLUSIONS: POAG adversely affects structures along the full visual pathway, from the optic nerve to the optic radiation. Moreover, MRI in combination with automated morphometry can be used to aid the detection and assessment of glaucomatous damage in the brain.

Changes in cortical grey matter density associated with long-standing retinal visual field defects.

Retinal lesions caused by eye diseases such as glaucoma and age-related macular degeneration can, over time, eliminate stimulation of parts of the visual cortex. This could lead to degeneration of inactive cortical neuronal tissue, but this has not been established in humans. Here, we used magnetic resonance imaging to assess the effects of prolonged sensory deprivation in human visual cortex. High-resolution anatomical magnetic resonance images were obtained in subjects with foveal (age-related macular degeneration) and peripheral (glaucoma) retinal lesions as well as age-matched controls. Comparison of grey matter between patient and control groups revealed density reductions in the approximate retinal lesion projection zones in visual cortex. This indicates that long-term cortical deprivation, due to retinal lesions acquired later in life, is associated with retinotopic-specific neuronal degeneration of visual cortex. Such degeneration could interfere with therapeutic strategies such as the future application of artificial retinal implants to overcome lesion-induced visual impairment.

Occipital proton magnetic resonance spectroscopy (1H-MRS) reveals normal metabolite concentrations in retinal visual field defects.

BACKGROUND: Progressive visual field defects, such as age-related macular degeneration and glaucoma, prevent normal stimulation of visual cortex. We investigated whether in the case of visual field defects, concentrations of metabolites such as N-acetylaspartate (NAA), a marker for degenerative processes, are reduced in the occipital brain region. METHODOLOGY/PRINCIPAL FINDINGS: Participants known with glaucoma, age-related macular degeneration (the two leading causes of visual impairment in the developed world), and controls were examined by proton MR spectroscopic ((1)H-MRS) imaging. Absolute NAA, Creatine and Choline concentrations were derived from a single-voxel in the occipital region of each brain hemisphere. No significant differences in metabolites concentrations were found between the three groups. CONCLUSIONS/SIGNIFICANCE: We conclude that progressive retinal visual field defects do not affect metabolite concentration in visual brain areas suggesting that there is no ongoing occipital degeneration. We discuss the possibility that metabolite change is too slow to be detectable.

Functional magnetic resonance imaging of brightness induction in the human visual cortex.

A grey surface on a bright background appears to be darker than the same surface on a dark background. We used functional magnetic resonance imaging to study this phenomenon called brightness induction. While being scanned, participants viewed centre-surround displays in which either centre or surround luminance was modulated in time. In both cases, participants perceive similar brightness changes in the central surface. In the region of the visual cortex encoding this central surface, both modulations evoked comparable functional magnetic resonance imaging responses. However, the surround modulation signal showed a considerable delay relative to the onset of the brightness percept. This suggests that, although correlated, the functional magnetic resonance imaging signals do not bear a direct relationship with perceived brightness. We conclude that retinotopically organized visual cortex does not represent brightness per se.

Visual stimulation, 1H MR spectroscopy and fMRI of the human visual pathways.

The purpose was to assess changes in lactate content and other brain metabolites under visual stimulation in optical chiasm, optic radiations and occipital cortex using multiple voxel MR spectroscopy (MRS). 1H chemical shift imaging (CSI) examinations of transverse planes centered to include the above structures were performed in four subjects at an echo time of 135 ms. Functional MRI (fMRI) was used to confirm the presence of activity in the visual cortex during the visual stimulation. Spectral maps of optical chiasm were of poor quality due to field disturbances caused by nearby large blood vessels and/or eye movements. The optic radiations and the occipital lobe did not show any significant MR spectral change upon visual stimulation, i.e., the peak areas of inositol, choline, creatine, glutamate and N-acetylaspartate were not affected. Reproducible lactate signals were not observed. fMRI confirmed the presence of strong activations in stimulated visual cortex. Prolonged visual stimulation did not cause significant changes in MR spectra. Any signal observed near the 1.33 ppm resonance frequency of the lactate methyl-group was artifactual, originating from lipid signals from outside the volume of interest (VOI). Previous claims about changes in lactate levels in the visual cortex upon visual stimulation may have been based on such erroneous observations.