Cognitive reserve in granulin-related frontotemporal dementia: from preclinical to clinical stages

OBJECTIVE Consistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+). METHODS Education and occupation attainments were assessed and combined to define Reserve Index (RI) in 32 FTD patients, i.e. 12 GRN+ and 20 GRN-, and in 17 aGRN+. Changes in functional connectivity were estimated by resting state fMRI, focusing on the salience network (SN), executive network (EN) and bilateral frontoparietal networks (FPNs). Cognitive status was measured by FTD-modified Clinical Dementia Rating Scale. RESULTS In FTD patients higher level of premorbid cognitive reserve was associated with reduced connectivity within the SN and the EN. EN was more involved in FTD patients without GRN mutations, while SN was more affected in GRN pathology. In aGRN+, cognitive reserve was associated with reduced SN. CONCLUSIONS This study suggests that cognitive reserve modulates functional connectivity in patients with FTD, even in monogenic disease. In GRN inherited FTD, cognitive reserve mechanisms operate even in presymptomatic to clinical stages

Stimulus-Related Independent Component and Voxel-Wise Analysis of Human Brain Activity during Free Viewing of a Feature Film

Understanding how the brain processes stimuli in a rich natural environment is a fundamental goal of neuroscience. Here, we showed a feature film to 10 healthy volunteers during functional magnetic resonance imaging (fMRI) of hemodynamic brain activity. We then annotated auditory and visual features of the motion picture to inform analysis of the hemodynamic data. The annotations were fitted to both voxel-wise data and brain network time courses extracted by independent component analysis (ICA). Auditory annotations correlated with two independent components (IC) disclosing two functional networks, one responding to variety of auditory stimulation and another responding preferentially to speech but parts of the network also responding to non-verbal communication. Visual feature annotations correlated with four ICs delineating visual areas according to their sensitivity to different visual stimulus features. In comparison, a separate voxel-wise general linear model based analysis disclosed brain areas preferentially responding to sound energy, speech, music, visual contrast edges, body motion and hand motion which largely overlapped the results revealed by ICA. Differences between the results of IC- and voxel-based analyses demonstrate that thorough analysis of voxel time courses is important for understanding the activity of specific sub-areas of the functional networks, while ICA is a valuable tool for revealing novel information about functional connectivity which need not be explained by the predefined model. Our results encourage the use of naturalistic stimuli and tasks in cognitive neuroimaging to study how the brain processes stimuli in rich natural environments

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis

Extra-Visual Functional and Structural Connection Abnormalities in Leber's Hereditary Optic Neuropathy

We assessed abnormalities within the principal brain resting state networks (RSNs) in patients with Leber's hereditary optic neuropathy (LHON) to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT) MRI data. Neuro-ophthalmologic assessment, DT MRI and RS fMRI data were acquired from 13 LHON patients and 13 healthy controls. RS fMRI data were analyzed using independent component analysis and SPM5. A DT MRI connectivity-based parcellation analysis was performed using the primary visual and auditory cortices, bilaterally, as seed regions. Compared to controls, LHON patients had a significant increase of RS fluctuations in the primary visual and auditory cortices, bilaterally. They also showed decreased RS fluctuations in the right lateral occipital cortex and right temporal occipital fusiform cortex. Abnormalities of RS fluctuations were correlated significantly with retinal damage and disease duration. The DT MRI connectivity-based parcellation identified a higher number of clusters in the right auditory cortex in LHON vs. controls. Differences of cluster-centroid profiles were found between the two groups for all the four seeds analyzed. For three of these areas, a correspondence was found between abnormalities of functional and structural connectivities. These results suggest that functional and structural abnormalities extend beyond the visual network in LHON patients. Such abnormalities also involve the auditory network, thus corroborating the notion of a cross-modal plasticity between these sensory modalities in patients with severe visual deficits

Assessing the Influence of Different ROI Selection Strategies on Functional Connectivity Analyses of fMRI Data Acquired During Steady-State Conditions

In blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI), assessing functional connectivity between and within brain networks from datasets acquired during steady-state conditions has become increasingly common. However, in contrast to connectivity analyses based on task-evoked signal changes, selecting the optimal spatial location of the regions of interest (ROIs) whose timecourses will be extracted and used in subsequent analyses is not straightforward. Moreover, it is also unknown how different choices of the precise anatomical locations within given brain regions influence the estimates of functional connectivity under steady-state conditions. The objective of the present study was to assess the variability in estimates of functional connectivity induced by different anatomical choices of ROI locations for a given brain network. We here targeted the default mode network (DMN) sampled during both resting-state and a continuous verbal 2-back working memory task to compare four different methods to extract ROIs in terms of ROI features (spatial overlap, spatial functional heterogeneity), signal features (signal distribution, mean, variance, correlation) as well as strength of functional connectivity as a function of condition. We show that, while different ROI selection methods produced quantitatively different results, all tested ROI selection methods agreed on the final conclusion that functional connectivity within the DMN decreased during the continuous working memory task compared to rest

Brain Structural Networks Associated with Intelligence and Visuomotor Ability

Increasing evidence indicates that multiple structures in the brain are associated with intelligence and cognitive function at the network level. The association between the grey matter (GM) structural network and intelligence and cognition is not well understood. We applied a multivariate approach to identify the pattern of GM and link the structural network to intelligence and cognitive functions. Structural magnetic resonance imaging was acquired from 92 healthy individuals. Source-based morphometry analysis was applied to the imaging data to extract GM structural covariance. We assessed the intelligence, verbal fluency, processing speed, and executive functioning of the participants and further investigated the correlations of the GM structural networks with intelligence and cognitive functions. Six GM structural networks were identified. The cerebello-parietal component and the frontal component were significantly associated with intelligence. The parietal and frontal regions were each distinctively associated with intelligence by maintaining structural networks with the cerebellum and the temporal region, respectively. The cerebellar component was associated with visuomotor ability. Our results support the parieto-frontal integration theory of intelligence by demonstrating how each core region for intelligence works in concert with other regions. In addition, we revealed how the cerebellum is associated with intelligence and cognitive functions

Stronger Neural Modulation by Visual Motion Intensity in Autism Spectrum Disorders

Theories of autism spectrum disorders (ASD) have focused on altered perceptual integration of sensory features as a possible core deficit. Yet, there is little understanding of the neuronal processing of elementary sensory features in ASD. For typically developed individuals, we previously established a direct link between frequency-specific neural activity and the intensity of a specific sensory feature: Gamma-band activity in the visual cortex increased approximately linearly with the strength of visual motion. Using magnetoencephalography (MEG), we investigated whether in individuals with ASD neural activity reflect the coherence, and thus intensity, of visual motion in a similar fashion. Thirteen adult participants with ASD and 14 control participants performed a motion direction discrimination task with increasing levels of motion coherence. A polynomial regression analysis revealed that gamma-band power increased significantly stronger with motion coherence in ASD compared to controls, suggesting excessive visual activation with increasing stimulus intensity originating from motion-responsive visual areas V3, V6 and hMT/V5. Enhanced neural responses with increasing stimulus intensity suggest an enhanced response gain in ASD. Response gain is controlled by excitatory-inhibitory interactions, which also drive high-frequency oscillations in the gamma-band. Thus, our data suggest that a disturbed excitatoryinhibitory balance underlies enhanced neural responses to coherent motion in ASD

Non-Stationarity in the “Resting Brain’s” Modular Architecture

Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain’s modular organization and assign each region to a “meta-modular” group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer’s dementia and 56 cognitively normal elderly subjects matched 1∶2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer’s disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer’s dementia

The association between stress and mood across the adult lifespan on default mode network

Aging of brain structure and function is a complex process characterized by high inter- and intra-individual variability. Such variability may arise from the interaction of multiple factors, including exposure to stressful experience and mood variation, across the lifespan. Using a multimodal neuroimaging and neurocognitive approach, we investigated the association of stress, mood and their interaction, in the structure and function of the default mode network (DMN), both during rest and task-induced deactivation, throughout the adult lifespan. Data confirmed a decreased functional connectivity (FC) and task-induced deactivation of the DMN during the aging process and in subjects with lower mood; on the contrary, an increased FC was observed in subjects with higher perceived stress. Surprisingly, the association of aging with DMN was altered by stress and mood in specific regions. An increased difficulty to deactivate the DMN was noted in older participants with lower mood, contrasting with an increased deactivation in individuals presenting high stress, independently of their mood levels, with aging. Interestingly, this constant interaction across aging was globally most significant in the combination of high stress levels with a more depressed mood state, both during resting state and task-induced deactivations. The present results contribute to characterize the spectrum of FC and deactivation patterns of the DMN, highlighting the crucial association of stress and mood levels, during the adult aging process. These combinatorial approaches may help to understand the heterogeneity of the aging process in brain structure and function and several states that may lead to neuropsychiatric disorders.The work was supported by SwitchBox-FP7-HEALTH-2010-Grant 259772-2 and by ON.2, O NOVO NORTE, North Portugal Regional Operational Programme 2007/2013, of the National strategic Reference Framework (NSRF) 2007/2013, through the European Regional Development Fund (ERDF)info:eu-repo/semantics/publishedVersio

The supernatural characters and powers of sacred trees in the Holy Land

This article surveys the beliefs concerning the supernatural characteristics and powers of sacred trees in Israel; it is based on a field study as well as a survey of the literature and includes 118 interviews with Muslims and Druze. Both the Muslims and Druze in this study attribute supernatural dimensions to sacred trees which are directly related to ancient, deep-rooted pagan traditions. The Muslims attribute similar divine powers to sacred trees as they do to the graves of their saints; the graves and the trees are both considered to be the abode of the soul of a saint which is the source of their miraculous powers. Any violation of a sacred tree would be strictly punished while leaving the opportunity for atonement and forgiveness. The Druze, who believe in the transmigration of souls, have similar traditions concerning sacred trees but with a different religious background. In polytheistic religions the sacred grove/forest is a centre of the community's official worship; any violation of the trees is regarded as a threat to the well being of the community. Punishments may thus be collective. In the monotheistic world (including Christianity, Islam and Druze) the pagan worship of trees was converted into the worship/adoration of saints/prophets; it is not a part of the official religion but rather a personal act and the punishments are exerted only on the violating individual