The modulation of cerebral activity by performance is another important aging effect. For example, Wierenga et al. Other studies also point to a dissociation between high- and low-performing older adults, with the latter exhibiting less hemispheric asymmetry reduction than the former Cabeza et al. In terms of brain anatomy, normal aging is associated with structural changes, on account of extensive gray matter GM atrophy Raz et al. It is worth noting that, as is the case with cognitive functions, the spatial localization and degree of atrophy are not homogeneous across the brain in older adults for a review see Fjell et al.
The frontal and temporal lobes exhibit the highest degree of GM atrophy. Substantial changes have also been observed in the parietal lobe, whereas the occipital lobe appears to remain relatively intact. Recent findings have also reported GM volume reduction in the cerebellum Good et al. In order to noninvasively assess the structural cerebral changes associated with normal aging in vivo , voxel-based morphometry VBM has now become a routine method in the neuroimaging community. The VBM method enables an automated, quantitative and objective evaluation of the tissue volume GM volume across the brain Kurth et al.
Cross-sectional and longitudinal studies have demonstrated clear relationships between cognitive decline and the atrophy of specific brain regions. For example, reduced performance in episodic memory EM in normal older adults is correlated with reduced volume of the entorhinal cortex of the medial temporal lobe Jessen et al. Similarly, executive deficits in normal aging are associated with greater atrophy of prefrontal regions Raz and Rodrigue, However, only a limited number of longitudinal studies have evaluated the link between cognition in general and GM Nyberg et al.
In the present study, we evaluated the effect of age older group, OG relative to middle-aged group, MAG on GM volume, using a whole brain voxel-related GM analysis, in conjunction with a cognitive-score evaluation. To this end, we focused on how GM volume differs between MAG and OG in domain-specific regions involved in language and semantic memory but also in the domain-general regions involved in transversal cognitive processes and executive functions i.
Moreover, given the fact that cerebellar atrophy occurs with age Good et al. In comparison with standard pipelines for whole brain analyses, the present one allowed us to improve the accuracy of inter-subject alignment during normalization step and removal of supra-tentorial GM which could bias final results. We carried out a whole-brain analysis and specific cerebellar analysis to evaluate GM differences between middle-aged and older adults relative to middle-aged adults, we expected old adults to exhibit smaller GM volume in cerebral and cerebellar regions involved in both domain-general and specific processes, such as frontal areas involved in language processes and executive functioning.
Furthermore, we expected this reduced GM volume to be associated with differences in performance in cognitive tests evaluating the respective processes. There was no difference in education level between groups MAG vs. OG and lOG vs. Participants were right-handed Edinburgh Handedness Inventory; Oldfield, ; had normal or corrected-to-normal vision; and reported no history of neurological disorder or sensorimotor dysfunctions. The demographic and inclusion criteria are reported in Table 1. Several cognitive tests were administered to evaluate the cognitive level of each participant in terms of domain-general and domain-specific processes.
Domain-specific evaluations concerned mainly language and semantic memory and included assessments of vocabulary and verbal intelligence Mill-Hill vocabulary scale; Deltour, ; lexical retrieval and generation picture naming, PN; DO, Metz-Lutz et al. As this test is sensitive to aging, older adults generally perform better than younger participants. Finally, we tested word fluency using a categorical fluency test Cardebat et al.
Cognitive scores and significant differences between groups are reported in Table 2. Table 2. Table 3. None of the participants exhibited abnormalities in brain structures. Cognitive scores were normalized based on the mean and SD considering all participants. In order to evaluate how cognitive performance varies among older adults and classify OG participants in the hOG and lOG, we first evaluated the normal distribution Kolmogorov-Smirnov of the scores for each test.
We controlled for outliers by examining that scores did not exceed three times the interquartile interval.
Next, the GM, WM and CSF tissue classes obtained during the segmentation step, were used to create a custom template based on our sample. For each participant, flow-fields were computed during template creation to provide the transformation matrix from each native image to the template. Finally, images obtained in the previous step were normalized to the MNI space voxel size of 1 mm isotropic , modulated and smoothed using an 8-mm full width at half maximum FWHM Gaussian kernel. Morphological analyses were performed with the general linear model Friston et al.
In addition, in order to prevent potential bias related to brain size and gender differences between groups, the TICV and gender were included in the statistical model, as covariates of no interest. Finally, we converted the MNI coordinates of voxels with maximal statistical significances into Talairach Talairach and Tournoux, coordinates, by using the MNi2TAL function Matthew Brett 3 to facilitate comparisons with other studies.
Based on results reported by previous studies showing the role of the cerebellum in several cognitive domains Buckner, and to deal with the poor alignment performance for cerebellar structures during spatial processing steps of the whole-brain analysis, we performed a specific cerebellum GM voxel based analysis using the SPM toolbox SUIT Diedrichsen, ; Diedrichsen et al. This cerebellar-specific pipeline also allowed us to better remove supra-tentorial GM which could bias final results.
First, for each participant, the anatomical scans were manually reoriented in order to set them to the origin 0, 0, 0; anterior commissure.
Then, GM isolated maps were corrected to exclude images with the GM located outside the cerebellum. The cognitive-test results suggest that aging is mainly associated with lower performances for domain-general processes—and, to a lesser extent, for domain-specific processes. The whole brain voxel-based GM analyses and comparisons between groups revealed significantly smaller GM volume for OG compared to MAG in frontal, parietal, temporal and occipital regions, as well as of the cerebellum Table 3 and Figure 1.
Figure 1. Cerebral regions whole brain analysis showing the significant differences between groups older adults vs. The location of this region corresponds to the lobule crus I of the right cerebellar hemisphere Figure 2. This result was displayed on a two-dimensional cerebellum template implemented in the SUIT toolbox Diedrichsen and Zotow, Figure 3 shows a comparison of the two spatial processing pipelines used. Figure 2. Cerebellum region cerebellar analysis showing significant differences between groups older adults vs.
Figure 3. The present study aimed to assess: 1 how aging impacts GM volume; in relation to; 2 how aging impacts performance in tasks involving both domain-general i.
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The older adults included in this study exhibited: a decreased performance on tests reflecting executive functioning, frontal efficiency and processing speed; and b difficulty in retrieving and generating words and performing semantic processing. Older adults also showed a greater frequency of verbal automatisms. These findings are consistent with previous studies Bherer et al. At the cerebral level, VBM analyses comparing the OG to the MAG revealed that aging was also associated with significantly smaller bilateral GM volume in frontal, temporal, parietal and occipital regions.
Smaller GM volume in the frontal lobe concerned first the middle frontal gyrus, with a greater extent in the right hemisphere. This region is known to be involved in cognitive control and to play a key role in reorienting attention according to the task demands Rossi et al. This pattern is consistent with a number of studies reporting changes in the capacity to switch between tasks or to disregard distractors in older participants Rajah et al. GM volume differences also concerned the bilateral inferior frontal gyrus, as well as the left superior temporal gyrus.
These regions are involved in motor planning and articulation, and in executive processing related to accessing phonological representations Hickok, Finally, significantly smaller GM volume of the bilateral insula, involved in word retrieval and generation Abel et al. Interestingly, the OG in the present study exhibited lower cognitive performance for a number of language tests reflecting lexical retrieval and generation and semantic processing, and recruiting executive functions such as switching, inhibition and strategic search abilities, as well as working memory processes Troyer et al.
Together with behavioral results, the smaller GM volume of frontal areas in aging observed here therefore appears to be consistent with previous studies suggesting a relationship between executive decline and GM volume of the frontal lobe Good et al. The age-related smaller GM volume observed in our study also pertained to regions that are part of a larger fronto-parietal network involved in attentional processes, including the right supramarginal and angular gyri.
These regions are involved in attention processes related to executive functions Seghier, and the control of attentional shifts in space Chen et al. This network, including notably the left frontal cortex as a hub, in relation to the dorsal attentional network DAN and the default-mode-network DMN , have been also reported to play a key role to maintain the memory performance in normal and pathological aging Franzmeier et al. Finally, diminished GM volume of the bilateral superior occipital gyri and transverse temporal gyrus primary auditory cortex was also observed in the OG.
This result is consistent with a previous finding that reported global thinning of the cerebral cortex, including the cerebral regions dedicated to perceptual processing with age Salat et al. To sum up, our findings of age-related smaller GM volume in frontal, temporal and occipital cortical areas consistent with previous results, which suggest that decreased GM volume of these areas is associated with diminished executive efficiency Tisserand et al. Although previous structural and functional studies on cognitive and GM changes in normal aging mostly focused on the cerebral cortex, the present study also addressed GM changes in the cerebellum, by using a specific analysis pipeline optimized for this structure.
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Over the past decades, evidence has indicated that cerebellar functioning extends beyond the scope of classical sensorimotor control and is related to domains such as attention, language, executive function and social cognition. In a recent opinion article, Sokolov et al. Recent results show that the most human cerebellum maps are related to cerebral association networks.
Furthermore, Kelly and Strick found that large regions near crus I and crus II exhibit connections with prefrontal cortex area 46 which is involved in executive processes in non-human primates. Importantly, this cortical circuit between the cerebellum and prefrontal cortex overlaps with regions dedicated to motor control Buckner, Another study revealed that lobule HVIIa, including crus I, is connected to a large association network involved in executive control Habas et al. The cerebellum is also significantly involved in language, social cognition and cognition in general Buckner, Right crus I atrophy in older adults may be related to their lower semantic cognitive scores, given that this region is connected to the left cerebral regions that are thought to be involved in the semantic demands of task processing Petersen et al.
The present VBM study has a number of limitations. In particular, as this analysis is exclusively cross-sectional it provides no information concerning causality and temporal changes.
This issue remains particularly relevant for gaining a greater understanding of the concurrent changes in cognitive scores and GM volume as they relate to cognitive performance. Indeed, one critical question remains regarding the extent to which smaller GM volume in older relative to middle-aged participant also varies according to cognitive performance. It is for example possible that older adults with higher cognitive performance exhibit less GM volume reduction than those with lower cognitive performance.
For example, a recent study adopted a cross-sectional approach to structural MRI to investigate differences in GM volume in relation to cognitive performance Nissim et al. Using a longitudinal approach, another study Tisserand et al. These studies suggested a link between GM volume of the frontal lobe and cognitive performance, suggesting that GM volume in this region might be a predictor of cognitive functioning in older adults.
When it comes to normal or pathological aging, cerebral reserve Katzman, ; Satz, and cognitive reserve Stern, , are key concepts that need to be taken into consideration. Cerebral reserve designates the amount of cerebral deterioration that can be tolerated before a critical threshold is reached whose clinical or functional consequences are inevitable, whereas cognitive reserve refers to the ability to use the available cerebral reserve to perform a task flexibly and efficiently.
With respect to this conceptual framework, several researches on animal and humans posit the benefic role for successful aging of a rich environment and a greater education to maintain cognitive performance relatively well in face of age-related brain modifications and pathology Freret et al. However, due to the relatively small sample of older participant, further analyses comparing GM volume between low- and high performers could not be performed in the present study.
Moreover, our sample size remains too week to discern subtle GM differences or a distinct pattern of results depending on the sex of the participants Weiner et al. Further studies including a larger sample would thus allow to precisely test these hypotheses. Further research, including the collection of genetic, structural and functional brain connectivity information, is also needed on the individual trajectories of the brain structure in normal aging, and in relation to cognitive scores.
Such research would help to make the distinction between transitional phases and normal cognitive and brain aging patterns in pathological settings. The present VBM study aimed to assess the effect of aging on GM and to interpret results in relation to the cognitive performance. Overall, this study provided a broad picture on domain-general cognitive functioning, but also language-specific processes in normal aging, as well as the associated anatomical differences in the whole brain, including the cerebellum.
A decrease of GM volume was observed in several regions in older compared to middle-aged adults, interpreted in relation to lower cognitive scores in tests assessing either domain general or specific processes. These results replicate and further support previous findings suggesting a general decline in cognitive processes associated with smaller GM volume in the course of normal aging.
Moreover, these results emphasize the importance of taking into account the cerebellum structure when studying changes associated with normal aging, which clearly extend beyond the cerebral cortex. These findings open up new perspectives for the development and application of innovative training methods and programs that aim to promote successful normal aging.
MB and NB: conceived the study. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank the participants of this study for their valuable contributions. Abe, O.
Aging 29, — Abel, S. Correct and erroneous picture naming responses in healthy subjects. Alexander, G. Regional network of magnetic resonance imaging grey matter volume in healthy aging. Neuroreport 17, — Ashburner, J. A fast diffeomorphic image registration algorithm. Neuroimage 38, 95— Voxel-based morphometry—the methods. Neuroimage 26, — First, this study only included a small sample size. The small sample size limits the power of the statistical analyses and may have led to false positive or negative findings. Third, cognitive assessment was not performed and evaluated in this study.
A previous study showed that GM damage, especially in the hippocampus and deep GM, has a strong correlation with cognitive impairment in MS Further research should be performed to evaluate the correlation between synthetic qMRI parameters with cognitive impairment in MS. However, in this study, GBBS was used to minimize the partial volume contamination by skeletonizing the GM and projecting the metrics to a cortical ribbon However, considering the limitations of this study, the findings should be clinically interpreted with caution.
Gray matter and white matter abnormalities in online game addiction.
All data from the participants were obtained following the revised Helsinki Declaration of This study was approved by the institutional review board of Juntendo University Hospital. Written informed consent was obtained from each participant after we provided detailed information. As defined by Chard et al. Neurological disability in these patients was assessed by EDSS. Synthetic qMRI was performed using a MAGiC magnetic resonance imaging compilation pulse sequence—a multi-slice, multi-echo, and multi-saturation delay saturation-recovery turbo spin-echo acquisition method.
Combinations of two echo times TEs, We utilized parallel imaging with an acceleration factor of 2. After image acquisition, SyMRI software version 8. Warntjes et al. The estimation of myelin partial volume in this model considers magnetization exchange between the myelin water component trapped between the myelin sheaths and the surrounding intracellular and extracellular water 18 , This was performed by running Bloch equations and optimizing model parameters in a spatially normalized and averaged brain from a group of 20 healthy controls In addition, the myelin measurement is not performed using the amplitude of multiexponential decay parameters, which would be mathematically impossible with only two echoes.
Instead, it measures the dominant, slow-decay component of both T1 and T2 relaxation and the amplitude of PD to infer the presence of myelin. It is therefore the effect of the magnetization exchange of the fast myelin water with the observed cellular water that is detected, and not the fast component itself. We consider the two-echo approach reliable to measure T2 relaxation as it is corrected for RF pulse profile effects and B1 inhomogeneity effects and shows high accuracy in phantom measurements in comparison to a high number of echoes GBSS is an analogue pipeline of tract-based spatial statistics TBSS 50 used to perform voxel-wise statistical analysis on GM and ensures accurate anatomical alignment between subjects by using a skeleton projection step Herein, we used GBSS to reduce the effects of residual spatial misalignment between subjects that may have resulted from the complex cortical geometry and pathology.
In the pipeline, the full Jacobian was internally calculated and used. The resulting GM image was used to create a mean GM skeleton with a threshold of 0. Then, we thresholded the mask at 0. Finally, the total GM mask was created by adding the thresholded synthetic GM and deep GM masks and then applied to the myelin map. The cortical and subcortical areas then were labeled with the Desikan-Killiany atlas 82 ROIs in total. The Shapiro-Wilk test was used to assess the normality of the data. The results were then corrected for multiple comparisons by controlling family-wise error FWE and applying threshold-free cluster enhancement TFCE.
Pairwise comparisons were then performed to detect significant main effects on any area with significant FDR-corrected p -values by conducting nonparametric Mann-Whitney U tests. Group differences in cortical thickness were also assessed using a GLM with one-way ANOVA and corrected for multiple comparisons by Monte Carlo simulation on the significant clusters using 10, permutations. Pairwise comparisons for significant main effects were performed with the Mann-Whitney U test. Calabrese, M. Exploring the origins of grey matter damage in multiple sclerosis.
Nat Rev Neurosci 16 , — Chard, D. Progressive grey matter atrophy in clinically early relapsing-remitting multiple sclerosis. Mult Scler 10 , — Jacobsen, C. MRI evaluation of grey matter atrophy and disease course in multiple sclerosis: an overview of current knowledge. Acta Neurol Scand Suppl , 32—36 Peterson, J. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50 , — Bakshi, R. MRI in multiple sclerosis: current status and future prospects.
Lancet Neurol 7 , — Honce, J. Mult Scler Int , Yoshida, M. Diffusional kurtosis imaging of normal-appearing white matter in multiple sclerosis: preliminary clinical experience. Jpn J Radiol 31 , 50—55 Callaghan, M. Synthetic quantitative MRI through relaxometry modelling. NMR Biomed 29 , — Wilhelm, M. Direct magnetic resonance detection of myelin and prospects for quantitative imaging of myelin density. Vavasour, I. Is the magnetization transfer ratio a marker for myelin in multiple sclerosis? J Magn Reson Imaging 33 , — Gracien, R.
Assessment of cortical damage in early multiple sclerosis with quantitative T2 relaxometry. Changes and variability of proton density and T1 relaxation times in early multiple sclerosis: MRI markers of neuronal damage in the cerebral cortex. Eur Radiol 26 , — MacKay, A. In vivo visualization of myelin water in brain by magnetic resonance. Magn Reson Med 31 , — Laule, C. Myelin water imaging in multiple sclerosis: quantitative correlations with histopathology. Mult Scler 12 , — Myelin water imaging to detect demyelination and remyelination and its validation in pathology.
Brain Pathol 28 , — Yarnykh, V. Fast whole-brain three-dimensional macromolecular proton fraction mapping in multiple sclerosis. Radiology , — Mangeat, G. Changes in structural network are associated with cortical demyelination in early multiple sclerosis. Hum Brain Mapp 39 , — Hagiwara, A. Invest Radiol 52 , — Invest Radiol 54 , 39—47 Warntjes, J.
Rapid magnetic resonance quantification on the brain: Optimization for clinical usage. Magn Reson Med 60 , — Andica, C. Magn Reson Med Sci 16 , 91—92 GrayMatterAnalytics Does joining an innovative team to build native cloud AnalyticsProducts sound exciting to you? GrayMatterAnalytics A new executive order will require that both payers and providers give estimates for out-of-pocket costs, and that hospital share pre-negotiated insurer rates are public. What do you think of this new push for Transparency?
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