Age-Related Changes in Episodic Processing of Scenes: A Functional Activation and Connectivity Study.

The posterior-to-anterior shift in aging (PASA) effect is seen as a compensatory model that enables older adults to meet increased cognitive demands to perform comparably as their young counterparts. However, empirical support for the PASA effect investigating age-related changes in the inferior frontal gyrus (IFG), hippocampus, and parahippocampus has yet to be established. 33 older adults and 48 young adults were administered tasks sensitive to novelty and relational processing of indoor/outdoor scenes in a 3-Tesla MRI scanner. Functional activation and connectivity analyses were applied to examine the age-related changes on the IFG, hippocampus, and parahippocampus among low/high-performing older adults and young adults. Significant parahippocampal activation was generally found in both older (high-performing) and young adults for novelty and relational processing of scenes. Younger adults had significantly greater IFG and parahippocampal activation than older adults, and greater parahippocampal activation compared to low-performing older adults for relational processing-providing partial support for the PASA model. Observations of significant functional connectivity within the medial temporal lobe and greater negative left IFG-right hippocampus/parahippocampus functional connectivity for young compared to low-performing older adults for relational processing also supports the PASA effect partially.

The role of regional heterogeneity in age-related differences in functional hemispheric asymmetry: an fMRI study.

Neuroimaging literature has documented age-related hemispheric asymmetry reduction in frontal regions during task performances. As most studies employed working memory paradigms, it is therefore less clear if this pattern of neural reorganization is constrained by working memory processes or it would also emerge in other cognitive domains which are predominantly lateralized. Using blocked functional magnetic resonance imaging (fMRI), the present study used a homophone judgment task and a line judgment task to investigate age-related differences in functional hemispheric asymmetry in language and visuospatial processing respectively. Young and older adults achieved similar task accuracy although older adults required a significantly longer time. Age-related functional hemispheric asymmetry reduction was found only in dorsal inferior frontal gyrus and was associated with better performance when the homophone condition was contrasted against fixation, and not line condition. Our data thus highlights the importance of considering regional heterogeneity of aging effects together with general age-related cognitive processes.

A Comprehensive Analysis of Connectivity and Aging Over the Adult Life Span.

Aging has been associated with decreased intra- and internetwork connectivity during rest and task. Recent work has shown the influential role of the salience network over the default mode network (DMN) and executive control network (ECN). This study comprehensively investigates age-related changes in intra- and internetwork connectivity and effective connectivity between the DMN, ECN, and salience network across the adult life span. Two hundred ten participants completed a working memory task, an inhibition task, and a resting-state functional magnetic resonance imaging scan. Networks were extracted using independent component analysis; then, regression analyses and t-tests between three age groups, 21-40 (younger), 41-60 (middle), and 61-80 (older), were conducted. Older age was associated with decreased intranetwork connectivity. Functional network connectivity analyses revealed older age was associated with increased internetwork connectivity between the salience network and the ECNs and DMNs. In both cases, the effects were more pronounced in the tasks compared to resting state. Granger causality analyses indicated the salience network was influenced by the DMN and ECN in all age groups during both tasks, but not rest. However, middle adults showed increased influence from the salience network to the right ECN compared to younger adults during the flanker task. Taking everything into account, these findings indicate the role of the salience network changes over the life span, which may have implications for the early detection of pathophysiology in older adults.

Adaptation of brain functional and structural networks in aging.

The human brain, especially the prefrontal cortex (PFC), is functionally and anatomically reorganized in order to adapt to neuronal challenges in aging. This study employed structural MRI, resting-state fMRI (rs-fMRI), and high angular resolution diffusion imaging (HARDI), and examined the functional and structural reorganization of the PFC in aging using a Chinese sample of 173 subjects aged from 21 years and above. We found age-related increases in the structural connectivity between the PFC and posterior brain regions. Such findings were partially mediated by age-related increases in the structural connectivity of the occipital lobe within the posterior brain. Based on our findings, it is thought that the PFC reorganization in aging could be partly due to the adaptation to age-related changes in the structural reorganization of the posterior brain. This thus supports the idea derived from task-based fMRI that the PFC reorganization in aging may be adapted to the need of compensation for resolving less distinctive stimulus information from the posterior brain regions. In addition, we found that the structural connectivity of the PFC with the temporal lobe was fully mediated by the temporal cortical thickness, suggesting that the brain morphology plays an important role in the functional and structural reorganization with aging.

Meta-analytic investigations of structural grey matter, executive domain-related functional activations, and white matter diffusivity in obsessive compulsive disorder: an integrative review.

Obsessive-compulsive disorder (OCD) is a debilitating disorder. However, existing neuroimaging findings involving executive function and structural abnormalities in OCD have been mixed. Here we conducted meta-analyses to investigate differences in OCD samples and controls in: Study 1 - grey matter structure; Study 2 - executive function task-related activations during (i) response inhibition, (ii) interference, and (iii) switching tasks; and Study 3 - white matter diffusivity. Results showed grey matter differences in the frontal, striatal, thalamus, parietal and cerebellar regions; task domain-specific neural differences in similar regions; and abnormal diffusivity in major white matter regions in OCD samples compared to controls. Our results reported concurrence of abnormal white matter diffusivity with corresponding abnormalities in grey matter and task-related functional activations. Our findings suggested the involvement of other brain regions not included in the cortico-striato-thalamo-cortical network, such as the cerebellum and parietal cortex, and questioned the involvement of the orbitofrontal region in OCD pathophysiology. Future research is needed to clarify the roles of these brain regions in the disorder.

Age-related differences in effective connectivity of brain regions involved in Japanese kanji processing with homophone judgment task.

Reading is a complex process involving neural networks in which connections may be influenced by task demands and other factors. We employed functional magnetic resonance imaging and dynamic causal modeling to examine age-related influences on left-hemispheric kanji reading networks. During a homophone judgment task, activation in the middle frontal gyrus, and dorsal and ventral inferior frontal gyri were identified, representing areas involved in orthographic, phonological, and semantic processing, respectively. The young adults showed a preference for a semantically-mediated pathway from orthographic inputs to the retrieval of phonological representations, whereas the elderly preferred a direct connection from orthographic inputs to phonological lexicons prior to the activation of semantic representations. These sequential pathways are in line with the lexical semantic and non-semantic routes in the dual-route cascaded model. The shift in reading pathways accompanied by slowed reaction time for the elderly might suggest age-related declines in the efficiency of network connectivity.

A meta-analysis of cerebellar contributions to higher cognition from PET and fMRI studies.

A growing interest in cerebellar function and its involvement in higher cognition have prompted much research in recent years. Cerebellar presence in a wide range of cognitive functions examined within an increasing body of neuroimaging literature has been observed. We applied a meta-analytic approach, which employed the activation likelihood estimate method, to consolidate results of cerebellar involvement accumulated in different cognitive tasks of interest and systematically identified similarities among the studies. The current analysis included 88 neuroimaging studies demonstrating cerebellar activations in higher cognitive domains involving emotion, executive function, language, music, timing and working memory. While largely consistent with a prior meta-analysis by Stoodley and Schmahmann ([2009]: Neuroimage 44:489-501), our results extended their findings to include music and timing domains to provide further insights into cerebellar involvement and elucidate its role in higher cognition. In addition, we conducted inter- and intradomain comparisons for the cognitive domains of emotion, language, and working memory. We also considered task differences within the domain of verbal working memory by conducting a comparison of the Sternberg with the n-back task, as well as an analysis of the differential components within the Sternberg task. Results showed a consistent cerebellar presence in the timing domain, providing evidence for a role in time keeping. Unique clusters identified within the domain further refine the topographic organization of the cerebellum.

Stable signatures of schizophrenia in the cortical-subcortical-cerebellar network using fMRI of verbal working memory.

A dysfunction in working memory (WM) is a core cognitive impairment in schizophrenia that involves the cortical-subcortical-cerebellar network. We propose that in addition to other often-referred markers, the signal reduction in the network during verbal working memory (VWM) is a stable and intrinsic indicator of illness. We presented a Sternberg VWM task to 46 patients with schizophrenia and 46 healthy controls matched on performance accuracy during functional magnetic resonance imaging (fMRI). Reduced activation was demonstrated in the thalamus, cerebellar vermis, pons and the triangular part of the inferior frontal gyrus (IFG) in the patient group. We also found a "failure of deactivation" in the default mode network (DMN) in patients as represented by a low versus high load VWM. In addition, a reduced left lateralization in the triangular and opercular parts of the IFG was observed in the patient group replicating previous "failure of lateralization" findings in schizophrenia. A comparison of long (10 to 19 years) and short (3 to 9 years) durations of illness (DoIs) demonstrated that the DoI was only associated with the activation changes in the middle frontal gyrus and lateral temporal cortex but not with the IFG-subcortico-cerebellar regions observed. These alterations were consistent with the cognitive dysmetria described in the cortical-subcortical-cerebellar network in schizophrenia. In conclusion, the combination of reduced activation in the cortical-subcortical-cerebellar network during VWM in particular, reduced deactivation in the DMN and reduced lateralization in the IFG is thought to be stable neuroimaging signatures of schizophrenia.

Age-related decline in associative learning in healthy Chinese adults.

Paired associates learning (PAL) has been widely used in aging-related research, suggesting an age-related decline in associative learning. However, there are several cognitive processes (attention, spatial and recognition memory, strategy, and associative learning) involved in PAL. It is unclear which component contributes to the decline in PAL performance associated with age effects. The present study determines whether age effects on associative learning are independent of other cognitive processes involved in PAL. Using a validated computerized cognitive program (CANTAB), we examined cognitive performance of associative learning, spatial and recognition memory, attention and strategy use in 184 Singaporean Chinese adults aged from 21 to 80 years old. Linear regression revealed significant age-related decline in associative learning, spatial and recognition memory, and the level of strategy use. This age-related decline in associative learning remains even after adjusting for attention, spatial and recognition memory, and strategy use. These results show that age effects on associative learning are independent of other cognitive processes involved in PAL.

Evolution of hippocampal shapes across the human lifespan.

Aberrant hippocampal morphology plays an important role in the pathophysiology of aging. Volumetric analysis of the hippocampus has been performed in aging studies; however, the shape morphometry--which is potentially more informative in terms of related cognition--has yet to be examined. In this paper, we employed an advanced brain mapping technique, large deformation diffeomorphic metric mapping (LDDMM), and a dimensionality reduction approach, locally linear diffeomorphic metric embedding (LLDME), to explore age-related changes in hippocampal shape as delineated from magnetic resonance (MR) images of 302 healthy adults aged from 18 to 94 years. Compared with the hippocampal volumes, the hippocampal shapes clearly showed the nonlinear trajectory of biological aging across the human lifespan, where the variation of hippocampal shapes by age was characterized by a cubic polynomial. By integrating of LDDMM and LLDME, we were also able to illustrate the average hippocampal shapes in each individual decade. In addition, LDDMM and LLDME facilitated the identification of 63 years as a threshold beyond which hippocampal morphological changes were accelerated. Adults over 63 years of age showed the inward-deformation bilaterally in the head of the hippocampi and the left subiculum regardless of hippocampal volume reduction when compared to adults younger than 63. Hence, we demonstrated that the shape of anatomical structures added another dimension of structural morphological quantification beyond the volume in understanding aging.

A meta-analysis of fMRI studies on Chinese orthographic, phonological, and semantic processing.

A growing body of neuroimaging evidence has shown that Chinese character processing recruits differential activation from alphabetic languages due to its unique linguistic features. As more investigations on Chinese character processing have recently become available, we applied a meta-analytic approach to summarize previous findings and examined the neural networks for orthographic, phonological, and semantic processing of Chinese characters independently. The activation likelihood estimation (ALE) method was used to analyze eight studies in the orthographic task category, eleven in the phonological and fifteen in the semantic task categories. Converging activation among three language-processing components was found in the left middle frontal gyrus, the left superior parietal lobule and the left mid-fusiform gyrus, suggesting a common sub-network underlying the character recognition process regardless of the task nature. With increasing task demands, the left inferior parietal lobule and the right superior temporal gyrus were specialized for phonological processing, while the left middle temporal gyrus was involved in semantic processing. Functional dissociation was identified in the left inferior frontal gyrus, with the posterior dorsal part for phonological processing and the anterior ventral part for semantic processing. Moreover, bilateral involvement of the ventral occipito-temporal regions was found for both phonological and semantic processing. The results provide better understanding of the neural networks underlying Chinese orthographic, phonological, and semantic processing, and consolidate the findings of additional recruitment of the left middle frontal gyrus and the right fusiform gyrus for Chinese character processing as compared with the universal language network that has been based on alphabetic languages.

AveLI: a robust lateralization index in functional magnetic resonance imaging using unbiased threshold-free computation.

The laterality index (LI) is often applied in functional magnetic resonance imaging (fMRI) studies to determine functional hemispheric lateralization. A difficulty in using conventional LI methods lies in ensuring a legitimate computing procedure with a clear rationale. Another problem with LI is dealing with outliers and noise. We propose a method called AveLI that follows a simple and unbiased computational principle using all voxel t-values within regions of interest (ROIs). This method first computes subordinate LIs (sub-LIs) using each of the task-related positive voxel t-values in the ROIs as the threshold as follows: sub-LI=(Lt-Rt)/(Lt+Rt), where Lt and Rt are the sums of the t-values at and above the threshold in the left and right ROIs, respectively. The AveLI is the average of those sub-LIs and indicates how consistently lateralized the performance of the subject is across the full range of voxel t-value thresholds. Its intrinsic weighting of higher t-value voxels in a data-driven manner helps to reduce noise effects. The resistance against outliers is demonstrated using a simulation. We applied the AveLI as well as other "non-thresholding" and "thresholding" LI methods to two language tasks using participants with right- and left-hand preferences. The AveLI showed a moderate index value among 10 examined indices. The rank orders of the participants did not vary between indices. AveLI provides an index that is not only comprehensible but also highly resistant to outliers and to noise, and it has a high reproducibility between tasks and the ability to categorize functional lateralization.

Age-related vulnerabilities along the hippocampal longitudinal axis.

Evidence for an anterior-posterior gradient of age-related volume reduction along the hippocampal longitudinal axis has been reported in normal aging, but functional changes have yet to be systematically investigated. The current study applied an advanced brain mapping technique, large deformation diffeomorphic metric mapping (LDDMM), automatically delineating the hippocampus into the anterior and posterior segments based on anatomical landmarks. We studied this anterior-posterior gradient in terms of structural and functional MRI in 66 participants aged from 19 to 79 years. The results showed age-related structural volume reduction in both anterior and posterior hippocampi, with greater tendency for anterior decrease. FMRI task contrasts that robustly activated the anterior (associative/relational processing) and posterior (novelty) hippocampus independently, showed only significant reduction of activation in the anterior hippocampus as age increased. Our results revealed positive correlation between structural atrophy and functional decrease in the anterior hippocampi, regardless of task performance in normal aging. These findings suggest that anatomy and functions related to the anterior hippocampus may be more vulnerable to aging, than previously thought.

Role of the premotor cortex in leg selection and anticipatory postural adjustments associated with a rapid stepping task in patients with stroke.

The premotor cortex (PMC) plays an important role in selecting and preparing for movement. This study investigates how stroke-induced PMC lesions affect stepping leg selection and anticipatory postural adjustments (APAs) preparation. Fifteen hemi-paretic patients (eight with PMC lesions (PMC(Lesion)) and seven PMC spared (PMC(Spared))) and eight age- and sex-matched healthy adults participated in the study. The subjects performed rapid forward stepping with the right or left leg under simple and choice reaction time conditions. The percentage of trials in which the subject showed the correct initial vertical ground reaction force pattern before lift-off of the stepping leg indicated the accuracy in selecting the designated stepping leg. The latency of bilateral contractions in the tibialis anterior (TA) and the reaction time (RT) of the stepping leg represented the time needed to prepare for stepping-related APAs and stepping movement, respectively. All three groups demonstrated a similar rate of accuracy of the stepping leg selection under both conditions. However, in both conditions, the PMC(Lesion) group exhibited a longer RT and TA contraction latency of the affected leg than the healthy and PMC(Spared) groups. The PMC(Lesion) group also presented a longer TA contraction latency of the unaffected leg than the healthy group in both conditions. These results suggest that the PMC is involved in APAs associated with leg stepping movement and that a PMC lesion in one hemisphere impairs APAs of both the contralateral and ipsilateral legs during stepping.

Neural substrates of phonological selection for Japanese character Kanji based on fMRI investigations.

Japanese and Chinese both share the same ideographic/logographic character system. How these characters are processed, however, is inherently different for each language. We harnessed the unique property of homophone judgment in Japanese kanji to provide an analogous Chinese condition using event-related functional magnetic resonance imaging (fMRI) in 33 native Japanese speakers. We compared two types of kanji: (1) kanji that usually evokes only one pronunciation to Japanese speakers, which is representative of most Chinese characters (monophonic character); (2) kanji that evoked multiple pronunciation candidates, which is typical in Japanese kanji (heterophonic character). Results showed that character pairs with multiple sound possibilities increased activation in posterior regions of the left, middle and inferior frontal gyri (MFG and IFG), the bilateral anterior insulae, and the left anterior cingulate cortex as compared with those of kanji with only one sound. The activity seen in the MFG, dorsal IFG, and ventral IFG in the left posterior lateral prefrontal cortex, which was thought to correspond with language components of orthography, phonology, and semantics, respectively, was discussed in regards to their potentially important roles in information selection among competing sources of the components. A comparison with previous studies suggested that detailed analyses of activation in these language areas could explain differences between Japanese and Chinese, such as a greater involvement of the prefrontal language production regions for Japanese, whereas, for Chinese there is more phonological processing of inputs in the superior temporal gyrus.