Structural Imaging Measures of Brain Aging

During the course of normal aging, biological changes occur in the brain that are associated with changes in cognitive ability. This review presents data from neuroimaging studies of primarily “normal” or healthy brain aging. As such, we focus on research in unimpaired or nondemented older adults, but also include findings from lifespan studies that include younger and middle aged individuals as well as from populations with prodromal or clinically symptomatic disease such as cerebrovascular or Alzheimer’s disease. This review predominantly addresses structural MRI biomarkers, such as volumetric or thickness measures from anatomical images, and measures of white matter injury and integrity respectively from FLAIR or DTI, and includes complementary data from PET and cognitive or clinical testing as appropriate. The findings reveal highly consistent age-related differences in brain structure, particularly frontal lobe and medial temporal regions that are also accompanied by age-related differences in frontal and medial temporal lobe mediated cognitive abilities. Newer findings also suggest that degeneration of specific white matter tracts such as those passing through the genu and splenium of the corpus callosum may also be related to age-related differences in cognitive performance. Interpretation of these findings, however, must be tempered by the fact that comorbid diseases such as cerebrovascular and Alzheimer’s disease also increase in prevalence with advancing age. As such, this review discusses challenges related to interpretation of current theories of cognitive aging in light of the common occurrence of these later-life diseases. Understanding the differences between “Normal” and “Healthy” brain aging and identifying potential modifiable risk factors for brain aging is critical to inform potential treatments to stall or reverse the effects of brain aging and possibly extend cognitive health for our aging society.     

Splenium development and early spoken language in human infants

The association between developmental trajectories of language‐related white matter fiber pathways from 6 to 24 months of age and individual differences in language production at 24 months of age was investigated. The splenium of the corpus callosum, a fiber pathway projecting through the posterior hub of the default mode network to occipital visual areas, was examined as well as pathways implicated in language function in the mature brain, including the arcuate fasciculi, uncinate fasciculi, and inferior longitudinal fasciculi. The hypothesis that the development of neural circuitry supporting domain‐general orienting skills would relate to later language performance was tested in a large sample of typically developing infants. The present study included 77 infants with diffusion weighted MRI scans at 6, 12 and 24 months and language assessment at 24 months. The rate of change in splenium development varied significantly as a function of language production, such that children with greater change in fractional anisotropy (FA) from 6 to 24 months produced more words at 24 months. Contrary to findings from older children and adults, significant associations between language production and FA in the arcuate, uncinate, or left inferior longitudinal fasciculi were not observed. The current study highlights the importance of tracing brain development trajectories from infancy to fully elucidate emerging brain–behavior associations while also emphasizing the role of the splenium as a key node in the structural network that supports the acquisition of spoken language.     

What Does Diffusion Tensor Imaging Reveal About the Brain and Cognition in Fetal Alcohol Spectrum Disorders?

Over the past 5 years, Diffusion Tensor Imaging (DTI) has begun to provide new evidence about the effects of prenatal alcohol exposure on white matter development. DTI, which examines microstructural tissue integrity, is sensitive to more subtle white matter abnormalities than traditional volumetric MRI methods. Thus far, the available DTI data suggest that white matter microstructural abnormalities fall on a continuum of severity in Fetal Alcohol Spectrum Disorder (FASD). Abnormalities are prominent in the corpus callosum, but also evident in major anterior-posterior fiber bundles, corticospinal tracts, and cerebellum. These subtle abnormalities are correlated with neurocognitive deficits, especially in processing speed, non-verbal ability, and executive functioning. Future studies using larger samples, increasingly sophisticated DTI methods, and additional functional MRI connectivity measures will better characterize the full range of abnormalities in FASD. Ultimately, these measures may serve as indices of change in future longitudinal studies and in studies of interventions for FASD.     

Sex differences in the IQ-white matter microstructure relationship: A DTI study

Sex differences in the relationship between general intelligence and brain structure are a topic of increasing research interest. Early studies focused mainly on gray and white matter differences using voxel-based morphometry, while more recent studies investigated neural fiber tracts using diffusion tensor imaging (DTI) to analyze the white matter microstructure. In this study we used tract-based spatial statistics (TBSS) on DTI to test how intelligence is associated with brain diffusion indices and to see whether this relationship differs between men and women. 63 Men and women divided into groups of lower and higher intelligence were selected. Whole-brain DTI scans were analyzed using TBSS calculating maps of fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). The results reveal that the white matter microstructure differs between individuals as a function of intelligence and sex. In men, higher intelligence was related to higher FA and lower RD in the corpus callosum. In women, in contrast, intelligence was not related to the white matter microstructure. The higher values of FA and lower values of RD suggest that intelligence is associated with higher myelination and/or a higher number of axons particularly in men. This microstructural difference in the corpus callosum may increase cognitive functioning by reducing inter-hemispheric transfer time and thus account for more efficient brain functioning in men.     

Mapping the development of white matter tracts with diffusion tensor imaging

In this study, the development of white matter was studied using an optimized diffusion tensor imaging (DTI) protocol in 20 normal subjects (10–40 years old). The normal development of white matter tracts was addressed by comparing the diffusion anisotropy results between two sub‐groups: eight adults (26–38 years old) and eight adolescents (13–15 years old). The difference in myelination extent between these two groups as indexed by the fractional anisotropy was identified by conducting a student t‐test of the measured diffusion anisotropy maps. Significant differences (p < 0.01) were detected in the gyrus frontalis medialis (GFM), gyrus temporalis medialis (GTM) and gyrus cinguli (GC), in addition to the developmental changes in corpus callosum. A brief overview of previous published DTI studies in developmental science and current progress in DTI techniques is also given at the end of this paper. It may be useful for readers interested in using DTI to study developmental problems but who are not familiar with the various technical aspects.     

Myelin breakdown mediates age-related slowing in cognitive processing speed in healthy elderly men

Background

To assess the hypothesis that in a sample of very healthy elderly men selected to minimize risk for Alzheimer’s disease (AD) and cerebrovascular disease, myelin breakdown in late-myelinating regions mediates age-related slowing in cognitive processing speed (CPS).

Materials and methods

The prefrontal lobe white matter and the genu of the corpus callosum myelinate later in brain development (late-myelinating white matter; LMWM) and are more vulnerable to breakdown due to the effects of normal aging. An in vivo MRI biomarker of myelin integrity (transverse relaxation rates; R₂) of LMWM was obtained for 38 very healthy elderly adult men (mean age = 66.3 years; SD = 6.0; range = 55–76). To evaluate regional specificity, we also assessed a contrasting early-myelinating region (splenium of the corpus callosum; SWM), which primarily contains axons involved in visual processing. CPS was assessed using the Trail Making Test.

Results

LMWM R₂ and CPS measures were significantly correlated (r = .515, p = .0009), but no significant association between R₂ and CPS was detected in the splenium (p = .409). LMWM R₂, but not SWM R₂, was a significant mediator of the relationship between age and CPS (p = .037).

Conclusions

In this very healthy elderly sample, age-related slowing in CPS is mediated by myelin breakdown in highly vulnerable late-myelinating regions but not in the splenium.     

Cerebral White Matter Integrity and Cognitive Aging: Contributions from Diffusion Tensor Imaging

The integrity of cerebral white matter is critical for efficient cognitive functioning, but little is known regarding the role of white matter integrity in age-related differences in cognition. Diffusion tensor imaging (DTI) measures the directional displacement of molecular water and as a result can characterize the properties of white matter that combine to restrict diffusivity in a spatially coherent manner. This review considers DTI studies of aging and their implications for understanding adult age differences in cognitive performance. Decline in white matter integrity contributes to a disconnection among distributed neural systems, with a consistent effect on perceptual speed and executive functioning. The relation between white matter integrity and cognition varies across brain regions, with some evidence suggesting that age-related effects exhibit an anterior–posterior gradient. With continued improvements in spatial resolution and integration with functional brain imaging, DTI holds considerable promise, both for theories of cognitive aging and for translational application.     

Smaller splenium in children with nonverbal learning disability compared to controls,high-functioning autism and ADHD

The current study investigated morphological differences in the corpus callosum in children ages 8 to 18 years old with nonverbal learning disability (NLD; n = 19), high-functioning autism (HFA; n = 23), predominantly inattentive ADHD (ADHD:PI; n = 23), and combined type ADHD (ADHD:C; n = 25), as well as those demonstrating typical development (n = 57). Midsagittal area of the corpus callosum and five midsagittal anterior-to-posterior corpus callosum segments were examined using magnetic resonance imaging. Controlling for midsagittal brain area and age, no group differences were found for total corpus callosum area. This finding indicates that higher functioning children on the autistic spectrum do not have smaller corpus callosi as has been found in previous research with heterogeneous samples. Following segmentation of the corpus callosum, the NLD group was observed to have significantly smaller splenia compared to all other groups. Smaller splenia in the NLD group was associated with lower WASI PIQ scores but not WASI VIQ scores. Children with HFA were observed to have larger midbody areas than children with NLD and neurotypically developing children. Children with HFA and NLD demonstrated behavioral symptoms of inattention and hyperactivity similar to the ADHD groups indicating that corpus callosum differences seen in the NLD and HFA groups are not related to these behaviors.     

Altered White-Matter Microstructure in Conduct Disorder Is Specifically Associated with Elevated Callous-Unemotional Traits

Adolescents with conduct disorder (CD) and elevated callous-unemotional (CU) traits have been reported to present with a more severe and persistent pattern of antisocial behaviour than those with low levels of CU traits. However, relatively few studies have investigated whether there are differences in brain structure between these subgroups.We acquired diffusion tensor imaging data and used tract-based spatial statistics (TBSS) to compare adolescents with CD and high levels of CU traits (CD/CU+; n?=?18, CD and low levels of CU traits (CD/CU-; n?=?17) and healthy controls (HC; n?=?32) on measures of fractional anisotropy (FA), axial (AD), radial (RD) and mean (MD) diffusivity. Compared to CD/CU- adolescents, those with CD/CU+ presented increased FA and reduced RD and MD (lower diffusivity) in several tracts including: body and splenium of the corpus callosum, right inferior longitudinal fasciculus, ILF; right inferior fronto-occipital fasciculus, IFOF; left superior longitudinal fasciculus, SLF; left cerebral peduncle, bilateral internal capsule, left superior and posterior corona radiata, bilateral thalamic radiation and left external capsule. In addition, relative to CD/CU- individuals, adolescents with CD/CU+ showed lower diffusivity (indexed by reduced RD and MD) in left uncinate fasciculus and bilateral fornix. Finally, relative to healthy controls, CD/CU+ individuals showed lower diffusivity (reduced RD) in the genu and body of the corpus callosum and left anterior corona radiata. These results suggest that CD/CU+ individuals present with white-matter microstructural abnormalities compared to both CD/CU- individuals and age-matched healthy controls. This finding is consistent with emerging evidence suggesting that CD/CU+ represents a distinct subtype of CD, and illustrates the importance of accounting for heterogeneity within CD populations.     

White matter integrity and pictorial reasoning in high-functioning children with autism

The current study investigated the neurobiological role of white matter in visuospatial versus linguistic processing abilities in autism using diffusion tensor imaging. We examined differences in white matter integrity between high-functioning children with autism (HFA) and typically developing controls (CTRL), in relation to the groups’ response times (RT) on a pictorial reasoning task under three conditions: visuospatial, V, semantic, S, and V + S, a hybrid condition allowing language use to facilitate visuospatial transformations.     

Microstructural organization of corpus callosum projections to prefrontal cortex predicts bimanual motor learning

The corpus callosum (CC) is the largest white matter tract in the brain. It enables interhemispheric communication, particularly with respect to bimanual coordination. Here, we use diffusion tensor imaging (DTI) in healthy humans to determine the extent to which structural organization of subregions within the CC would predict how well subjects learn a novel bimanual task. A single DTI scan was taken prior to training. Participants then practiced a bimanual visuomotor task over the course of 2 wk, consisting of multiple coordination patterns. Findings revealed that the predictive power of fractional anisotropy (FA) was a function of CC subregion and practice. That is, FA of the anterior CC, which projects to the prefrontal cortex, predicted bimanual learning rather than the middle CC regions, which connect primary motor cortex. This correlation was specific in that FA correlated significantly with performance of the most difficult frequency ratios tested and not the innately preferred, isochronous frequency ratio. Moreover, the effect was only evident after training and not at initiation of practice. This is the first DTI study in healthy adults which demonstrates that white matter organization of the interhemispheric connections between the prefrontal structures is strongly correlated with motor learning capability.     

Receptive vocabulary and semantic knowledge in children with SLI and children with Down syndrome

Receptive vocabulary and associated semantic knowledge were compared within and between groups of children with specific language impairment (SLI), children with Down syndrome (DS), and typically developing children. To overcome the potential confounding effects of speech or language difficulties on verbal tests of semantic knowledge, a novel task was devised based on picture-based semantic association tests used to assess adult patients with semantic dementia. Receptive vocabulary, measured by word-picture matching, of children with SLI was weak relative to chronological age and to nonverbal mental age but their semantic knowledge, probed across the same lexical items, did not differ significantly from that of vocabulary-matched typically developing children. By contrast, although receptive vocabulary of children with DS was a relative strength compared to nonverbal cognitive abilities (p < .0001), DS was associated with a significant deficit in semantic knowledge (p < .0001) indicative of dissociation between word-picture matching vocabulary and depth of semantic knowledge. Overall, these data challenge the integrity of semantic-conceptual development in DS and imply that contemporary theories of semantic cognition should also seek to incorporate evidence from atypical conceptual development.     

The neuropsychological profile of vascular cognitive impairment not demented: A meta‐analysis

The most common cause of vascular cognitive impairment not demented (VCIND) is cerebral small vessel disease leading to diffuse subcortical white matter lesions. While many studies indicate that the core cognitive features of VCIND are executive dysfunction and impaired processing speed, this finding is not always consistent, and may be partially dependent on the comparison group applied. Hence, we undertook two systematic meta‐analytic reviews on neuropsychological test performance across eight cognitive domains: between VCIND and healthy controls (data from 27 studies), and between VCIND and non‐vascular mild cognitive impairment (nv‐MCI; data from 20 studies). Our quantitative synthesis of the research literature demonstrates that individuals with VCIND show weaknesses across all cognitive domains relative to healthy controls, with the greatest impairment in the domain of processing speed (Md = ?1.36), and the least affected being working memory (Md = ?.48) and visuospatial construction (Md = ?.63). When compared directly with nv‐MCI, individuals with VCIND had significantly greater deficits in processing speed (Md = ?.55) and executive functioning (Md = ?.40), while those with nv‐MCI exhibited a greater relative deficit in delayed memory (Md = .41). Our analyses indicate that disruption to subcortical white matter tracts impairs more cognitive processes than is typically thought to be directly related to the fronto‐subcortical network. The data also suggest that differing brain aetiologies can be responsible for similar cognitive profiles. Although the findings do not evince diagnostic value, they allude to the interconnectivity of disparate cognitive processes and call for further research on the behavioural outcome of network disruption.     

Expanding the Nexus of Cognitive and Psychomotor Abilities

A study was conducted to expand the nexus of cognitive and psychomotor abilities. A cognitive aptitude battery and a psychomotor battery were administered to 429 military recruits. A confirmatory factor analysis yielded higher-order factors of general cognitive ability (g) and psychomotor/technical knowledge (PM/TK). PM/TK was interpreted as Vernon's (1969) practical factor (k:m). In the joint analysis of these batteries, g and PM/TK each accounted for about 31% of the common variance. No residualized lower-order factor accounted for more than 7% PM/TK influenced a broad range of lower-order psychomotor factors. The first practical implication of these findings is that psychomotor tests are expected to be at least generally interchangeable. A second implication is that the incremental validity of psychomotor tests beyond cognitive tests is expected to be small. These findings should help guide test developers and inform personnel selecting agencies regarding the expected utility of psychomotor tests.     

Cognitive empathy moderates the relationship between affective empathy and wellbeing in adolescents with autism spectrum disorder

Background: Individuals with autism spectrum disorder (ASD) reportedly have reduced cognitive empathy (CE), yet intact levels of affective empathy (AE) when compared to typically developing individuals. To date, no research has examined the implications of this empathic imbalance on personal wellbeing (PWB). Method: Twenty four high-functioning adolescents with ASD (M _age = 13.21, SD = 2.83, 14 males) and 24 non-clinical control adolescents (M _age = 13.10, SD = 2.73, 15 males) took part in the present study. CE and AE were measured using the interpersonal reactivity index, while PWB was assessed via the personal wellbeing index-school children. Results: Participants in the ASD group scored significantly lower than the control group on measures of CE and AE. Moderated regression analyses revealed that for the ASD group only, CE appeared to moderate the relationship between AE and PWB. Specifically, when CE was low, the relationship between AE and PWB was significant and negative. However, when CE was high, the relationship between AE and PWB was significant and positive. Conclusions: CE appears central to the PWB of those with ASD. Only when CE is high were participants able to experience the positive relationship between AE and PWB. Interventions that target the cognitive dimensions of empathy may improve PWB.     

The Role of the Corpus Callosum in Interhemispheric Transfer of Information: Excitation or Inhibition?

The corpus callosum is the major neural pathway that connects homologous cortical areas of the two cerebral hemispheres. The nature of how that interhemispheric connection is manifested is the topic of this review; specifically, does the corpus callosum serve to communicate an inhibitory or excitatory influence on the contralateral hemisphere? Several studies take the position that the corpus callosum provides the pathway through which a hemisphere or cortical area can inhibit the other hemisphere or homologous cortical area in order to facilitate optimal functional capacity. Other studies suggest that the corpus callosum integrates information across cerebral hemispheres and thus serves an excitatory function in interhemispheric communication. This review examines these two contrasting theories of interhemispheric communication. Studies of callosotomies, callosal agenesis, language disorders, theories of lateralization and hemispheric asymmetry, and comparative research are critically considered. The available research, no matter how limited, primarily supports the notion that the corpus callosum serves a predominantly excitatory function. There is evidence, however, to support both theories and the possibility remains that the corpus callosum can serve both an inhibitory and excitatory influence on the contralateral hemisphere.     

Cognitive impairment and whole brain diffusion in patients with neuromyelitis optica after acute relapse

The objective of this study investigated cognitive impairments and their correlations with fractional anisotropy (FA) and mean diffusivity (MD) in patients with neuromyelitis optica (NMO) without visible lesions on conventional brain MRI during acute relapse. Twenty one patients with NMO and 21 normal control subjects received several cognitive tests to assess cognitive function. Head diffusion tensor imaging (DTI) of all patients with NMO were collected with a 3-T MR system. Correlations of cognitive test scores and whole brain FA and MD were examined by voxel-based analysis. Region-of-interest analysis was applied to the significantly correlated regions which the most frequently appeared. We found that NMO patients without visible brain lesions had significantly impaired learning and memory, decreased information processing speed, and damaged attention compared with normal control subjects. These impaired cognitive domains were significantly correlated with FA and MD in local regions of corpus callosum, anterior cingulate and medial frontal cortex. In corpus callosum of NMO patients, mean FA was significantly lower and mean MD higher than normal control subjects. Our findings suggest that cognitive impairments in learning and memory, information processing speed and attention occur in NMO patients without visible brain lesions during acute relapse. The impairments in immediate and short-term memory in NMO patients may be due to information encoding deficits in the process of information acquisition. The corpus callosum of such patients may have local microscopic damages that play a role in cognitive impairments during acute relapse.     

Growth of white matter in the adolescent brain: Myelin or axon?

White matter occupies almost half of the human brain. It contains axons connecting spatially segregated modules and, as such, it is essential for the smooth flow of information in functional networks. Structural maturation of white matter continues during adolescence, as reflected in age-related changes in its volume, as well as in its microstructure. Here I review recent observations obtained with magnetic resonance imaging in typically developing adolescents and point out some of the known variations in structural properties of white matter vis-à-vis brain function in health and disease. I conclude by re-focusing the interpretations of MR-based studies of white matter from myelin to axon.     

Parenting,corpus callosum,and executive function in preschool children

In this longitudinal population-based study (N?=?544), we investigated whether early parenting and corpus callosum length predict child executive function abilities at 4 years of age. The length of the corpus callosum in infancy was measured using postnatal cranial ultrasounds at 6 weeks of age. At 3 years, two aspects of parenting were observed: maternal sensitivity during a teaching task and maternal discipline style during a discipline task. Parents rated executive function problems at 4 years of age in five domains of inhibition, shifting, emotional control, working memory, and planning/organizing, using the Behavior Rating Inventory of Executive Function-Preschool Version. Maternal sensitivity predicted less executive function problems at preschool age. A significant interaction was found between corpus callosum length in infancy and maternal use of positive discipline to determine child inhibition problems: The association between a relatively shorter corpus callosum in infancy and child inhibition problems was reduced in children who experienced more positive discipline. Our results point to the buffering potential of positive parenting for children with biological vulnerability.     

Simultaneously cooperative, but serially antagonistic: a neuropsychological study of diagonistic dyspraxia in a case of Marchiafava-Bignami disease

We describe a patient with Marchiafava-Bignami disease who showed, in addition to signs of callosal interruption, a peculiar form of diagonistic dyspraxia. Unlike the typical diagonistic dyspraxia, both of the patient's hands could simultaneously cooperate in a sequence of bimanual actions. More specifically, his right hand could start a commanded action with the cooperation of his left hand. However, once the action was completed, his left hand started an antagonistic action, undoing the result, with the cooperation of his right hand. Once this countermanding action was completed, the original action started again. These antagonistic actions repeated themselves alternately unless he was restrained. The patient's diagonistic dyspraxia was apparent in only some bimanual actions, and he showed no diagonistic dyspraxia when performing voluntary actions; the antagonistic actions occurred in response to oral commands or by imitation. Magnetic resonance imaging showed symmetrical demyelination with partial necrosis in the genu, body, and anterior splenium of the corpus callosum. We speculate that the bimanual coordination is possible because part of the corpus callosum is intact, whereas the antagonistic actions may be caused by conflict between the two hemispheres due to interhemispheric disinhibition elicited by the demyelinated part of the corpus callosum.