Episodic Memory Dysfunction and Effective Connectivity in Adult Patients With Newly Diagnosed Nonlesional Temporal Lobe Epilepsy.

OBJECTIVE: Epilepsy is associated with both changes in brain connectivity and memory function, usually studied in the chronic patients. The aim of this study was to explore the presence of connectivity alterations measured by EEG in the parietofrontal network in patients with temporal lobe epilepsy (TLE), and to examine episodic memory, at the time point of diagnosis. METHODS: The parietofrontal network of newly diagnosed patients with TLE (N = 21) was assessed through electroencephalography (EEG) effective connectivity and compared with that of matched controls (N = 21). Furthermore, we assessed phenomenological aspects of episodic memory in both groups. Association between effective connectivity and episodic memory were assessed through correlation. RESULTS: Patients with TLE displayed decreased episodic (p ≤ 0.001, t = -5.18) memory scores compared with controls at the time point of diagnosis. The patients showed a decreased right parietofrontal connectivity (p = 0.03, F = 4.94) compared with controls, and significantly weaker connectivity in their right compared with their left hemisphere (p = 0.008, t = -2.93). There were no significant associations between effective connectivity and episodic memory scores. CONCLUSIONS: We found changes in both memory function and connectivity at the time point of diagnosis, supporting the notion that TLE involves complex memory functions and brain networks beyond the seizure focus to strongly interconnected brain regions, already early in the disease course. Whether the observed connectivity changes can be interpreted as functionally important to the alterations in memory function, it remains speculative.

Cognition in adult patients with newly diagnosed non-lesional temporal lobe epilepsy.

OBJECTIVE: To evaluate whether cognitive performance is affected in newly diagnosed temporal lobe epilepsy (TLE) and to determine the most vulnerable cognitive domains. METHODS: In this baseline longitudinal study, differences in memory and non-memory cognitive functions were assessed using comprehensive neuropsychological test batteries in 21 adult patients with newly diagnosed non-lesional TLE and individually matched controls. In addition, the analyses included ratings of self-perceived emotional status. RESULTS: The patients performed more poorly than the control group regarding delayed visual memory (p = 0.013) and executive function tasks related to switching (Trail Making Test and verbal fluency shifting; p = 0.025 and p = 0.03, respectively). We found no differences in verbal learning and memory, attention/working memory/processing speed, and other executive functions. SIGNIFICANCE: Our results show that patients with TLE often have specific cognitive deficits at time of diagnosis, even in the absence of structural brain abnormalities. This supports the hypothesis that memory dysfunction is linked to an underlying pathology rather than to the effect of recurrent seizures, long-term use of anti-seizure medication, or other epilepsy-related factors. As certain executive functions are affected at an early stage, the pathology may involve brain regions beyond the temporal lobe and may comprise larger brain networks. These results indicate the need for greater awareness of cognition at the time of diagnosis of TLE and before initiation of treatment, and integration of neuropsychological assessment into early routine clinical care.

Aicardi syndrome and cognitive abilities: A report of five cases.

Aicardi syndrome is a rare neurodevelopmental disorder with agenesis of corpus callosum, chorioretinal lacunae, and infantile spasms as the main features. The outcome is in general severe, with poor cognitive development and difficult-to-treat epilepsy. In this study, we assessed the level of cognitive function of five girls with Aicardi syndrome, using normed population based tests and questionnaires. Their cognitive abilities varied from mild to profound intellectual disabilities. The more severe the epilepsy, the poorer were the cognitive skills. To the best of our knowledge, this is the first study that systematically applies validated cognitive assessment tools to study patients with this syndrome. Knowledge about cognitive functioning is crucial for providing optimal special education and finding appropriate alternative communication with parents and caregivers.

Seizure outcomes of temporal lobe epilepsy surgery in patients with normal MRI and without specific histopathology.

BACKGROUND: Seizure outcome following surgery in pharmacoresistant temporal lobe epilepsy patients with normal magnetic resonance imaging and normal or non-specific histopathology is not sufficiently presented in the literature. METHODS: In a retrospective design, we reviewed data of 263 patients who had undergone temporal lobe epilepsy surgery and identified 26 (9.9%) who met the inclusion criteria. Seizure outcomes were determined at 2-year follow-up. Potential predictors of Engel class I (satisfactory outcome) were identified by logistic regression analyses. RESULTS: Engel class I outcome was achieved in 61.5% of patients, 50% being completely seizure free (Engel class IA outcome). The strongest predictors of satisfactory outcome were typical ictal seizure semiology (p = 0.048) and localised ictal discharges on scalp EEG (p = 0.036). CONCLUSION: Surgery might be an effective treatment choice for the majority of these patients, although outcomes are less favourable than in patients with magnetic resonance imaging-defined lesional temporal lobe epilepsy. Typical ictal seizure semiology and localised ictal discharges on scalp EEG were predictors of Engel class I outcome.

Regional hippocampal volumes and development predict learning and memory.

The hippocampus is an anatomically and functionally heterogeneous structure, but longitudinal studies of its regional development are scarce and it is not known whether protracted maturation of the hippocampus in adolescence is related to memory development. First, we investigated hippocampal subfield development using 170 longitudinally acquired brain magnetic resonance imaging scans from 85 participants aged 8-21 years. Hippocampal subfield volumes were estimated by the use of automated segmentation of 7 subfields, including the cornu ammonis (CA) sectors and the dentate gyrus (DG), while longitudinal subfield volumetric change was quantified using a nonlinear registration procedure. Second, associations between subfield volumes and change and verbal learning/memory across multiple retention intervals (5 min, 30 min and 1 week) were tested. It was hypothesized that short and intermediate memory would be more closely related to CA2-3/CA4-DG and extended, remote memory to CA1. Change rates were significantly different across hippocampal subfields, but nearly all subfields showed significant volume decreases over time throughout adolescence. Several subfield volumes were larger in the right hemisphere and in males, while for change rates there were no hemisphere or sex differences. Partly in support of the hypotheses, greater volume of CA1 and CA2-3 was related to recall and retention after an extended delay, while longitudinal reduction of CA2-3 and CA4-DG was related to learning. This suggests continued regional development of the hippocampus across adolescence and that volume and volume change in specific subfields differentially predict verbal learning and memory over different retention intervals, but future high-resolution studies are called for.

Longitudinal working memory development is related to structural maturation of frontal and parietal cortices.

Parallels between patterns of brain maturation and cognitive development have been observed repeatedly, but studies directly testing the relationships between improvements in specific cognitive functions and structural changes in the brain are lacking. Working memory development extends throughout childhood and adolescence and likely plays a central role for cognitive development in multiple domains and in several neurodevelopmental disorders. Neuroimaging, lesion, and electrophysiological studies indicate that working memory emerges from coordinated interactions of a distributed neural network in which fronto-parietal cortical regions are critical. In the current study, verbal working memory function, as indexed by performance on the Keep Track task, and volumes of brain regions were assessed at two time points in 79 healthy children and adolescents in the age range of 8-22 years. Longitudinal change in cortical and subcortical volumes was quantified by the use of Quantitative Anatomical Regional Change. Improvement in working memory was related to cortical volume reduction in bilateral prefrontal and posterior parietal regions and in regions around the central sulci. Importantly, these relationships were not explained by differences in gender, age, or intelligence level or change in intellectual abilities. Furthermore, the relationships did not interact with age and were not significantly different in children, young adolescents, and old adolescents. The results provide the first direct evidence that structural maturation of a fronto-parietal cortical network supports working memory development.

Brain development and aging: overlapping and unique patterns of change.

Early-life development is characterized by dramatic changes, impacting lifespan function more than changes in any other period. Developmental origins of neurocognitive late-life functions are acknowledged, but detailed longitudinal magnetic resonance imaging studies of brain maturation and direct comparisons with aging are lacking. To these aims, a novel method was used to measure longitudinal volume changes in development (n=85, 8-22 years) and aging (n=142, 60-91 years). Developmental reductions exceeded 1% annually in much of the cortex, more than double to that seen in aging, with a posterior-to-anterior gradient. Cortical reductions were greater than the subcortical during development, while the opposite held in aging. The pattern of lateral cortical changes was similar across development and aging, but the pronounced medial temporal reduction in aging was not precast in development. Converging patterns of change in adolescents and elderly, particularly in the medial prefrontal areas, suggest that late developed cortices are especially vulnerable to atrophy in aging. A key question in future research will be to disentangle the neurobiological underpinnings for the differences and the similarities between brain changes in development and aging.

Mental time travel and default-mode network functional connectivity in the developing brain.

A core brain network is engaged in remembering the past and envisioning the future. This network overlaps with the so-called default-mode network, the activity of which increases when demands for focused attention are low. Because of their shared brain substrates, an intriguing hypothesis is that default-mode activity, measured at rest, is related to performance in separate attention-focused recall and imagination tasks. However, we do not know how functional connectivity of the default-mode network is related to individual differences in reconstruction of the past and imagination of the future. Here, we show that functional connectivity of the default-mode network in children and adolescents is related to the quality of past remembering and marginally to future imagination. These results corroborate previous findings of a common neuronal substrate for memory and imagination and provide evidence suggesting that mental time travel is modulated by the task-independent functional architecture of the default-mode network in the developing brain. A further analysis showed that local cortical arealization also contributed to explain recall of the past and imagination of the future, underscoring the benefits of studying both functional and structural properties to understand the brain basis for complex human cognition.

Becoming consistent: developmental reductions in intraindividual variability in reaction time are related to white matter integrity.

Cognitive development is known to involve improvements in accuracy, capacity, and processing speed. Less is known about the role of performance consistency, and there has been virtually no empirical examination of the neural underpinnings of within-person variability in development. In a sample of 92 healthy children and adolescents aged 8-19 years, we aimed to characterize age-related changes in trial-to-trial intraindividual variability (IIV) of reaction time (RT) and to test whether IIV is related to white matter (WM) integrity as indexed by diffusion tensor imaging. IIV was quantified as the SD of correct RTs in a speeded arrow flanker task, and Tract-Based Spatial Statistics was used to test relationships with diffusion characteristics. Large age-related reductions in IIV in both simple congruent trials and more complex incongruent trials were found. Independently of sex, age, and median RT (mRT), lower IIV was associated with higher fractional anisotropy and lower overall diffusivity. Effects were seen for IIV in one or both trial types in the corticospinal tract, the left superior longitudinal fasciculus, the uncinate fasciculus, the forceps minor, and in the genu and splenium of the corpus callosum. There were no significant associations between mRT and any of the diffusion indices. The findings support the proposition that developmental reductions in IIV reflect maturation of WM connectivity and highlight the importance of considering within-person variability in theories of cognitive development and its neurobiological foundation.

Dissociating memory processes in the developing brain: the role of hippocampal volume and cortical thickness in recall after minutes versus days.

Retention of information over extended time periods places special demands on the brain. The neural correlates of memory performance after a short delay of 30 min and a long delay of 1 week are likely partly different, but we do not know how structural maturation of the brain contributes to the differential development of these functions. This question was investigated in a sample of 107 children and adolescents aged 8-19 years. Measures used were structural magnetic resonance imaging and the Rey Complex Figure Test copy, organizational strategy, and 30-min and 1-week recall. While the amount of details copied and later recalled after both 30 min and 1 week increased with age, the relative saving over 1 week (1-week/30-min ratio score) did not increase with age. Thirty minutes recall performance was related to thinner left orbitofrontal cortex independently of age and organizational strategy measured during copy, possibly reflecting executive components of retrieval or encoding processes. In contrast, the 1-week/30-min ratio, likely reflecting consolidation of memory traces, was related to larger bilateral hippocampal volume. This indicates that differential developmental effects on memory for short and long periods of time are related to differentially developing brain structures.

Morphometry and connectivity of the fronto-parietal verbal working memory network in development.

Two distinctly different maturational processes - cortical thinning and white matter maturation - take place in the brain as we mature from late childhood to adulthood. To what extent does each contribute to the development of complex cognitive functions like working memory? The independent and joint contributions of cortical thickness of regions of the left fronto-parietal network and the diffusion characteristics of the connecting pathway of the left superior longitudinal fasciculus (SLF) in accounting for verbal working memory performance were investigated, using a predefined regions of interest-approach. 108 healthy participants aged 8-19 years underwent MRI, including anatomical and diffusion tensor imaging (DTI), as well as cognitive testing using a digit span task. Radial diffusivity of the SLF, as well as cortical thickness of supramarginal gyrus and rostral middle frontal cortex, were negatively related to digit span forwards performance, independently of age. Radial diffusivity of the SLF was also negatively related to digit span backwards. A multi-modal analysis showed that cortical thickness and SLF microstructure were complementary in explaining working memory span. Furthermore, SLF microstructure and cortical thickness had different impact on working memory performance during the developmental period, suggesting a complex developmental interplay. The results indicate that cortical and white matter maturation each play unique roles in the development of working memory.

The brain dynamics of intellectual development: waxing and waning white and gray matter.

Distributed brain areas support intellectual abilities in adults. How structural maturation of these areas in childhood enables development of intelligence is not established. Neuroimaging can be used to monitor brain development, but studies to date have typically considered single imaging modalities. To explore the impact of structural brain maturation on the development of intelligence, we used a combination of cortical thickness, white matter (WM) volume and WM microstructure in 168 healthy participants aged 8-30 years. Principal component analyses (PCAs) were conducted separately for cortical thickness, WM volume, fractional anisotropy (FA) and mean diffusivity (MD) in 64 different brain regions. For all four parameters, the PCAs revealed a general factor explaining between 40% and 53% of the variance across regions. When tested separately, negative age-independent relationships were found between intellectual abilities and cortical thickness and MD, respectively, while WM volume and FA were positively associated with intellectual abilities. The relationships between intellectual abilities and brain structure varied with age, with stronger relationships seen in children and adolescents than in young adults. Multiple regression analysis with the different imaging measures as simultaneous predictors, showed that cortical thickness, WM volume and MD all yielded unique information in explaining intellectual abilities in development. The present study demonstrates that different imaging modalities and measures give complementary information about the neural substrates of intellectual abilities in development, emphasizing the importance of multimodal imaging in investigations of neurocognitive development.

Neuroanatomical correlates of executive functions in children and adolescents: a magnetic resonance imaging (MRI) study of cortical thickness.

A range of cognitive abilities improves in childhood and adolescence. It has been proposed that the protracted development of executive functions is related to the relatively late maturation of the prefrontal cortex. However, this has rarely been directly investigated. In this cross-sectional study, 98 healthy children and adolescents (8-19 years old) were tested with six tasks considered to index three frequently postulated executive functions; updating (Keep track and Letter memory), inhibition (Antisaccade and Stroop) and shifting (Plus minus and Trail making). Task performance was then related to magnetic resonance imaging (MRI) measures of cortical thickness. The behavioral results did not indicate any clear organization of the executive function measures in the domains updating, inhibition and shifting. Limitations associated with the use of speed-based scores from the tasks considered to index shifting ability were also indicated. Independently of the effects of age, performance on the Keep track task was associated with thinner cortex bilaterally in clusters encompassing parietal and frontal regions, including the left inferior frontal gyrus, while performance on the Antisaccade task was associated with thinner cortex bilaterally in occipital and parietal regions. Further, levels of performance on the Antisaccade and Stroop tasks were related to estimated rates of cortical maturation in posterior brain regions, but not in the prefrontal cortex. The results from the present study add to previous knowledge about the cortical correlates of executive functions by indicating an important role of posterior cerebral areas in executive development.

Differentiating maturational and aging-related changes of the cerebral cortex by use of thickness and signal intensity.

Cortical thickness decreases from childhood throughout life, as estimated by magnetic resonance imaging (MRI). This monotone trajectory does not reflect the fundamentally different neurobiological processes underlying morphometric changes in development versus aging. We hypothesized that intracortical gray matter (GM) and subjacent white matter (WM) T1-weighted signal intensity would distinguish developmental and age-related changes in the cortex better than thickness. Intracortical GM and subjacent WM signal intensity and cortical thickness was measured across the brain surface in a healthy life span sample (n=429, 8-85 years). We also computed the relaxation rate of T2* (R2*) from multiecho sequences and mapped intracortical GM and subjacent WM values to the surface to delineate age-related variability in R2* and to adjust the T1 signal intensity for possible confounds of accumulated iron. While monotone age-related reductions in thickness were found, both intracortical GM and subcortical WM signal intensity showed inverted U patterns with peaks from eight to approximately 30 years of age. The spatial pattern of intracortical neurodevelopment followed a posterior-anterior gradient, with earliest maturation of occipital visual cortices and most protracted in superior frontal regions. From 50s and 60s, substantial signal reductions were observed in several regions, including the insula, cingulate, and inferior temporal gyrus. R2* showed similar patterns but peaked much later than the T1-weighted signal intensity measures. The results are presented as animations yielding detailed depictions of the dynamic regional variability in cortical neurodevelopment and aging and demonstrate that cortical thickness and T1-weighted signal intensity are sensitive to different cortical maturational and aging-related processes.

Intellectual abilities and white matter microstructure in development: a diffusion tensor imaging study.

Higher-order cognitive functions are supported by distributed networks of multiple interconnected cortical and subcortical regions. Efficient cognitive processing depends on fast communication between these regions, so the integrity of the connections between them is of great importance. It is known that white matter (WM) development is a slow process, continuing into adulthood. While the significance of cortical maturation for intellectual development is described, less is known about the relationships between cognitive functions and maturation of WM connectivity. In this cross-sectional study, we investigated the associations between intellectual abilities and development of diffusion tensor imaging (DTI) derived measures of WM microstructure in 168 right-handed participants aged 8-30 years. Independently of age and sex, both verbal and performance abilities were positively related to fractional anisotropy (FA) and negatively related to mean diffusivity (MD) and radial diffusivity (RD), predominantly in the left hemisphere. Further, verbal, but not performance abilities, were associated with developmental differences in DTI indices in widespread regions in both hemispheres. Regional analyses showed relations with both FA and RD bilaterally in the anterior thalamic radiation and the cortico-spinal tract and in the right superior longitudinal fasciculus. In these regions, our results suggest that participants with high verbal abilities may show accelerated WM development in late childhood and a subsequent earlier developmental plateau, in contrast to a steadier and prolonged development in participants with average verbal abilities. Longitudinal data are needed to validate these interpretations. The results provide insight into the neurobiological underpinnings of intellectual development.

When does brain aging accelerate? Dangers of quadratic fits in cross-sectional studies.

Many brain structures show a complex, non-linear pattern of maturation and age-related change. Often, quadratic models (beta(0) + beta(1)age + beta(2)age(2) + epsilon) are used to describe such relationships. Here, we demonstrate that the fitting of quadratic models is substantially affected by seemingly irrelevant factors, such as the age-range sampled. Hippocampal volume was measured in 434 healthy participants between 8 and 85 years of age, and quadratic models were fit to subsets of the sample with different age-ranges. It was found that as the bottom of the age-range increased, the age at which volumes appeared to peak was moved upwards and the estimated decline in the last part of the age-span became larger. Thus, whether children were included or not affected the estimated decline between 60 and 85 years. We conclude that caution should be exerted in inferring age-trajectories from global fit models, e.g. the quadratic model. A nonparametric local smoothing technique (the smoothing spline) was found to be more robust to the effects of different starting ages. The results were replicated in an independent sample of 309 participants.

Life-span changes of the human brain white matter: diffusion tensor imaging (DTI) and volumetry.

Magnetic resonance imaging volumetry studies report inverted U-patterns with increasing white-matter (WM) volume into middle age suggesting protracted WM maturation compared with the cortical gray matter. Diffusion tensor imaging (DTI) is sensitive to degree and direction of water permeability in biological tissues, providing in vivo indices of WM microstructure. The aim of this cross-sectional study was to delineate age trajectories of WM volume and DTI indices in 430 healthy subjects ranging 8-85 years of age. We used automated regional brain volume segmentation and tract-based statistics of fractional anisotropy, mean, and radial diffusivity as markers of WM integrity. Nonparametric regressions were used to fit the age trajectories and to estimate the timing of maximum development and deterioration in aging. Although the volumetric data supported protracted growth into the sixth decade, DTI indices plateaued early in the fourth decade across all tested regions and then declined slowly into late adulthood followed by an accelerating decrease in senescence. Tractwise and voxel-based analyses yielded regional differences in development and aging but did not provide ample evidence in support of a simple last-in-first-out hypothesis of life-span changes.

Brain maturation in adolescence and young adulthood: regional age-related changes in cortical thickness and white matter volume and microstructure.

The development of cortical gray matter, white matter (WM) volume, and WM microstructure in adolescence is beginning to be fairly well characterized by structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI) studies. However, these aspects of brain development have rarely been investigated concurrently in the same sample and hence the relations between them are not understood. We delineated the age-related changes in cortical thickness, regional WM volume, and diffusion characteristics and investigated the relationships between these properties of brain development. One hundred and sixty-eight healthy participants aged 8-30 years underwent sMRI and DTI. The results showed regional age-related cortical thinning, WM volume increases, and changes in diffusion parameters. Cortical thickness was the most strongly age-related parameter. All classes of measures showed unique associations with age. The results indicate that cortical thinning in adolescence cannot be explained by WM maturation in underlying regions as measured by volumetry or DTI. Moderate associations between cortical thickness and both volume and diffusion parameters in underlying WM regions were also found, although the relationships were not strong. It is concluded that none of the measures are redundant and that the integration of the 3 will yield a more complete understanding of brain maturation.

Heterogeneity in subcortical brain development: A structural magnetic resonance imaging study of brain maturation from 8 to 30 years.

Brain development during late childhood and adolescence is characterized by decreases in gray matter (GM) and increases in white matter (WM) and ventricular volume. The dynamic nature of development across different structures is, however, not well understood, and the present magnetic resonance imaging study took advantage of a whole-brain segmentation approach to describe the developmental trajectories of 16 neuroanatomical volumes in the same sample of children, adolescents, and young adults (n = 171; range, 8-30 years). The cerebral cortex, cerebral WM, caudate, putamen, pallidum, accumbens area, hippocampus, amygdala, thalamus, brainstem, cerebellar GM, cerebellar WM, lateral ventricles, inferior lateral ventricles, third ventricle, and fourth ventricle were studied. The cerebral cortex was further analyzed in terms of lobar thickness and surface area. The results revealed substantial heterogeneity in developmental trajectories. GM decreased nonlinearly in the cerebral cortex and linearly in the caudate, putamen, pallidum, accumbens, and cerebellar GM, whereas the amygdala and hippocampus showed slight, nonlinear increases in GM volume. WM increased nonlinearly in both the cerebrum and cerebellum, with an earlier maturation in cerebellar WM. In addition to similarities in developmental trajectories within subcortical regions, our results also point to differences between structures within the same regions: among the basal ganglia, the caudate showed a weaker relationship with age than the putamen and pallidum, and in the cerebellum, differences were found between GM and WM development. These results emphasize the importance of studying a wide range of structural variables in the same sample, for a broader understanding of brain developmental principles.