Rosanna K. Olsen

Neural Basis of Genetically Determined Visuospatial Construction Deficit in Williams Syndrome

A unique opportunity to understand genetic determinants of cognition is offered by Williams syndrome (WS), a well-characterized hemideletion on chromosome 7q11.23 that causes extreme, specific weakness in visuospatial construction (the ability to visualize an object as a set of parts or construct a replica). Using multimodal neuroimaging, we identified a neural mechanism underlying the WS visuoconstructive deficit. Hierarchical assessment of visual processing with fMRI showed isolated hypoactivation in WS in the parietal portion of the dorsal stream. In the immediately adjacent parietooccipital/intraparietal sulcus, structural neuroimaging showed a gray matter volume reduction in participants with WS. Path analysis demonstrated that the functional abnormalities could be attributed to impaired input from this structurally altered region. Our observations confirm a longstanding hypothesis about dorsal stream dysfunction in WS, demonstrate effects of a localized abnormality on visual information processing in humans, and define a systems-level phenotype for mapping genetic determinants of visuoconstructive function.

Shared and distinct neurophysiological components of the digits forward and backward tasks as revealed by functional neuroimaging

The digits forward (DF) and backward (DB) tasks are widely used neuropsychological measures believed to tap overlapping systems of phonological processing and working memory. Studies of focal brain lesions have partially elucidated the brain regions essential for these tasks; however relatively little information exists on the underlying functional neuroanatomy in the intact brain. We therefore examined the shared and separate neural systems of these tasks in two positron emission tomography (PET) experiments. In Experiment 1, eight healthy participants performed verbal DF, DB, and a sensorimotor control task during measurement of regional cerebral blood flow (rCBF). DF and DB each activated frontal, parietal, and cerebellar regions as well as prominently activating medial occipital cortex. To eliminate possible visuospatial confounds, Experiment 2 replicated the first experiment in six additional healthy participants who were blindfolded during the study. No differences in activation were found between the two experimental groups. Combined data from both experiments demonstrate that DF and DB rely upon a largely overlapping functional neural system associated with working memory, most notably right dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL) as well as the anterior cingulate, a region associated with attentional effort. The degree of activation increased linearly with increasing task difficulty in DF. DB additionally recruited bilateral DLPFC, left IPL, and Brocas area. Medial occipital cortex (including higher and lower visual processing areas) was robustly activated in both DF and DB and could not be attributed to visual processing per se, suggesting a possible visual imagery strategy for these aural-verbal tasks.

The hippocampus supports multiple cognitive processes through relational binding and comparison.

It has been well established that the hippocampus plays a pivotal role in explicit long-term recognition memory. However, findings from amnesia, lesion and recording studies with non-human animals, eye-movement recording studies, and functional neuroimaging have recently converged upon a similar message: the functional reach of the hippocampus extends far beyond explicit recognition memory. Damage to the hippocampus affects performance on a number of cognitive tasks including recognition memory after short and long delays and visual discrimination. Additionally, with the advent of neuroimaging techniques that have fine spatial and temporal resolution, findings have emerged that show the elicitation of hippocampal responses within the first few 100 ms of stimulus/task onset. These responses occur for novel and previously viewed information during a time when perceptual processing is traditionally thought to occur, and long before overt recognition responses are made. We propose that the hippocampus is obligatorily involved in the binding of disparate elements across both space and time, and in the comparison of such relational memory representations. Furthermore, the hippocampus supports relational binding and comparison with or without conscious awareness for the relational representations that are formed, retrieved and/or compared. It is by virtue of these basic binding and comparison functions that the reach of the hippocampus extends beyond long-term recognition memory and underlies task performance in multiple cognitive domains.

Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: Towards a harmonized segmentation protocol

OBJECTIVE An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol. METHOD MRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement. RESULTS The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail. CONCLUSIONS The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

Genetic Contributions to Human Gyrification: Sulcal Morphometry in Williams Syndrome

Although gyral and sulcal patterns are highly heritable, and emerge in a tightly controlled sequence during development, very little is known about specific genetic contributions to abnormal gyrification or the resulting functional consequences. Williams syndrome (WS), a genetic disorder caused by hemizygous microdeletion on chromosome 7q11.23 and characterized by abnormal brain structure and striking cognitive (impairment in visuospatial construction) and behavioral (hypersocial/anxious) phenotypes, offers a unique opportunity to study these issues. We performed a detailed analysis of sulcal depth based on geometric cortical surface representations constructed from high-resolution magnetic resonance imaging scans acquired from participants with WS and from healthy controls who were matched for age, sex, and intelligence quotient, and compared between-group differences with those obtained from a voxel-based morphometry analysis. We found bilateral reductions in sulcal depth in the intraparietal/occipitoparietal sulcus (PS) in the brains of participants with WS, as well as in the collateral sulcus and the orbitofrontal region in the left hemisphere. The left-hemisphere PS in the WS group averaged 8.5 mm shallower than in controls. Sulcal depth findings in the PS corresponded closely to measures of reduced gray matter volume in the same area, providing evidence that the gray matter volume loss and abnormal sulcal geometry may be related. In the context of previous functional neuroimaging findings demonstrating functional alterations in the same cortical regions, our results further define the neural endophenotype underlying visuoconstructive deficits in WS, set the stage for defining the effects of specific genes, and offer insight into genetic mechanisms of cortical gyrification.

Performance-related sustained and anticipatory activity in human medial temporal lobe during delayed match-to-sample.

The medial temporal lobe (MTL)—hippocampus and surrounding perirhinal, parahippocampal, and entorhinal cortical areas—has long been known to be critical for long-term memory for events. Recent functional neuroimaging and neuropsychological data in humans performing short-delay tasks suggest that the MTL also contributes to performance even when retention intervals are brief, and single-unit data in rodents reveal sustained, performance-related delay activity in the MTL during delayed-non-match-to-sample tasks. The current study used functional magnetic resonance imaging to examine the relationship between activation in human MTL subregions and performance during a delayed-match-to-sample task with repeated (non-trial-unique) stimuli. On critical trials, the presentation of two faces was followed by a 30 s delay period, after which participants performed two-alternative forced-choice recognition. Functional magnetic resonance imaging revealed significant delay period activity in anterior hippocampus, entorhinal cortex, and perirhinal cortex over the 30 s retention interval, with the magnitude of activity being significantly higher on subsequently correct compared with subsequently incorrect trials. In contrast, posterior hippocampus, parahippocampal cortex, and fusiform gyrus activity linearly increased across the 30 s delay, suggesting an anticipatory response, and activity in parahippocampal cortex and hippocampus was greater during the probe period on correct compared with incorrect trials. These results indicate that at least two patterns of MTL delay period activation—sustained and anticipatory—are present during performance of short-delay recognition memory tasks, providing novel evidence that multiple processes govern task performance. Implications for understanding the role of the hippocampus and surrounding MTL cortical areas in recognition memory after short delays are discussed.

Reading, hearing, and the planum temporale

Many neuroimaging studies of single-word reading have been carried out over the last 15 years, and a consensus as to the brain regions relevant to this task has emerged. Surprisingly, the planum temporale (PT) does not appear among the catalog of consistently active regions in these investigations. Recently, however, several studies have offered evidence suggesting that the left posteromedial PT plays a role in both speech production and speech perception. It is not clear, then, why so many neuroimaging studies of single-word reading--a task requiring speech production--have tended not to find evidence of PT involvement. In the present work, we employed a high-powered rapid event-related fMRI paradigm involving both single pseudoword reading and single pseudoword listening to assess activity related to reading and speech perception in the PT as a function of the degree of spatial smoothing applied to the functional images. We show that the speech area of the PT [Sylvian-parietal-temporal (Spt)] is best identified when only a moderate (5 mm) amount of spatial smoothing is applied to the data before statistical analysis. Moreover, increasing the smoothing window to 10 mm obliterates activation in the PT, suggesting that failure to find PT activation in past studies may relate to this factor.

The effect of lifelong bilingualism on regional grey and white matter volume

Lifelong bilingualism is associated with the delayed diagnosis of dementia, suggesting bilingual experience is relevant to brain health in aging. While the effects of bilingualism on cognitive functions across the lifespan are well documented, less is known about the neural substrates underlying differential behaviour. It is clear that bilingualism affects brain regions that mediate language abilities and that these regions are at least partially overlapping with those that exhibit age-related decline. Moreover, the behavioural advantages observed in bilingualism are generally found in executive function performance, suggesting that the frontal lobes may also be sensitive to bilingualism, which exhibit volume reductions with age. The current study investigated structural differences in the brain of lifelong bilingual older adults (n=14, mean age=70.4) compared with older monolinguals (n=14, mean age=70.6). We employed two analytic approaches: 1) we examined global differences in grey and white matter volumes; and, 2) we examined local differences in volume and cortical thickness of specific regions of interest previously implicated in bilingual/monolingual comparisons (temporal pole) or in aging (entorhinal cortex and hippocampus). We expected bilinguals would exhibit greater volume of the frontal lobe and temporal lobe (grey and white matter), given the importance of these regions in executive and language functions, respectively. We further hypothesized that regions in the medial temporal lobe, which demonstrate early changes in aging and exhibit neural pathology in dementia, would be more preserved in the bilingual group. As predicted, bilinguals exhibit greater frontal lobe white matter compared with monolinguals. Moreover, increasing age was related to decreasing temporal pole cortical thickness in the monolingual group, but no such relationship was observed for bilinguals. Finally, Stroop task performance was positively correlated with frontal lobe white matter, emphasizing the importance of preserved white matter in maintaining executive function in aging. These results underscore previous findings implicating an association between bilingualism and preserved frontal and temporal lobe function in aging. This article is part of a Special Issue entitled SI: Memory Å.

Working memory and amnesia: The role of stimulus novelty

Despite the traditional view that damage to the hippocampus and/or surrounding areas of the medial temporal lobe (MTL) does not impair short-term or working memory (WM), recent research has shown MTL amnesics to be impaired on WM tasks that require maintaining a small amount of information over brief retention intervals (e.g., maintenance of a single face for one second). However, the types of tasks that have demonstrated WM impairments in amnesia tend to have involved novel stimuli. We hypothesized that WM may be impaired in amnesia for tasks that require maintaining novel information, but may be preserved for more familiar material, particularly if the material can be easily rehearsed. To test this hypothesis, patient HC, a 22-year-old developmental amnesic with relatively preserved semantic memory and 20 age and education matched controls performed a delayed match-to-sample task that required maintaining a single famous or non-famous face for 1-8s, digit span and reading span tasks, and a modified Brown-Peterson task that required maintaining a single high- or low-frequency word or a non-word for 4-8s. HCs performance was impaired for non-famous faces but preserved for famous faces, impaired for the reading span task but preserved for digit span, and it was impaired for non-words and unfamiliar low-frequency words but preserved for familiar words. These results support the hypothesis that an intact hippocampus is necessary for maintaining a single novel stimulus in WM. However, stimulus familiarity and rehearsal support WM via cortical regions independent of the MTL.

Volumetric analysis of medial temporal lobe subregions in developmental amnesia using high-resolution magnetic resonance imaging

There is great interest in the cognitive consequences of hippocampal volume loss in developmental amnesia (DA). In many DA cases, volume loss occurs before the hippocampus is fully developed, and yet little is known about the locus, extent, and distribution of damage in these cases. We used high‐resolution MRI to manually segment the medial temporal lobe (MTL) subregions in H.C., an adult with DA, and a group of sex‐, age‐ and education‐matched control participants (n = 10). The hippocampus was defined and divided into anterior (head) and posterior (body and tail) segments. Within the body of the hippocampus, the subregions (CA1, DG/CA2/3, and subiculum) were defined. Finally, the entorhinal (ERC), perirhinal (PRC), and parahippocampal (PHC) cortices were segmented. Anterior hippocampus was reduced bilaterally and posterior hippocampus was significantly reduced on the right. In the body of the hippocampus, all three subregions were reduced in the left hemisphere, whereas CA1 and subiculum were reduced in the right hemisphere. No group differences were observed in the PRC and ERC, whereas left PHC volume was marginally increased in H.C. compared to controls. These results can be used to inform patterns of spared and impaired cognitive abilities in DA and perhaps in amnesia more generally.