Naomi J. Goodrich-Hunsaker

The interactions and dissociations of the dorsal hippocampus subregions: How the dentate gyrus, CA3, and CA1 process spatial information.

Several studies have demonstrated the significance of a spatial cognitive map and its role for guided and accurate navigation through the environment. Learning and recalling spatial knowledge depends upon proper topological and metric spatial information processing. The present objectives are to better characterize the role of the hippocampus for processing topological and metric spatial information. Rats with dorsal hippocampal subregional lesions (dDG, dCA3, dCA1) were tested on a previously established metric task and topological task. The results of the present study suggest that dCA1, but not dDG or dCA3, mediates topological memory. Furthermore, dDG, dCA3, and dCA1 mediate metric memory. Dorsal DG is required for spatial information processing via pattern separation or orthogonalization of sensory inputs to generate metric representations. Dorsal CA3 and dCA1 then receive these metric representations transmitted from dDG along the trisynaptic loop. The present data add to a growing body of literature suggesting a diversity of function among the hippocampal subregions.

Dissociating the role of the parietal cortex and dorsal hippocampus for spatial information processing

Dorsal hippocampus, parietal cortex, and control lesioned rats were tested on both a metric and topological task. The metric task consisted of 2 different objects placed 68 cm apart on a cheese board. After habituation, the objects were moved to a separation of 38 cm on Day 1 and to a separation of 98 cm on Day 2. The topological task consisted of 4 different objects placed in a square orientation. After habituation, the first 2 objects were switched, and after the rats habituated to that change, the back 2 objects were switched. This was repeated on a different day with 4 new objects. The data suggest that the hippocampus is necessary for metric representations, whereas the parietal cortex is necessary for topological representations.

Spatial Deficits in a Virtual Water Maze in Amnesic Participants with Hippocampal Damage

The Morris water maze is a standard paradigm for the testing of hippocampal function in laboratory animals. Virtual versions of the Morris water maze are now available and can be used to assess spatial learning and memory ability in both healthy and brain injured participants. To evaluate the importance of the hippocampus in spatial learning and memory, we tested five amnesic participants with selective hippocampal damage using a virtual water maze called the Arena Maze. The amnesic participants with hippocampal damage were impaired on the invisible platform (place) task that required them to use distal cues, but were able to navigate almost as well as comparison participants when the invisible platform was marked by a single proximal cue. These results not only confirm that the hippocampus plays a necessary role in human navigation in large‐scale environments but also provides a new link between the mnemonic and navigational roles of the hippocampus.

YOUNG ADULT FEMALE FRAGILE X PREMUTATION CARRIERS SHOW AGE- AND GENETICALLY-MODULATED COGNITIVE IMPAIRMENTS

The high frequency of the fragile X premutation in the general population and its emerging neurocognitive implications highlight the need to investigate the effects of the premutation on lifespan cognitive development. Until recently, cognitive function in fragile X premutation carriers (fXPCs) was presumed to be unaffected by the mutation. Here we show that young adult female fXPCs show subtle, yet significant, age- and FMR1 gene mutation-modulated cognitive impairments as tested by a quantitative magnitude comparison task. Our results begin to define the neurocognitive endophenotype associated with the premutation in adults, who are at risk for developing a neurodegenerative disorder associated with the fragile X premutation. Results from the present study may potentially be applied toward the design of early interventions wherein we might be able to target premutation carriers most at risk for degeneration for preventive treatment.

Adult female fragile X premutation carriers exhibit age- and CGG repeat length-related impairments on an attentionally based enumeration task

The high frequency of the fragile X premutation in the general population and its emerging neurocognitive implications highlight the need to investigate the effects of the premutation on lifespan cognitive development. Until recently, cognitive function in fragile X premutation carriers (fXPCs) was presumed to be unaffected by the mutation. Although as a group fXPCs did not differ from healthy controls (HCs), we show that young adult female fXPCs show subtle age- and significant fragile X mental retardation 1 (FMR1) gene mutation-modulated cognitive function as tested by a basic numerical enumeration task. These results indicate that older women with the premutation and fXPCs with greater CGG repeat lengths were at higher risk for difficulties in the deployment of volitional attention required to count 5–8 items, but spared performance when spatial shifts of attention were minimized to subitize a few (1–3). Results from the current study add to a growing body of evidence that suggests the premutation allele is associated with a subtle phenotype and implies that the cognitive demands necessary for counting are less effectively deployed in female fXPCs compared to HCs.

Temporal ordering deficits in female CGG KI mice heterozygous for the fragile X premutation.

The fragile X premutation is a tandem CGG trinucleotide repeat expansion on the FMR1 gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse with CGG repeat lengths between 70 and 350 has been developed and used to characterize the histopathology and cognitive deficits reported in carriers of the fragile X premutation. Previous studies have shown that CGG KI mice show progressive deficits in processing spatial information. To further characterize cognitive deficits in the fragile X premutation, temporal ordering in CGG knock-in (CGG KI) mice was evaluated. Female CGG KI mice were tested for their ability to remember the temporal order in which two objects were presented. The results demonstrate that at 48 weeks of age, female CGG KI mice with CGG repeat expansions between 150 and 200 CGG repeats performed more poorly on tests of temporal order than wildtype mice, whereas female CGG KI mice with between 80 and 100 CGG repeats performed similarly to wildtype mice. No mice had any difficulty in detecting the presence of a novel object. These data suggest female CGG KI mice show a CGG repeat length-sensitive deficit for temporal ordering.

Motor Deficits on a Ladder Rung Task in Male and Female Adolescent and Adult CGG Knock-in Mice

The fragile X premutation is a tandem CGG trinucleotide repeat expansion on the FMR1 gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse with CGG trinucleotide repeat lengths between 70 and 350 has been developed and used to model the histopathology and cognitive deficits reported in carriers of the fragile X premutation. Previous studies have shown that CGG KI mice show progressive deficits in processing spatial and temporal information. To characterize the motor deficits associated with the fragile X premutation, male and female CGG KI mice ranging from 2 to 16 months of age with trinucleotide repeats ranging from 72 to 240 CGG in length were tested for their ability to perform a skilled ladder rung walking test. The results demonstrate that both male and female CGG KI mice showed a greater number of foot slips as a function of increased CGG repeat length, independent of the age of the animal or general activity level.

Functional neuroimaging evidence for high cognitive effort on the Word Memory Test in the absence of external incentives.

Primary objective: This study presents data from a functional neuroimaging experiment which brings into question whether poor performance on the Word Memory Test (WMT) can be construed as straightforward evidence for ‘poor effort’ in the context of cognitive assessment, as asserted in a recent report in this journal. Methods and procedures: Functional magnetic resonance image (fMRI) data were acquired from four participants without brain injury who engaged in the delayed recognition (DR) portion of Greens WMT protocol. Outcomes and results: Compared to a simple perceptual identification control task, this study found a highly reliable activation pattern across all participants which was restricted almost exclusively to cortical areas most commonly associated with task difficulty, memory load, concentration and other forms of cognitive effort These areas include dorsolateral prefrontal cortex, anterior insula, superior parietal cortex and the dorsal anterior cingulate. Conclusions: These findings demonstrate that the WMT activates numerous cortical regions that are critical for cognitive effort. Given the extensive neural network necessary to perform the WMT, this study raises important questions about what WMT ‘failure’ truly means in patients with traumatic brain injury, who have increased likelihood of disruption within this neural network of vision, language, attention, effort and working memory.

Word memory test performance in amnesic patients with hippocampal damage.

Many symptom validity tests (SVTs) assess performance validity via declarative memory paradigms. One widely used SVT, the Word Memory Test (WMT), uses a variety of memory tests to assess performance. It is well known that declarative memory requires the hippocampus and related medial temporal lobe structures. In the present study, WMT performance was examined in nonlitigating amnesic subjects (n = 3) with well-documented focal bilateral hippocampal atrophy who were nondemented and otherwise cognitively unimpaired compared with matched controls. The amnesic subjects had no external incentives. Amnesic subjects performed significantly below the level of matched comparison subjects but above established cutoff scores on the immediate recognition and delay recognition subtests and consistency component. In contrast, the amnesic subjects were impaired relative to our comparison subjects on the multiple-choice, paired associate, free-recall, and long delay free-recall subtests and had extremely low performance on these measures. Thus, there was a differential effect of hippocampal damage on WMT performance where the recognition subtests were performed within the normal range, yet the free recall was profoundly impaired in amnesic subjects. Such an approach where SVT performance is assessed in populations with well-known cognitive impairments adds breadth to SVT clinical interpretations.

Enhanced Manual and Oral Motor Reaction Time in Young Adult Female Fragile X Premutation Carriers

A previous study reported preliminary results of enhanced processing of simple visual information in the form of faster reaction times, in female fragile X premutation carriers (fXPCs). In this study, we assessed manual and oral motor reaction times in 30 female fXPCs and 20 neurotypical (NT) controls. Participants completed two versions of the reaction time task; one version required a manual motor response and the other version required an oral motor response. Results revealed that the female fXPCs displayed faster reaction times for both manual and oral motor responses relative to NT controls. Molecular measures including CGG repeat length, FMR1 mRNA levels, and age were not associated with performance in either group. Given previously reported age and CGG repeat modulated performance on a magnitude comparison task in this same group of premutation carriers, results from the current study seem to suggest that female fXPCs may have spared basic psychomotor functionality.