Derek A. Hamilton

Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder

BACKGROUND Reduced hippocampal volumes in posttraumatic stress disorder (PTSD) patients are thought to reflect specific changes of this structure. Previous magnetic resonance imaging (MRI) studies have not consistently examined indices of overall brain atrophy, therefore it cannot be completely ruled out that hippocampal changes are explained by whole-brain atrophy. The purpose of this study was to assess hippocampal and whole-brain volume in civilian PTSD. METHODS Twelve subjects with PTSD and 10 control subjects underwent brain MRI. Hippocampal volumes were visually quantified using a computerized volumetric program. Whole-brain volumes were obtained with automated k-means-based segmentation. RESULTS No differences were found in intracranial volumes (ICV). Subjects with PTSD had higher cerebrospinal fluid (CSF)/ICV ratios and lower white matter/ICV ratios, consistent with generalized white matter (WM) atrophy. The effect of age on CSF/ICV was more pronounced in the PTSD group. Subjects with PTSD had smaller absolute and normalized bilateral hippocampal volumes. These differences persisted after adjusting for lifetime weeks of alcohol intoxication. Posttraumatic stress disorder and depression scores correlated negatively with left hippocampal volume, but PTSD scores were a better predictor of hippocampal volumes. CONCLUSIONS Our results replicate previous findings of reduced hippocampal volume in PTSD but also suggest independent, generalized, white matter atrophy.

Virtual navigation in humans: the impact of age, sex, and hormones on place learning.

Certain cognitive processes, including spatial ability, decline with normal aging. Spatial ability is also a cognitive domain with robust sex differences typically favoring males. However, tests of spatial ability do not seem to measure a homogeneous class of processes. For many, mentally matching rotated three-dimensional images is the gold standard for measuring spatial cognition in humans, while the Morris water task (MWT) is a preferred method in the domain of nonhuman animal research. The MWT is sensitive to hippocampal damage, a structure critical for normal learning and memory and often implicated in age-related cognitive decline. A computerized (virtual) version of the MWT (VMWT) appears to require and engage human hippocampal circuitry, and has proven useful in studying sex differences and testing spatial learning theories. In Experiment 1, we tested participants (20-90 years of age) in the VMWT and compared their performance to that on the Vandenberg Mental Rotation Test. We report an age-related deficit in performance on both tasks. In Experiment 2, we tested young (age 20-39) and elderly (age >60) participants in the VMWT and correlated their performance to the circulating levels of testosterone and cortisol. Our findings indicate that the persistence of male spatial advantage may be related to circulating testosterone, but not cortisol levels, and independent of generalized age-related cognitive decline.

Children with Fetal Alcohol Syndrome are impaired at place learning but not cued-navigation in a virtual Morris water task

We employed a computerized (virtual) Morris water task (VMWT) to measure place learning and cued-navigation in eight adolescent males (9.5-16.5 years old) diagnosed with Fetal Alcohol Syndrome (FAS). Eight adolescent males matched for age and ethnicity with no history of prenatal alcohol exposure served as controls. Participants were trained to navigate to a hidden platform in a fixed location relative to a set of four conspicuous extramaze cues. After 20 hidden platform trials, a single no-platform probe trial was conducted, followed by 8 trials during which the platform was visible (cued-navigation). The FAS group traveled further than controls to navigate to the hidden platform during training. During the probe trial, controls navigated more directly to the platform region and persisted in searching where the platform had been more than the FAS group. Cued-navigation was comparable in both groups, suggesting that group differences in place learning were not attributable to visual-motor or motivational deficits in the FAS subjects. This pattern of impaired place learning and spared cued-navigation is similar to that reported in rats exposed to ethanol during periods of prenatal or early postnatal brain growth, as well as in animals with hippocampal damage.

Retrograde amnesia after hippocampal damage: Recent vs. remote memories in two tasks

We review evidence from experiments conducted in our laboratory on retrograde amnesia in rats with damage to the hippocampal formation. In a new experiment reported here, we show that N‐methyl‐D‐aspartate (NMDA)‐induced hippocampal damage produced retrograde amnesia for both hidden platform and two‐choice visible platform discriminations in the Morris water task. For both problems there was a significant trend for longer training‐surgery intervals to be associated with worse retention performance. Little support is offered by our work for the concept that there is a process involving hippocampal‐dependent consolidation of memories in extrahippocampal permanent storage sites. Long‐term memory consolidation may take place within the hippocampus. The hippocampus may be involved permanently in storage and/or retrieval of a variety of relational and nonrelational memories if it was intact at the time of learning, even involving information which is definitely not affected in anterograde amnesia after hippocampal damage. Hippocampus 2001;11:27–42.

Prenatal exposure to moderate levels of ethanol alters social behavior in adult rats: Relationship to structural plasticity and immediate early gene expression in frontal cortex

The goals of the present study were to characterize the effects of prenatal exposure to moderate levels of ethanol on adult social behavior, and to evaluate fetal-ethanol-related effects on dendritic morphology, structural plasticity and activity-related immediate early gene (IEG) expression in the agranular insular (AID) and prelimbic (Cg3) regions of frontal cortex. Baseline fetal-ethanol-related alterations in social behavior were limited to reductions in social investigation in males. Repeated experience with novel cage-mates resulted in comparable increases in wrestling and social investigation among saccharin- and ethanol-exposed females, whereas social behavioral effects among males were more evident in ethanol-exposed animals. Male ethanol-exposed rats also displayed profound increases in wrestling when social interaction was motivated by 24h of isolation. Baseline decreases in dendritic length and spine density in AID were observed in ethanol-exposed rats that were always housed with the same cage-mate. Modest experience-related decreases in dendritic length and spine density in AID were observed in saccharin-exposed rats housed with various cage-mates. In contrast, fetal-ethanol-exposed rats displayed experience-related increases in dendritic length in AID, and no experience-related changes in spine density. The only effect observed in Cg3 was a baseline increase in basilar dendritic length among male ethanol-exposed rats. Robust increases in activity-related IEG expression in AID (c-fos and Arc) and Cg3 (c-fos) were observed following social interaction in saccharin-exposed rats, however, activity-related increases in IEG expression were not observed in fetal-ethanol-exposed rats in either region. The results indicate that deficits in social behavior are among the long-lasting behavioral consequences of moderate ethanol exposure during brain development, and implicate AID, and to a lesser degree Cg3, in fetal-ethanol-related social behavior abnormalities.

How do room and apparatus cues control navigation in the Morris water task? Evidence for distinct contributions to a movement vector.

The present study compared the relative influence of location and direction on navigation in the Morris water task. Rats were trained with a fixed hidden or cued platform, and probe trials were conducted with the pool repositioned such that the absolute spatial location of the platform was centered in the opposite quadrant of the pool. Rather than swimming to the platform location, rats swam in the direction that was reinforced during training, resulting in navigation to the relative location of the platform in the pool and search at the appropriate distance from the pool wall. Pool relocation tests revealed disruptions in cued navigation if the cued platform remained at the absolute location, whereas no disruption was observed if the platform remained at the relative location (same direction). The results indicate that direction holds greater influence than does location and further demonstrate that this observation is not altered by the amount of training or time on the platform. The authors propose that navigation in the water task involves a movement vector in which the distal cues and apparatus provide direction and distance information, respectively.

Blocking in human place learning: Evidence from virtual navigation

The associative conditioning phenomenon of blocking has recently been demonstrated in nonhuman place-learning paradigms, including the Morris water task (MWT). We demonstrate blocking in humans learning to place navigate in a computerized version of the MWT. Participants trained to locate an invisible goal with an initial set of distal cues were deficient in learning to locate the goal with a set of cues inserted later during training. This outcome is inconsistent with the spontaneous integration of novel environmental features into a unified spatial representation proposed by cognitive mapping theory (O’Keefe & Nadel, 1978) and suggests that error-correcting associative learning principles operate in the human spatial mapping system.

Spatial Memory Deficits in Patients with Chronic Bilateral Vestibular Failure

The role of the vestibular system for navigation and spatial memory has been demonstrated in animals but not in humans. Vestibular signals are necessary for location‐specific “place cell” activity in the hippocampus which provides a putative neural substrate for the spatial representation involved in navigation. To investigate the spatial memory in patients with bilateral vestibular failure due to NF2 with bilateral neurectomy, a virtual variant (on a PC) of the Morris water task adapted to humans was used. Significant spatial learning and memory deficits were shown in 12 patients as compared to 10 healthy controls. These data suggest that functional hippocampal deficits manifest due to a chronic lack of vestibular input in these patients. These deficits can even be demonstrated with the subjects stationary, i.e., without any actual vestibular or somatosensory stimulation.

Structural and functional plasticity of the hippocampal formation in professional dancers and slackliners

The acquisition of special skills can induce plastic changes in the human hippocampus, a finding demonstrated in expert navigators (Maguire et al. ( 2000 ) Proc Natl Acad Sci USA 97:4,398–403). Conversely, patients with acquired chronic bilateral vestibular loss develop atrophy of the hippocampus, which is associated with impaired spatial memory (Brandt et al. ( 2005 ) Brain 128:2,732–741). This suggests that spatial memory relies on vestibular input. In this study 21 professional dancers and slackliners were examined to assess whether balance training with extensive vestibulo‐visual stimulation is associated with altered hippocampal formation volumes or spatial memory. Gray matter voxel‐based morphometry showed smaller volumes in the anterior hippocampal formation and in parts of the parieto‐insular vestibular cortex of the trained subjects but larger volumes in the posterior hippocampal formation and the lingual and fusiform gyri bilaterally. The local volumes in the right anterior hippocampal formation correlated negatively and those in the right posterior hippocampal formation positively with the amount of time spent training ballet/ice dancing or slacklining at the time of the study. There were no differences in general memory or in spatial memory as assessed by the virtual Morris water task. Trained subjects performed significantly better on a hippocampal formation‐dependent task of nonspatial memory (transverse patterning). The smaller anterior hippocampal formation volumes of the trained subjects may be the result of a long‐term suppression of destabilizing vestibular input. This is supported by the associated volume loss in the parieto‐insular vestibular cortex. The larger volumes in the posterior hippocampal formation of the trained subjects might result from their increased utilization of visual cues for balance. This is supported by the concomitant larger volumes in visual areas like the lingual and fusiform gyri. Our findings indicate that there is a spatial separation of vestibular and visual processes in the human hippocampus.

Proton magnetic resonance spectroscopy of the hippocampus and occipital white matter in PTSD: Preliminary results

Objective: Previous proton magnetic resonance spectroscopy (1H-MRS) studies in posttraumatic stress disorder (PTSD) report decreased hippocampal N-acetylaspartate (NAA), an indicator of neuronal integrity. However, other areas of the brain need to be explored. The objective of this study was to investigate the specificity of hippocampal NAA concentration changes in PTSD by also examining a control region, the occipital white matter (OWM). Methods: Eight patients with PTSD and 5 control subjects underwent single-voxel 1H-MRS of the hippocampi and bilateral OWM. Absolute neurometabolite concentrations were determined. Preliminary Results: Trends toward reduced left hippocampal NAA and creatine (Cre) were found in the PTSD group. PTSD subjects also had reduced bilateral OWM Cre. Conclusions: The preliminary results of our study in civilians with PTSD replicate previous MRS studies and are consistent with decreased hippocampal neuronal integrity without effects in the OWM. Replication of our findings is needed.