The human brain representation of odor identification.

Odor identification (OI) tests are increasingly used clinically as biomarkers for Alzheimer's disease and schizophrenia. The aim of this study was to directly compare the neuronal correlates to identified odors vs. nonidentified odors. Seventeen females with normal olfactory function underwent a functional magnetic resonance imaging (fMRI) experiment with postscanning assessment of spontaneous uncued OI. An event-related analysis was performed to compare within-subject activity to spontaneously identified vs. nonidentified odors at the whole brain level, and in anatomic and functional regions of interest (ROIs) in the medial temporal lobe (MTL). Parameter estimate values and blood oxygenated level-dependent (BOLD) signal curves for correctly identified and nonidentified odors were derived from functional ROIs in hippocampus, entorhinal, piriform, and orbitofrontal cortices. Number of activated voxels and max parameter estimate values were obtained from anatomic ROIs in the hippocampus and the entorhinal cortex. At the whole brain level the correct OI gave rise to increased activity in the left entorhinal cortex and secondary olfactory structures, including the orbitofrontal cortex. Increased activation was also observed in fusiform, primary visual, and auditory cortices, inferior frontal plus inferior temporal gyri. The anatomic MTL ROI analysis showed increased activation in the left entorhinal cortex, right hippocampus, and posterior parahippocampal gyri in correct OI. In the entorhinal cortex and hippocampus the BOLD signal increased specifically in response to identified odors and decreased for nonidentified odors. In orbitofrontal and piriform cortices both identified and nonidentified odors gave rise to an increased BOLD signal, but the response to identified odors was significantly greater than that for nonidentified odors. These results support a specific role for entorhinal cortex and hippocampus in OI, whereas piriform and orbitofrontal cortices are active in both smelling and OI. Moreover, episodic as well as semantic memory systems appeared to support OI.

Persistent posterior and transient anterior medial temporal lobe activity during navigation.

A functional segregation along the posterior-anterior axis of the medial temporal lobe (MTL) has been suggested. In brief, it is thought that the posterior hippocampus represents environmental detail and/or encodes space, whereas the anterior part represents the environment more as a whole and/or subserves behavior. Different phases of navigation should thus recruit different structures within the MTL. Based on animal studies and neuroimaging data from humans, the initial phase of navigation, i.e., self-localization, target localization and path planning, should depend on the anterior MTL independent of upcoming navigational demands, whereas posterior MTL should be active throughout navigation. We tested this prediction using fMRI with navigation in a learned large-scale virtual office landscape with numerous complex landmarks under different navigational conditions. The initial navigational phase specifically engaged the anterior MTL. Increased activity was found bilaterally in the rostral and caudal entorhinal cortex. This is, to our knowledge, the first report of entorhinal activity in virtual navigation detected in a direct comparison. Also bilateral anterior hippocampus and anterior parahippocampal cortex were significantly more active during the initial phase. Activity lasting throughout the navigational period was found in the right posterior hippocampus and parahippocampal cortex. Hippocampal activity for the entire navigation period was only detected when the virtual environment remained unaltered. Navigational success was positively correlated with activity in the anterior right hippocampus for the initial phase, and more posteriorly in the hippocampus for the whole navigation period. Plots of the BOLD signal time course demonstrated that activity in the anterior hippocampus was transient whereas activity in the posterior hippocampus peaked regularly throughout the entire navigation period. These results support a functional segregation within the MTL with regard to navigational phases. The anterior MTL appears to complete associations related to the environment at large and provide a behavioral plan for navigation, whereas the posterior part keeps track of current location.

The Human Brain Representation of Odor Identification in Amnestic Mild Cognitive Impairment and Alzheimer's Dementia of Mild Degree.

Background: Odor identification (OI) ability is a suggested early biomarker of Alzheimer's disease. In this study, we investigated brain activity within the brain's olfactory network associated with OI in patients with amnestic mild cognitive impairment (aMCI) and mild Alzheimer's dementia (mAD) to uncover the neuronal basis of this impairment. Materials and Methods: Patients with aMCI (n = 11) or mAD (n = 6) and 28 healthy older adults underwent OI functional MRI (fMRI) at 3T, OI, odor discrimination, and cognitive tests and apolipoprotein-e4 (APOE4) genotyping. Eleven patients had cerebrospinal fluid (CSF) analyzed. Those with aMCI were followed for 2 years to examine conversion to dementia. Results: The aMCI/mAD group performed significantly worse on all OI tests and the odor discrimination test compared to controls. The aMCI/mAD group had reduced activation in the right anterior piriform cortex compared to the controls during OI fMRI [Gaussian random field (GRF) corrected cluster threshold, p < 0.05]. This group difference remained after correcting for age, sex education, and brain parenchymal fraction. This difference in piriform activity was driven primarily by differences in odor discrimination ability and to a lesser extent by OI ability. There was no group by odor discrimination/identification score interaction on brain activity. Across both groups, only odor discrimination score was significantly associated with brain activity located to the right piriform cortex. Brain activity during OI was not associated with Mini Mental Status Examination scores. At the group level, the aMCI/mAD group activated only the anterior insula, while the control group had significant activation within all regions of the olfactory network during OI fMRI. There was no association between brain activity during OI fMRI and total beta-amyloid levels in the CSF in the aMCI/mAD group. Conclusion: The OI impairment in aMCI/mAD patients is associated with significantly reduced activity in the piriform cortex compared to controls. Activation of downstream regions within the olfactory network is also significantly affected in the aMCI/mAD group, except the anterior insula, which is impinged late in the course of Alzheimer's disease. OI tests thus reflect Alzheimer's disease pathology in olfactory brain structures.

Changes in spatial cognition and brain activity after a single dose of testosterone in healthy women.

Studies have consistently shown that males perform better than females on several spatial tasks. Animal and human literature suggests that sex hormones have an important role in both establishing and maintaining this difference. The aim of the present study was to examine the effects of exogenous testosterone on spatial cognition and brain activity in healthy women. A cross-sectional, double-blind, randomized, placebo-controlled study was performed in 42 healthy young women who either received one dose of 0.5mg sublingual testosterone or placebo. They then learned a virtual environment and performed navigation tasks during functional magnetic resonance imaging (fMRI). Subsequently, their knowledge of the virtual environment, self-reported navigation strategy, and mental rotation abilities were measured. The testosterone group had improved representations of the directions within the environment and performed significantly better on the mental rotation task compared to the placebo group, but navigation success and navigation strategy were similar in the two groups. Nevertheless, the testosterone group had significantly increased activity within the medial temporal lobe during successful navigation compared to the placebo group, and a positive correlation between testosterone load and medial temporal lobe activity was found. Fetal testosterone levels, measured as second-to-fourth digit length ratio, interacted significantly with parahippocampal activity and tended towards giving higher mental rotation task scores. These results demonstrated that testosterone had a limited effect pertaining specifically to spatial cognition involving 3D-visualization in healthy women, while complex behaviors such as navigation, relying more on learned strategies, were not altered despite increased neuronal activity in relevant brain regions.

Effect of Task-Correlated Physiological Fluctuations and Motion in 2D and 3D Echo-Planar Imaging in a Higher Cognitive Level fMRI Paradigm.

PURPOSE: To compare 2D and 3D echo-planar imaging (EPI) in a higher cognitive level fMRI paradigm. In particular, to study the link between the presence of task-correlated physiological fluctuations and motion and the fMRI contrast estimates from either 2D EPI or 3D EPI datasets, with and without adding nuisance regressors to the model. A signal model in the presence of partly task-correlated fluctuations is derived, and predictions for contrast estimates with and without nuisance regressors are made. MATERIALS AND METHODS: Thirty-one healthy volunteers were scanned using 2D EPI and 3D EPI during a virtual environmental learning paradigm. In a subgroup of 7 subjects, heart rate and respiration were logged, and the correlation with the paradigm was evaluated. FMRI analysis was performed using models with and without nuisance regressors. Differences in the mean contrast estimates were investigated by analysis-of-variance using Subject, Sequence, Day, and Run as factors. The distributions of group level contrast estimates were compared. RESULTS: Partially task-correlated fluctuations in respiration, heart rate and motion were observed. Statistically significant differences were found in the mean contrast estimates between the 2D EPI and 3D EPI when using a model without nuisance regressors. The inclusion of nuisance regressors for cardiorespiratory effects and motion reduced the difference to a statistically non-significant level. Furthermore, the contrast estimate values shifted more when including nuisance regressors for 3D EPI compared to 2D EPI. CONCLUSION: The results are consistent with 3D EPI having a higher sensitivity to fluctuations compared to 2D EPI. In the presence partially task-correlated physiological fluctuations or motion, proper correction is necessary to get expectation correct contrast estimates when using 3D EPI. As such task-correlated physiological fluctuations or motion is difficult to avoid in paradigms exploring higher cognitive functions, 2D EPI seems to be the preferred choice for higher cognitive level fMRI paradigms.

Marked effects of intracranial volume correction methods on sex differences in neuroanatomical structures: a HUNT MRI study.

To date, there is no consensus whether sexual dimorphism in the size of neuroanatomical structures exists, or if such differences are caused by choice of intracranial volume (ICV) correction method. When investigating volume differences in neuroanatomical structures, corrections for variation in ICV are used. Commonly applied methods are the ICV-proportions, ICV-residuals and ICV as a covariate of no interest, ANCOVA. However, these different methods give contradictory results with regard to presence of sex differences. Our aims were to investigate presence of sexual dimorphism in 18 neuroanatomical volumes unrelated to ICV-differences by using a large ICV-matched subsample of 304 men and women from the HUNT-MRI general population study, and further to demonstrate in the entire sample of 966 healthy subjects, which of the ICV-correction methods gave results similar to the ICV-matched subsample. In addition, sex-specific subsamples were created to investigate whether differences were an effect of head size or sex. Most sex differences were related to volume scaling with ICV, independent of sex. Sex differences were detected in a few structures; amygdala, cerebellar cortex, and 3rd ventricle were larger in men, but the effect sizes were small. The residuals and ANCOVA methods were most effective at removing the effects of ICV. The proportions method suffered from systematic errors due to lack of proportionality between ICV and neuroanatomical volumes, leading to systematic mis-assignment of structures as either larger or smaller than their actual size. Adding additional sexual dimorphic covariates to the ANCOVA gave opposite results of those obtained in the ICV-matched subsample or with the residuals method. The findings in the current study explain some of the considerable variation in the literature on sexual dimorphisms in neuroanatomical volumes. In conclusion, sex plays a minor role for neuroanatomical volume differences; most differences are related to ICV.

Long-axis specialization of the human hippocampus.

Investigation of the hippocampus has historically focused on computations within the trisynaptic circuit. However, discovery of important anatomical and functional variability along its long axis has inspired recent proposals of long-axis functional specialization in both the animal and human literatures. Here, we review and evaluate these proposals. We suggest that various long-axis specializations arise out of differences between the anterior (aHPC) and posterior hippocampus (pHPC) in large-scale network connectivity, the organization of entorhinal grid cells, and subfield compositions that bias the aHPC and pHPC towards pattern completion and separation, respectively. The latter two differences give rise to a property, reflected in the expression of multiple other functional specializations, of coarse, global representations in anterior hippocampus and fine-grained, local representations in posterior hippocampus.