Accuracy of spatial normalization of the hippocampus: implications for fMRI research in memory disorders

Functional magnetic resonance imaging (fMRI) studies in memory impairment have detected functional alterations in medial temporal lobe (MTL) structures, notably the hippocampus. Many of these studies employ spatial normalization to place subjects in a standardized template space prior to analysis; however, little is known about the effects of local atrophy on the normalization process in structures such as the hippocampus. The purpose of this study was to compare the accuracy of spatial normalization of the hippocampus between memory-impaired patients and controls. Twenty clinically-defined mild cognitive impairment (MCI) subjects and twenty elderly controls were studied at 4T with structural and functional MRI during a memory encoding-retrieval task. Bilateral hippocampal regions-of-interest (ROIs) were manually drawn for all subjects and further divided into anterior/posterior subregions. To assess normalization accuracy to the Montreal Neurological Institute template, the percentage of each template-defined hippocampal ROI originating from true hippocampal tissue was determined for all subjects. To assess the ability of spatial normalization to equalize group differences in hippocampal volume, pre- and post-normalization hippocampal volumes were compared. Finally, fMRI measures from template and non-template analyses were compared. Poorer normalization accuracy of the bilateral hippocampi, particularly the posterior portions, was found for MCI subjects. Significant group differences were found in left hippocampal and bilateral posterior hippocampal volumes, and these differences were not corrected with normalization. Hippocampal volumes were significantly correlated with normalization accuracy across MCI and control groups, but some significant differences in normalization accuracy persisted independent of these volume differences. Template and non-template fMRI analyses were significantly correlated in controls, but not MCI subjects, during memory retrieval. These findings suggest decreased normalization accuracy in memory-impaired subjects is a potentially important confounder of template-based fMRI analyses in the hippocampus and MTL.     

Hippocampal head size associated with verbal memory performance in nondemented elderly

The hippocampus plays a crucial role in the consolidation of memory. Anatomically, the hippocampal head, body, and tail are connected to separate regions of the entorhinal cortex, which conveys processed information from the association cortices to the hippocampus. Little is known, however, about the functional segregation along its longitudinal axis. In the present study, we investigated whether the hippocampal head, body, or tail is selectively involved in verbal memory performance. A total of 511 nondemented participants, aged 60-90 years, underwent a three-dimensional HASTE brain scan in a 1.5-T MRI unit. Hippocampal volumes were measured by manual tracing on coronal slices. Segmentation was performed in anterior-posterior direction on the basis of predefined cutoffs allocating 35, 45, and 20% of slices to the head, body, and tail, respectively. Memory performance was assessed by a 15-word learning test including tasks of immediate and delayed recall. To analyze the association between head, body, and tail volumes and memory performance, we used multiple linear regression, adjusting for age, sex, education, and midsagittal area as a proxy for intracranial volume. Participants with larger hippocampal heads scored significantly higher in the memory test, most notably in delayed recall (0.41 word per SD increase in left hippocampal head (95% CI (0.16, 0.67)), 0.33 word per SD increase in right hippocampal head (95% CI 0.06, 0.59)). Our data suggest selective involvement of the hippocampal head in verbal memory, and add to recent findings of functional segregation along the longitudinal axis of the hippocampus.     

Fornix damage limits verbal memory functional compensation in multiple sclerosis

Selective atrophy of the hippocampus, in particular the left CA1 subregion, is detectable in relapsing-remitting MS (RRMS) and is correlated with verbal memory performance. We used novel high-resolution imaging techniques to assess the role that functional compensation and/or white matter integrity of mesial temporal lobe (MTL) structures may play in mediating verbal memory performance in RRMS. High-resolution cortical unfolding of structural MRI in conjunction with functional magnetic resonance imaging (fMRI) was used to localize MTL activity in 18 early RRMS patients and 16 healthy controls during an unrelated word-pairs memory task. Diffusion tensor imaging (DTI) and Tract-Based Spatial Statistics (TBSS) were used to assess the integrity of the fornix and the parahippocampal white matter (PHWM), the major efferents and afferents of the hippocampus. RRMS patients showed greater activity in hippocampal and extra-hippocampal areas during unrelated word-pair learning and recall. Increased hippocampal activity, particularly in the right anterior hippocampus and left anterior CA1 was associated with higher verbal memory scores. Furthermore, increased fractional anisotropy (FA) in the fornix was correlated with both greater fMRI activity in this region and better memory performance. Altered hippocampal fMRI activity in RRMS patients during verbal learning may result from both structural damage and compensatory mechanisms. Successful functional compensation for hippocampal involvement in RRMS may be limited in part by white matter damage to the fornix, consistent with the critical role of this pathway in the clinical expression of memory impairment in MS.     

Automated hippocampal shape analysis predicts the onset of dementia in mild cognitive impairment

The hippocampus is involved at the onset of the neuropathological pathways leading to Alzheimer's disease (AD). Individuals with mild cognitive impairment (MCI) are at increased risk of AD. Hippocampal volume has been shown to predict which MCI subjects will convert to AD. Our aim in the present study was to produce a fully automated prognostic procedure, scalable to high throughput clinical and research applications, for the prediction of MCI conversion to AD using 3D hippocampal morphology. We used an automated analysis for the extraction and mapping of the hippocampus from structural magnetic resonance scans to extract 3D hippocampal shape morphology, and we then applied machine learning classification to predict conversion from MCI to AD. We investigated the accuracy of prediction in 103 MCI subjects (mean age 74.1 years) from the longitudinal AddNeuroMed study. Our model correctly predicted MCI conversion to dementia within a year at an accuracy of 80% (sensitivity 77%, specificity 80%), a performance which is competitive with previous predictive models dependent on manual measurements. Categorization of MCI subjects based on hippocampal morphology revealed more rapid cognitive deterioration in MMSE scores (p<0.01) and CERAD verbal memory (p<0.01) in those subjects who were predicted to develop dementia relative to those predicted to remain stable. The pattern of atrophy associated with increased risk of conversion demonstrated initial degeneration in the anterior part of the cornus ammonis 1 (CA1) hippocampal subregion. We conclude that automated shape analysis generates sensitive measurements of early neurodegeneration which predates the onset of dementia and thus provides a prognostic biomarker for conversion of MCI to AD.     

Combined analyses of thalamic volume, shape and white matter integrity in first-episode schizophrenia

The thalamus has been considered to be integral to the pathophysiology of schizophrenia. To determine whether its anatomical abnormalities may be associated with cognitive deficits in the onset of schizophrenia, we assessed thalamic volume, shape, white matter integrity, and their correlations with cognition in patients with first-episode schizophrenia. T1-weighted magnetic resonance and diffusion tensor (DT) images were collected in 49 healthy comparison controls (CON) and 32 patients with FES (FES). Large deformation diffeomorphic metric mapping (LDDMM) algorithms were used to delineate and assess the thalamic shape from MRI scans. The thalamic white matter integrity was quantified by fractional anisotropy (FA) and mean diffusivity (MD) averaged over the thalamus using DTI. Our analysis revealed that FES did not differ from CON in FA and MD but did differ markedly from them in the thalamic volume and shape. Patients with FES also performed poorly in spatial working memory and executive tasks. The correlation study found that regional thalamic shapes highly correlate with the two cognitive scores in the entire sample and healthy comparison controls but not in patients with FES even though no correlation was found between the thalamic volumes with the two cognitive scores in any group. Left thalamic FA was correlated with spatial working memory deficits in FES. Our findings suggest that thalamic volume and shape abnormalities are evident at the onset of FES prior to thalamic abnormal white matter integrity. Altered microstructural white matter integrity assessed using DTI may not be apparent in FES but may be observed as the disease progresses. Cognitive deficits related to spatial working memory and executive functioning in FES were observed in the context of loss of their normal relationship with the thalamic shapes, that is, regionally-specific thalamic shape compression is associated with poor performance in executive functioning and spatial working memory.     

Examining the gateway to the limbic system with diffusion tensor imaging: the perforant pathway in dementia

Current treatments for Alzheimer's disease (AD) are only able to slow the progression of mental deterioration, making early and reliable diagnosis an essential part of any promising therapeutic strategy. In the initial stages of AD, the first neuropathological alterations occur in the perforant pathway (PP), a large neuronal fiber tract located at the entrance to the limbic system. However, to date, there is no sensitive diagnostic tool for performing in vivo assessments of this structure. In the present bimodal magnetic resonance imaging (MRI) study, we examined 10 elderly controls, 10 subjects suffering from mild cognitive impairment (MCI), and 10 AD patients in order to evaluate the sensitivity of diffusion tensor imaging (DTI), a new MRI technique, for detecting changes in the PP. Furthermore, the diagnostic explanatory power of DTI data of the PP should be compared to high-resolution MRI volumetry and intervoxel coherences (COH) of the hippocampus and the entorhinal cortex, two limbic regions also involved in the pathophysiology of early AD. DTI revealed a marked decrease in COH values in the PP region of MCI (right side: 26%, left side: 29%, as compared to controls) and AD patients (right side: 37%, left side: 43%, as compared to controls). Reductions in COH values of the PP region were significantly correlated with cognitive impairment. DTI data of the PP zone were the only parameter differing significantly between control subjects and MCI patients, while the volumetric measures and the COH values of the hippocampus and the entorhinal cortex did not. DTI of medial temporal brain regions is a promising non-invasive tool for the in vivo diagnosis of the early/preclinical stages of AD.     

Microstructural white matter abnormalities in type 2 diabetes mellitus: a diffusion tensor imaging study

This study investigated whether diffusion tensor imaging (DTI) could identify potential abnormalities in type 2 diabetes mellitus (T2DM) patients without cognitive complaints compared to healthy controls. In addition, the existence of associations between diffusion measures and clinical parameters was examined. Forty T2DM patients and 97 non-diabetic controls completed a clinical and biochemistry examination. Structural MRI scans (DTI, T1, T2, FLAIR) were subsequently acquired with a 1.5 Tesla scanner. In addition to a global DTI analysis, voxel-based analysis was performed on the fractional anisotropy (FA), mean diffusivity (MD), and axial (AD) and transverse (TD) diffusivity maps to investigate regions that exhibit (i) WM differences between patients and controls; and (ii) associations between clinical measurements and these DTI indices. There were no significant differences in age, gender, and WM hyperintensity scores derived by the conventional MRI scans between controls and T2DM patients. For the T2DM patients, however, the MD of the brain parenchyma was significantly increased compared to controls and was positively correlated with disease duration. The voxel based analyses revealed (i) a significantly decreased FA in the bilateral frontal WM compared to controls which was mainly caused by an increased TD and not a decreased AD within these regions; (ii) a significant association between disease duration and microstructural properties in several brain regions including bilateral cerebellum, temporal lobe WM, right caudate, bilateral cingulate gyrus, pons, and parahippocampal gyrus. Our findings indicate that microstructural WM abnormalities and associations with clinical measurements can be detected with DTI in T2DM patients.     

Improved reliability of hippocampal atrophy rate measurement in mild cognitive impairment using fluid registration

MRI-derived rates of hippocampal atrophy may serve as surrogate markers of disease progression in mild cognitive impairment (MCI). Manual delineation is the gold standard in hippocampal volumetry; however, this technique is time-consuming and subject to errors. We aimed to compare regional non-linear (fluid) registration measurement of hippocampal atrophy rates against manual delineation in MCI. Hippocampi of 18 subjects were manually outlined twice on MRI scan-pairs (interval+/-SD: 2.01+/-0.11 years), and volumes were subtracted to calculate change over time. Following global affine and local rigid registration, regional fluid registration was performed from which atrophy rates were derived from the Jacobian determinants over the hippocampal region. Atrophy rates as derived by fluid registration were computed using both forward (repeat onto baseline) and backward (baseline onto repeat) registration. Reliability for both methods and agreement between methods was assessed. Mean+/-SD hippocampal atrophy rates (%/year) derived by manual delineation were: left: 2.13+/-1.62; right: 2.36+/-1.78 and for regional fluid registration: forward: left: 2.39+/-1.68; right: 2.49+/-1.52 and backward: left: 2.21+/-1.51; right: 2.42+/-1.49. Mean hippocampal atrophy rates did not differ between both methods. Reliability for manual hippocampal volume measurements (cross-sectional) was high (intraclass correlation coefficient (ICC): baseline and follow-up, left and right, >0.99). However, the resulting ICC for manual measurements of hippocampal volume change (longitudinal) was considerably lower (left: 0.798; right: 0.850) compared with regional fluid registration (forward: left: 0.985; right: 0.988 and backward: left: 0.975; right: 0.989). We conclude that regional fluid registration is more reliable than manual delineation in assessing hippocampal atrophy rates, without sacrificing sensitivity to change. This method may be useful to quantify hippocampal volume change, given the reduction in operator time and improved precision.     

Hippocampal volume deficits and shape deformities in young biological relatives of schizophrenia probands

Hippocampal volume decrement may be one of the changes that most closely pre-date schizophrenia onset. Studying hippocampal developmental morphology in adolescent or young adult biological relatives of schizophrenia probands has the potential to further our understanding of the neurodevelopmental etiology of schizophrenia and to discover biomarkers that may aid its early identification. We utilized an artificial neural network segmentation algorithm to automatically define and reliably measure MRI hippocampus volumes. We compared 46 young, nonpsychotic biological relatives of probands against 46 healthy controls without family history of schizophrenia and 46 schizophrenia probands (age range = 13 to 28 years). We further contrasted hippocampal shape differences using spherical harmonic functions and assessed how obstetric complications (a trigger for aberrant in utero neurodevelopment) may contribute to hippocampal abnormalities. Similar to schizophrenia probands, unaffected biological relatives of probands had significantly smaller hippocampus volumes than controls; which correspond to inward displacements in shape deformities principally in the anterior hippocampal subregions. Examination of hippocampus volume–age relationships indicate that hippocampus volume normally decreases with age during late adolescence through early adulthood. In contrast, relatives of probands did not show these age-expected changes. Deviant hippocampus volume–age relationships suggest aberrant hippocampal neurodevelopment among biological relatives. Relatives with a history of obstetric complications had significantly smaller left and right hippocampi than relatives without obstetrics complications, including a dose relationship such that greater number of birth complications correlated with smaller hippocampus. Similar hippocampal volume deficits–obstetric complications relationships were observed among schizophrenia probands. Hippocampal abnormalities in schizophrenia are likely to be mediated by different neurobiological mechanisms, including factors associated with obstetric complications which occur during early neurodevelopment. Other brain maturational anomalies affecting the hippocampus in schizophrenia may manifest closer to illness onset in adolescence/early adulthood.     

Regional cortical thickness matters in recall after months more than minutes

The aim of this study was to determine the role of regional cortical thickness in recall of verbal material over an extended time period. MRI scans of healthy adults of varying ages were obtained. Two scans were averaged per person to achieve high spatial resolution, and a semi-automated method for continuous measurement of thickness across the entire cortical mantle was employed. Verbal memory tests assessing recall after 5 min, 30 min, and a mean interval of 83 days were administered. A general linear model (GLM) of the effects of thickness at each vertex on the different memory indices was computed, controlling for gender, age, IQ, and intracranial volume. These analyses were repeated with hippocampal volume as an additional variable to be controlled for, to assess to which extent effects of cortical thickness were independent of hippocampal size. Minute effects of cortical thickness were observed with regard to shorter time intervals (5 and 30 min). However, even when controlling for the effects of hippocampal volume, higher recall across months was associated with thicker cortex of distinct areas including parts of the gyrus rectus, the middle frontal gyrus, the parieto-occipital sulcus and the lingual gyrus of both hemispheres. In addition, hemisphere-specific associations were found in parts of the right temporal and parietal lobe as well as parts of the left precuneus. This supports a unique and critical role of the thickness of distinct cortical areas in recall after months, more than after minutes.