Multi-template analysis of human perirhinal cortex in brain MRI: Explicitly accounting for anatomical variability.

RATIONAL: The human perirhinal cortex (PRC) plays critical roles in episodic and semantic memory and visual perception. The PRC consists of Brodmann areas 35 and 36 (BA35, BA36). In Alzheimer's disease (AD), BA35 is the first cortical site affected by neurofibrillary tangle pathology, which is closely linked to neural injury in AD. Large anatomical variability, manifested in the form of different cortical folding and branching patterns, makes it difficult to segment the PRC in MRI scans. Pathology studies have found that in ~97% of specimens, the PRC falls into one of three discrete anatomical variants. However, current methods for PRC segmentation and morphometry in MRI are based on single-template approaches, which may not be able to accurately model these discrete variants METHODS: A multi-template analysis pipeline that explicitly accounts for anatomical variability is used to automatically label the PRC and measure its thickness in T2-weighted MRI scans. The pipeline uses multi-atlas segmentation to automatically label medial temporal lobe cortices including entorhinal cortex, PRC and the parahippocampal cortex. Pairwise registration between label maps and clustering based on residual dissimilarity after registration are used to construct separate templates for the anatomical variants of the PRC. An optimal path of deformations linking these templates is used to establish correspondences between all the subjects. Experimental evaluation focuses on the ability of single-template and multi-template analyses to detect differences in the thickness of medial temporal lobe cortices between patients with amnestic mild cognitive impairment (aMCI, n=41) and age-matched controls (n=44). RESULTS: The proposed technique is able to generate templates that recover the three dominant discrete variants of PRC and establish more meaningful correspondences between subjects than a single-template approach. The largest reduction in thickness associated with aMCI, in absolute terms, was found in left BA35 using both regional and summary thickness measures. Further, statistical maps of regional thickness difference between aMCI and controls revealed different patterns for the three anatomical variants.

Short-Term Memory Depends on Dissociable Medial Temporal Lobe Regions in Amnestic Mild Cognitive Impairment.

Short-term memory (STM) has generally been thought to be independent of the medial temporal lobe (MTL) in contrast to long-term memory (LTM). Prodromal Alzheimer's disease (AD) is a condition in which the MTL is a major early focus of pathology and LTM is thought disproportionately affected relative to STM. However, recent studies have suggested a role for the MTL in STM, particularly hippocampus, when binding of different elements is required. Other work has suggested involvement of extrahippocampal MTL structures, particularly in STM tasks that involve item-level memory. We examined STM for individual objects, locations, and object-location conjunctions in amnestic mild cognitive impairment (MCI), often associated with prodromal AD. Relative to age-matched, cognitively normal controls, MCI patients not only displayed impairment on object-location conjunctions but were similarly impaired for non-bound objects and locations. Moreover, across all participants, these conditions displayed dissociable correlations of cortical thinning along the long axis of the MTL and associated cortical nodes of anterior and posterior MTL networks. These findings support the role of the MTL in visual STM tasks and the division of labor of MTL in support of different types of memory representations, overlapping with findings in LTM.

Does Transcranial Direct Current Stimulation Improve Healthy Working Memory?: A Meta-analytic Review.

Transcranial direct current stimulation (tDCS) has been reported to improve working memory (WM) performance in healthy individuals, suggesting its value as a means of cognitive enhancement. However, recent meta-analyses concluded that tDCS has little or no effect on WM in healthy participants. In this article, we review reasons why these meta-analyses may have underestimated the effect of tDCS on WM and report a more comprehensive and arguably more sensitive meta-analysis. Consistent with our interest in enhancement, we focused on anodal stimulation. Thirty-one articles matched inclusion criteria and were included in four primary meta-analyses assessing the WM effects of anodal stimulation over the left and right dorsolateral pFC (DLPFC) and right parietal lobe as well as left DLPFC stimulation coupled with WM training. These analyses revealed a small but significant effect of left DLPFC stimulation coupled with WM training. Left DLPFC stimulation alone also enhanced WM performance, but the effect was reduced to nonsignificance after correction for publication bias. No other effects were significant, including a variety of tested moderators. Additional meta-analyses were undertaken with study selection criteria based on previous meta-analyses, to reassess the findings from these studies using the analytic methods of this study. These analyses revealed a mix of significant and nonsignificant small effects. We conclude that the primary WM enhancement potential of tDCS probably lies in its use during training.

Automated volumetry and regional thickness analysis of hippocampal subfields and medial temporal cortical structures in mild cognitive impairment.

We evaluate a fully automatic technique for labeling hippocampal subfields and cortical subregions in the medial temporal lobe in in vivo 3 Tesla MRI. The method performs segmentation on a T2-weighted MRI scan with 0.4 × 0.4 × 2.0 mm(3) resolution, partial brain coverage, and oblique orientation. Hippocampal subfields, entorhinal cortex, and perirhinal cortex are labeled using a pipeline that combines multi-atlas label fusion and learning-based error correction. In contrast to earlier work on automatic subfield segmentation in T2-weighted MRI [Yushkevich et al., 2010], our approach requires no manual initialization, labels hippocampal subfields over a greater anterior-posterior extent, and labels the perirhinal cortex, which is further subdivided into Brodmann areas 35 and 36. The accuracy of the automatic segmentation relative to manual segmentation is measured using cross-validation in 29 subjects from a study of amnestic mild cognitive impairment (aMCI) and is highest for the dentate gyrus (Dice coefficient is 0.823), CA1 (0.803), perirhinal cortex (0.797), and entorhinal cortex (0.786) labels. A larger cohort of 83 subjects is used to examine the effects of aMCI in the hippocampal region using both subfield volume and regional subfield thickness maps. Most significant differences between aMCI and healthy aging are observed bilaterally in the CA1 subfield and in the left Brodmann area 35. Thickness analysis results are consistent with volumetry, but provide additional regional specificity and suggest nonuniformity in the effects of aMCI on hippocampal subfields and MTL cortical subregions.

Increased functional connectivity within medial temporal lobe in mild cognitive impairment.

Pathology at preclinical and prodromal stages of Alzheimer's disease (AD) may manifest itself as measurable functional change in neuronal networks earlier than detectable structural change. Functional connectivity as measured using resting-state functional magnetic resonance imaging has emerged as a useful tool for studying disease effects on baseline states of neuronal networks. In this study, we use high resolution MRI to label subregions within the medial temporal lobe (MTL), a site of early pathology in AD, and report an increase in functional connectivity in amnestic mild cognitive impairment between entorhinal cortex and subregions of the MTL, with the strongest effect in the anterior hippocampus. However, our data also replicated the effects of decreased connectivity of the MTL to other nodes of the default mode network reported by other researchers. This dissociation of changes in functional connectivity within the MTL versus the MTL's connection with other neocortical structures can help enrich the characterization of early stages of disease progression in AD.

Clinical Application of Automatic Segmentation of Medial Temporal Lobe Subregions in Prodromal and Dementia-Level Alzheimer's Disease.

BACKGROUND: Volumetry of medial temporal lobe (MTL) structures to diagnose Alzheimer's disease (AD) in its earliest symptomatic stage could be of great importance for interventions or disease modifying pharmacotherapy. OBJECTIVE: This study aimed to demonstrate the first application of an automatic segmentation method of MTL subregions in a clinical population. Automatic segmentation of magnetic resonance images (MRIs) in a research population has previously been shown to detect evidence of neurodegeneration in MTL subregions and to help discriminate AD and mild cognitive impairment (MCI) from a healthy comparison group. METHODS: Clinical patients were selected and T2-weighted MRI scan quality was checked. An automatic segmentation method of hippocampal subfields (ASHS) was applied to scans of 67 AD patients, 38 amnestic MCI patients, and 57 healthy controls. Hippocampal subfields, entorhinal cortex (ERC), and perirhinal cortex were automatically labeled and subregion volumes were compared between groups. RESULTS: One fourth of all scans were excluded due to bad scan quality. There were significant volume reductions in all subregions, except BA36, in aMCIs (p < 0.001), most prominently in Cornu Ammonis 1 (CA1) and ERC, and in all subregions in AD. However, sensitivity of CA1 and ERC hardly differed from sensitivity of WH in aMCI and AD. CONCLUSION: Applying automatic segmentation of MTL subregions in a clinical setting as a potential biomarker for prodromal AD is feasible, but issues of image quality due to motion remain to be addressed. CA1 and ERC provided strongest group discrimination in differentiating aMCIs from controls, but discriminatory power of different subfields was low overall.

Anterior and posterior MTL networks in aging and MCI.

Two neuroanatomically dissociable, large-scale cortical memory networks, referred to as the anterior and posterior medial temporal lobe (MTL) networks have recently been described in young adults using resting-state blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI)-based functional connectivity (fc-BOLD). They have been hypothesized to subserve distinct mnemonic and non-memory cognitive functions and are thought to be associated with differential vulnerability in neurological disorders. In this article, we demonstrate the existence of these functional networks in an older adult population and in a cohort of patients diagnosed with amnestic mild cognitive impairment (aMCI). Anatomic subregions of interest in the MTL were defined using high-resolution T2-weighted MRI and used as seeds for defining the putative networks using fc-BOLD. Although the literature has suggested that the posterior MTL network is particularly vulnerable to early Alzheimer's disease, we show that both the networks are affected in MCI, to varying degrees, compared with the control group. Furthermore, cortical thickness in the brain regions defined by these networks was reduced in MCI.

Automatic clustering and thickness measurement of anatomical variants of the human perirhinal cortex.

The entorhinal cortex (ERC) and the perirhinal cortex (PRC) are subregions of the medial temporal lobe (MTL) that play important roles in episodic memory representations, as well as serving as a conduit between other neocortical areas and the hippocampus. They are also the sites where neuronal damage first occurs in Alzheimer's disease (AD). The ability to automatically quantify the volume and thickness of the ERC and PRC is desirable because these localized measures can potentially serve as better imaging biomarkers for AD and other neurodegenerative diseases. However, large anatomical variation in the PRC makes it a challenging area for analysis. In order to address this problem, we propose an automatic segmentation, clustering, and thickness measurement approach that explicitly accounts for anatomical variation. The approach is targeted to highly anisotropic (0.4x0.4x2.0mm3 ) T2-weighted MRI scans that are preferred by many authors for detailed imaging of the MTL, but which pose challenges for segmentation and shape analysis. After automatically labeling MTL substructures using multi-atlas segmentation, our method clusters subjects into groups based on the shape of the PRC, constructs unbiased population templates for each group, and uses the smooth surface representations obtained during template construction to extract regional thickness measurements in the space of each subject. The proposed thickness measures are evaluated in the context of discrimination between patients with Mild Cognitive Impairment (MCI) and normal controls (NC).

Familiarity-based memory as an early cognitive marker of preclinical and prodromal AD.

There is great interest in the development of cognitive markers that differentiate "normal" age-associated cognitive change from that of Alzheimer's disease (AD) in its prodromal (i.e., mild cognitive impairment; MCI) or even preclinical stages. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity. Familiarity-based memory has generally been considered to be spared during normal aging, but it remains controversial whether this type of memory is impaired in early AD. Here, we describe findings of estimates of recollection and familiarity in young adults (YA), cognitively normal older adults (CN), and patients with amnestic-MCI (a-MCI). These measures in the CN and a-MCI patients were then related to a structural imaging biomarker of AD that has previously been demonstrated to be sensitive to preclinical and prodromal AD, the Cortical Signature of AD (ADsig). Consistent with much work in the literature, recollection, but not familiarity, was impaired in CN versus YA. Replicating our prior findings, a-MCI patients displayed impairment in both familiarity and recollection. Finally, the familiarity measure was correlated with the ADsig biomarker across the CN and a-MCI group, as well as within the CN adults alone. No other standard psychometric measure was as highly associated with the ADsig, suggesting that familiarity may be a sensitive biomarker of AD-specific brain changes in preclinical and prodromal AD and that it may offer a qualitatively distinct measure of early AD memory impairment relative to normal age-associated change.