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.

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.

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).

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.

Parietal influence on temporal encoding indexed by simultaneous transcranial magnetic stimulation and electroencephalography.

Previous studies have suggested that contingent negative variation (CNV), as recorded by electroencaphalography (EEG), may serve as an index of temporal encoding. The interpretation of these studies is complicated by the fact that, in a majority of studies, the CNV signal was obtained at a time when subjects were not only registering stimulus duration but also making decisions and preparing to act. Previously, we demonstrated that repetitive transcranial magnetic stimulation (rTMS) of the right supramarginal gyrus (rSMG) in humans lengthened the perceived duration of a visual stimulus (Wiener et al., 2010a), suggesting the rSMG is involved in basic encoding processes. Here, we report a replication of this effect with simultaneous EEG recordings during the encoding of stimulus duration. Stimulation of the rSMG led to an increase in perceived duration and the amplitude of N1 and CNV components recorded from frontocentral sites. Furthermore, the size of the CNV amplitude, but not N1, positively correlated with the size of the rTMS effect but negatively correlated with bias (the baseline tendency to report a comparison stimulus as shorter), suggesting that the CNV indexes stimulus duration. These results suggest that a feedforward mechanism from parietal to prefrontal regions mediates temporal encoding and demonstrate a dissociation between early and late phases of encoding processes.

Mental motor imagery indexes pain: the hand laterality task.

Mental motor imagery is subserved by the same cognitive systems that underlie action. In turn, action is informed by the anticipated sensory consequences of movement, including pain. In light of these considerations, one would predict that motor imagery would provide a useful measure pain-related functional interference. We report a study in which 19 patients with chronic musculoskeletal or radiculopathic arm or shoulder pain, 24 subjects with chronic pain not involving the arm/shoulder and 41 normal controls were asked to indicate if a line drawing was a right or left hand. Previous work demonstrated that this task is performed by mental rotation of the subject's hand to match the stimulus. Relative to normal and pain control subjects, arm/shoulder pain subjects were significantly slower for stimuli that required greater amplitude rotations. For the arm/shoulder pain subjects only there was a correlation between degree of slowing and the rating of severity of pain with movement but not the non-specific pain rating. The hand laterality task may supplement the assessment of subjects with chronic arm/shoulder pain.

Mental motor imagery and chronic pain: the foot laterality task.

Several lines of evidence suggest that mental motor imagery is subserved by the same cognitive operations and brain structures that underlie action. Additionally, motor imagery is informed by the anticipated sensory consequences of action, including pain. We reasoned that motor imagery could provide a useful measure of chronic leg or foot pain. Forty subjects with leg pain (19 bilateral, 11 right, and 10 left leg pain), 42 subjects with chronic pain not involving the legs, and 38 controls were shown 12 different line drawings of the right or left foot and asked to indicate which foot was depicted. Previous work suggests that subjects perform this task by mentally rotating their foot to match the visually presented stimulus. All groups of subjects were slower and less accurate with stimuli that required a greater degree of mental rotation of their foot. Subjects with leg pain were both slower and less accurate than normal and pain control subjects in responding to drawings of a painful extremity. Furthermore, subjects with leg pain exhibited a significantly greater decrement in performance for stimuli that required larger amplitude mental rotations. These data suggest that motor imagery may provide important insights into the nature of the pain experience.