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      Frontotemporal networks and behavioral symptoms in primary progressive aphasia

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          Abstract

          Objective:

          To determine if behavioral symptoms in patients with primary progressive aphasia (PPA) were associated with degeneration of a ventral frontotemporal network.

          Methods:

          We used diffusion tensor imaging tractography to quantify abnormalities of the uncinate fasciculus that connects the anterior temporal lobe and the ventrolateral frontal cortex. Two additional ventral tracts were studied: the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus. We also measured cortical thickness of anterior temporal and orbitofrontal regions interconnected by these tracts. Thirty-three patients with PPA and 26 healthy controls were recruited.

          Results:

          In keeping with the PPA diagnosis, behavioral symptoms were distinctly less prominent than the language deficits. Although all 3 tracts had structural pathology as determined by tractography, significant correlations with scores on the Frontal Behavioral Inventory were found only for the uncinate fasciculus. Cortical atrophy of the orbitofrontal and anterior temporal lobe cortex was also correlated with these scores.

          Conclusions:

          Our findings indicate that damage to a frontotemporal network mediated by the uncinate fasciculus may underlie the emergence of behavioral symptoms in patients with PPA.

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          Most cited references18

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          RESTORE: robust estimation of tensors by outlier rejection.

          Signal variability in diffusion weighted imaging (DWI) is influenced by both thermal noise and spatially and temporally varying artifacts such as subject motion and cardiac pulsation. In this paper, the effects of DWI artifacts on estimated tensor values, such as trace and fractional anisotropy, are analyzed using Monte Carlo simulations. A novel approach for robust diffusion tensor estimation, called RESTORE (for robust estimation of tensors by outlier rejection), is proposed. This method uses iteratively reweighted least-squares regression to identify potential outliers and subsequently exclude them. Results from both simulated and clinical diffusion data sets indicate that the RESTORE method improves tensor estimation compared to the commonly used linear and nonlinear least-squares tensor fitting methods and a recently proposed method based on the Geman-McClure M-estimator. The RESTORE method could potentially remove the need for cardiac gating in DWI acquisitions and should be applicable to other MR imaging techniques that use univariate or multivariate regression to fit MRI data to a model. Copyright 2005 Wiley-Liss, Inc.
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            A novel frontal pathway underlies verbal fluency in primary progressive aphasia.

            The frontal aslant tract is a direct pathway connecting Broca's region with the anterior cingulate and pre-supplementary motor area. This tract is left lateralized in right-handed subjects, suggesting a possible role in language. However, there are no previous studies that have reported an involvement of this tract in language disorders. In this study we used diffusion tractography to define the anatomy of the frontal aslant tract in relation to verbal fluency and grammar impairment in primary progressive aphasia. Thirty-five patients with primary progressive aphasia and 29 control subjects were recruited. Tractography was used to obtain indirect indices of microstructural organization of the frontal aslant tract. In addition, tractography analysis of the uncinate fasciculus, a tract associated with semantic processing deficits, was performed. Damage to the frontal aslant tract correlated with performance in verbal fluency as assessed by the Cinderella story test. Conversely, damage to the uncinate fasciculus correlated with deficits in semantic processing as assessed by the Peabody Picture Vocabulary Test. Neither tract correlated with grammatical or repetition deficits. Significant group differences were found in the frontal aslant tract of patients with the non-fluent/agrammatic variant and in the uncinate fasciculus of patients with the semantic variant. These findings indicate that degeneration of the frontal aslant tract underlies verbal fluency deficits in primary progressive aphasia and further confirm the role of the uncinate fasciculus in semantic processing. The lack of correlation between damage to the frontal aslant tract and grammar deficits suggests that verbal fluency and grammar processing rely on distinct anatomical networks.
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              Limbic systems for emotion and for memory, but no single limbic system.

              The concept of a (single) limbic system is shown to be outmoded. Instead, anatomical, neurophysiological, functional neuroimaging, and neuropsychological evidence is described that anterior limbic and related structures including the orbitofrontal cortex and amygdala are involved in emotion, reward valuation, and reward-related decision-making (but not memory), with the value representations transmitted to the anterior cingulate cortex for action-outcome learning. In this 'emotion limbic system' a computational principle is that feedforward pattern association networks learn associations from visual, olfactory and auditory stimuli, to primary reinforcers such as taste, touch, and pain. In primates including humans this learning can be very rapid and rule-based, with the orbitofrontal cortex overshadowing the amygdala in this learning important for social and emotional behaviour. Complementary evidence is described showing that the hippocampus and limbic structures to which it is connected including the posterior cingulate cortex and the fornix-mammillary body-anterior thalamus-posterior cingulate circuit are involved in episodic or event memory, but not emotion. This 'hippocampal system' receives information from neocortical areas about spatial location, and objects, and can rapidly associate this information together by the different computational principle of autoassociation in the CA3 region of the hippocampus involving feedback. The system can later recall the whole of this information in the CA3 region from any component, a feedback process, and can recall the information back to neocortical areas, again a feedback (to neocortex) recall process. Emotion can enter this memory system from the orbitofrontal cortex etc., and be recalled back to the orbitofrontal cortex etc. during memory recall, but the emotional and hippocampal networks or 'limbic systems' operate by different computational principles, and operate independently of each other except insofar as an emotional state or reward value attribute may be part of an episodic memory. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Neurology
                Neurology
                neurology
                neur
                neurology
                NEUROLOGY
                Neurology
                Lippincott Williams & Wilkins (Hagerstown, MD )
                0028-3878
                1526-632X
                12 April 2016
                12 April 2016
                : 86
                : 15
                : 1393-1399
                Affiliations
                From Natbrainlab, Department of Forensic and Neurodevelopmental Sciences (L.D., M.T.d.S., F.D., M.C.), Department of Neuroimaging (F.D.), and Sackler Institute of Translational Neurodevelopment (D.M.), Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, UK; Neurology Clinic, Department of Experimental and Clinical Medical Sciences (L.D.), University of Udine Medical School; Department of Neurosciences (L.D.), “S. Maria della Misericordia” University Hospital, Udine, Italy; Cognitive Neurology and Alzheimer's Disease Center (M.M.M., C.W., A.M., D.C., E.R.) and Department of Neurology (M.M.M., A.M., D.C.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Brain Connectivity and Behaviour, Brain and Spine Institute (M.T.d.S.), CNRS UMR 7225 INSERM-UPMC UMRS 1127 La Salpêtrière, Paris, France.
                Author notes
                Correspondence to Dr. Catani: m.catani@ 123456iop.kcl.ac.uk or Dr. D'Anna: lucio.d'anna@ 123456kcl.ac.uk

                Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by Wellcome Trust.

                Article
                NEUROLOGY2015651331
                10.1212/WNL.0000000000002579
                4831038
                26992858
                2789f0bc-dcc3-4195-8099-07897b4ec2f8
                © 2016 American Academy of Neurology

                This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 03 March 2015
                : 07 January 2016
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