Publications by authors named "Ibai Diez"

35 Publications

Individual differences in interoceptive accuracy and prediction error in motor functional neurological disorders: A DTI study.

Hum Brain Mapp 2020 Dec 7. Epub 2020 Dec 7.

Department of Neurology, Functional Neurological Disorder Research Program, Behavioral Neurology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

In motor functional neurological disorders (mFND), relationships between interoception (a construct of high theoretical relevance to its pathophysiology) and neuroanatomy have not been previously investigated. This study characterized white matter in mFND patients compared to healthy controls (HCs), and investigated associations between fiber bundle integrity and cardiac interoception. Voxel-based analysis and tractography quantified fractional anisotropy (FA) in 38 mFND patients compared to 38 HCs. Secondary analyses compared functional seizures (FND-seiz; n = 21) or functional movement disorders (n = 17) to HCs. Network lesion mapping identified gray matter origins of implicated fiber bundles. Within-group mFND analyses investigated relationships between FA, heartbeat tracking accuracy and interoceptive trait prediction error (discrepancies between interoceptive accuracy and self-reported bodily awareness). Results were corrected for multiple comparisons, and all findings were adjusted for depression and trait anxiety. mFND and HCs did not show any between-group interoceptive accuracy or FA differences. However, the FND-seiz subgroup compared to HCs showed decreased integrity in right-lateralized tracts: extreme capsule/inferior fronto-occipital fasciculus, arcuate fasciculus, inferior longitudinal fasciculus, and thalamic/striatum to occipital cortex projections. These alterations originated predominantly from the right temporoparietal junction and inferior temporal gyrus. In mFND patients, individual differences in interoceptive accuracy and interoceptive trait prediction error correlated with fiber bundle integrity originating from the insula, temporoparietal junction, putamen and thalamus among other regions. In this first study investigating brain-interoception relationships in mFND, individual differences in interoceptive accuracy and trait prediction error mapped onto multimodal integration-related fiber bundles. Right-lateralized limbic and associative tract disruptions distinguished FND-seiz from HCs.
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http://dx.doi.org/10.1002/hbm.25304DOI Listing
December 2020

Creative Connections: Computational Semantic Distance Captures Individual Creativity and Resting-State Functional Connectivity.

J Cogn Neurosci 2021 Mar 7;33(3):499-509. Epub 2020 Dec 7.

Massachusetts General Hospital and Harvard Medical School.

Recent studies of creative cognition have revealed interactions between functional brain networks involved in the generation of novel ideas; however, the neural basis of creativity is highly complex and presents a great challenge in the field of cognitive neuroscience, partly because of ambiguity around how to assess creativity. We applied a novel computational method of verbal creativity assessment-semantic distance-and performed weighted degree functional connectivity analyses to explore how individual differences in assembly of resting-state networks are associated with this objective creativity assessment. To measure creative performance, a sample of healthy adults ( = 175) completed a battery of divergent thinking (DT) tasks, in which they were asked to think of unusual uses for everyday objects. Computational semantic models were applied to calculate the semantic distance between objects and responses to obtain an objective measure of DT performance. All participants underwent resting-state imaging, from which we computed voxel-wise connectivity matrices between all gray matter voxels. A linear regression analysis was applied between DT and weighted degree of the connectivity matrices. Our analysis revealed a significant connectivity decrease in the visual-temporal and parietal regions, in relation to increased levels of DT. Link-level analyses showed higher local connectivity within visual regions was associated with lower DT, whereas projections from the precuneus to the right inferior occipital and temporal cortex were positively associated with DT. Our results demonstrate differential patterns of resting-state connectivity associated with individual creative thinking ability, extending past work using a new application to automatically assess creativity via semantic distance.
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http://dx.doi.org/10.1162/jocn_a_01658DOI Listing
March 2021

Neurodegeneration trajectory in pediatric and adult/late DM1: A follow-up MRI study across a decade.

Ann Clin Transl Neurol 2020 10 2;7(10):1802-1815. Epub 2020 Sep 2.

Personality, Assessment and psychological treatment department; Psychology Faculty, University of the Basque Country (UPV/EHU), San Sebastián, Gipuzkoa, Spain.

Objective: To characterize the progression of brain structural abnormalities in adults with pediatric and adult/late onset DM1, as well as to examine the potential predictive markers of such progression.

Methods: 21 DM1 patients (pediatric onset: N = 9; adult/late onset: N = 12) and 18 healthy controls (HC) were assessed longitudinally over 9.17 years through brain MRI. Additionally, patients underwent neuropsychological, genetic, and muscular impairment assessment. Inter-group comparisons of total and voxel-level regional brain volume were conducted through Voxel Based Morphometry (VBM); cross-sectionally and longitudinally, analyzing the associations between brain changes and demographic, clinical, and cognitive outcomes.

Results: The percentage of GM loss did not significantly differ in any of the groups compared with HC and when assessed independently, adult/late DM1 patients and their HC group suffered a significant loss in WM volume. Regional VBM analyses revealed subcortical GM damage in both DM1 groups, evolving to frontal regions in the pediatric onset patients. Muscular impairment and the outcomes of certain neuropsychological tests were significantly associated with follow-up GM damage, while visuoconstruction, attention, and executive function tests showed sensitivity to WM degeneration over time.

Interpretation: Distinct patterns of brain atrophy and its progression over time in pediatric and adult/late onset DM1 patients are suggested. Results indicate a possible neurodevelopmental origin of the brain abnormalities in DM1, along with the possible existence of an additional neurodegenerative process. Fronto-subcortical networks appear to be involved in the disease progression at young adulthood in pediatric onset DM1 patients. The involvement of a multimodal integration network in DM1 is discussed.
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http://dx.doi.org/10.1002/acn3.51163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545612PMC
October 2020

Brain Circuit Alterations and Cognitive Disability in Late-Onset Cobalamin D Disorder.

J Clin Med 2020 Apr 2;9(4). Epub 2020 Apr 2.

Computational Neuroimaging Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain.

Neuroimaging studies describing brain circuits' alterations in cobalamin (vitamin B12)-deficient patients are limited and have not been carried out in patients with inborn errors of cobalamin metabolism. The objective of this study was to assess brain functionality and brain circuit alterations in a patient with an ultra-rare inborn error of cobalamin metabolism, methylmalonic aciduria, and homocystinuria due to cobalamin D disease, as compared with his twin sister as a healthy control (HC). We acquired magnetic resonance imaging (including structural, functional, and diffusion images) to calculate brain circuit abnormalities and combined these results with the scores after a comprehensive neuropsychological evaluation. As compared with HC, the patient had severe patterns of damage, such as a 254% increment of ventricular volume, pronounced subcortical and cortical atrophies (mainly at striatum, cingulate cortex, and precuneus), and connectivity alterations at fronto-striato-thalamic circuit, cerebellum, and corpus callosum. In agreement with brain circuit alterations, cognitive deficits existed in attention, executive function, inhibitory control, and mental flexibility. This is the first study that provides the clinical, genetic, neuroanatomical, neuropsychological, and psychosocial characterization of a patient with the cobalamin D disorder, showing functional alterations in central nervous system motor tracts, thalamus, cerebellum, and basal ganglia, that, as far as we know, have not been reported yet in vitamin B12-related disorders.
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http://dx.doi.org/10.3390/jcm9040990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231091PMC
April 2020

Central neurogenetic signatures of the visuomotor integration system.

Proc Natl Acad Sci U S A 2020 03 6;117(12):6836-6843. Epub 2020 Mar 6.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115;

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader-Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes-TBR1, SCN1A, MAGEL2, and CACNB4-to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.
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http://dx.doi.org/10.1073/pnas.1912429117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104395PMC
March 2020

Early-life trauma endophenotypes and brain circuit-gene expression relationships in functional neurological (conversion) disorder.

Mol Psychiatry 2020 Feb 12. Epub 2020 Feb 12.

Functional Neurology Research Group, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition whereby individuals present with sensorimotor symptoms incompatible with other neurological disorders. Early-life maltreatment (ELM) is a risk factor for developing FND, yet few studies have investigated brain network-trauma relationships in this population. In this neuroimaging-gene expression study, we used two graph theory approaches to elucidate ELM subtype effects on resting-state functional connectivity architecture in 30 patients with motor FND. Twenty-one individuals with comparable depression, anxiety, and ELM scores were used as psychiatric controls. Thereafter, we compared trauma endophenotypes in FND with regional differences in transcriptional gene expression as measured by the Allen Human Brain Atlas (AHBA). In FND patients only, we found that early-life physical abuse severity, and to a lesser extent physical neglect, correlated with corticolimbic weighted-degree functional connectivity. Connectivity profiles influenced by physical abuse occurred in limbic (amygdalar-hippocampal), paralimbic (cingulo-insular and ventromedial prefrontal), and cognitive control (ventrolateral prefrontal) areas, as well as in sensorimotor and visual cortices. These findings held adjusting for individual differences in depression/anxiety, PTSD, and motor phenotypes. In FND, physical abuse also correlated with amygdala and insula coupling to motor cortices. In exploratory analyses, physical abuse correlated connectivity maps overlapped with the AHBA spatial expression of three gene clusters: (i) neuronal morphogenesis and synaptic transmission genes in limbic/paralimbic areas; (ii) locomotory behavior and neuronal generation genes in left-lateralized structures; and (iii) nervous system development and cell motility genes in right-lateralized structures. These circuit-specific architectural profiles related to individual differences in childhood physical abuse burden advance our understanding of the pathophysiology of FND.
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http://dx.doi.org/10.1038/s41380-020-0665-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423688PMC
February 2020

Distance disintegration delineates the brain connectivity failure of Alzheimer's disease.

Neurobiol Aging 2020 04 14;88:51-60. Epub 2019 Dec 14.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. Electronic address:

Alzheimer's disease (AD) is associated with brain network dysfunction. Network-based investigations of brain connectivity have mainly focused on alterations in the strength of connectivity; however, the network breakdown in AD spectrum is a complex scenario in which multiple pathways of connectivity are affected. To integrate connectivity changes that occur under AD-related conditions, here we developed a novel metric that computes the connectivity distance between cortical regions at the voxel level (or nodes). We studied 114 individuals with mild cognitive impairment, 24 with AD, and 27 healthy controls. Results showed that areas of the default mode network, salience network, and frontoparietal network display a remarkable network separation, or greater connectivity distances, from the rest of the brain. Furthermore, this greater connectivity distance was associated with lower global cognition. Overall, the investigation of AD-related changes in paths and distances of connectivity provides a novel framework for characterizing subjects with cognitive impairment; a framework that integrates the overall network topology changes of the brain and avoids biases toward unreferenced connectivity effects.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085436PMC
April 2020

Brain connectivity and cognitive functioning in individuals six months after multiorgan failure.

Neuroimage Clin 2020 23;25:102137. Epub 2019 Dec 23.

Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain; IKERBASQUE, The Basque Foundation for Science, Bilbao, Spain; Department of Cell Biology and Histology, University of the Basque Country (UPV/EHU), Leioa, Spain. Electronic address:

Multiorgan failure (MOF) is a life-threating condition that affects two or more systems of organs not involved in the disorder that motivates admission to an Intensive Care Unit (ICU). Patients who survive MOF frequently present long-term functional, neurological, cognitive, and psychiatric sequelae. However, the changes to the brain that explain such symptoms remain unclear.

Objective: To determine brain connectivity and cognitive functioning differences between a group of MOF patients six months after ICU discharge and healthy controls (HC).

Methods: 22 MOF patients and 22 HC matched by age, sex, and years of education were recruited. Both groups were administered a 3T magnetic resonance imaging (MRI), including structural T1 and functional BOLD, as well as a comprehensive neuropsychological evaluation that included tests of learning and memory, speed of information processing and attention, executive function, visual constructional abilities, and language. Voxel-based morphometry was used to analyses T1 images. For the functional data at rest, functional connectivity (FC) analyses were performed.

Results: There were no significant differences in structural imaging and neuropsychological performance between groups, even though patients with MOF performed worse in all the cognitive tests. Functional neuroimaging in the default mode network (DMN) showed hyper-connectivity towards sensory-motor, cerebellum, and visual networks. DMN connectivity had a significant association with the severity of MOF during ICU stay and with the neuropsychological scores in tests of attention and visual constructional abilities.

Conclusions: In MOF patients without structural brain injury, DMN connectivity six months after ICU discharge is associated with MOF severity and neuropsychological impairment, which supports the use of resting-state functional MRI as a potential tool to predict the onset of long-term cognitive deficits in these patients. Similar to what occurs at the onset of other pathologies, the observed hyper-connectivity might suggest network re-adaptation following MOF.
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http://dx.doi.org/10.1016/j.nicl.2019.102137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957787PMC
December 2020

Regional brain atrophy in gray and white matter is associated with cognitive impairment in Myotonic Dystrophy type 1.

Neuroimage Clin 2019 6;24:102078. Epub 2019 Nov 6.

Neuroscience Area, Biodonostia Research Institute, San Sebastián, Gipuzkoa, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Institute Carlos III, Madrid, Spain; Personality, Assessment and psychological treatment department; Psychology Faculty, University of the Basque Country (UPV/EHU), San Sebastian, Gipuzkoa, Spain.

Background: Myotonic Dystrophy type 1 (DM1) is a slowly progressive myopathy characterized by varying multisystemic involvement. Several cerebral features such as brain atrophy, ventricular enlargement, and white matter lesions (WMLs) have frequently been described. The aim of this study is to investigate the structural organization of the brain that defines the disease through multimodal imaging analysis, and to analyze the relation between structural cerebral changes and DM1 clinical and neuropsychological profiles.

Method: 31 DM1 patients and 57 healthy controls underwent an MRI scan protocol, including T1, T2 and DTI. Global gray matter (GM), global white matter (WM), and voxel-level Voxel Based Morphometry (VBM) and voxel-level microstructural WM abnormalities through Diffusion Tensor Imaging (DTI) were assessed through group comparisons and linear regression analysis with age, degree of muscular impairment (MIRS score), CTG expansion size and neuropsychological outcomes from a comprehensive assessment.

Results: Compared with healthy controls, DM1 patients showed a reduction in both global GM and WM volume; and further regional GM decrease in specific primary sensory, multi-sensory and association cortical regions. Fractional anisotropy (FA) was reduced in both total brain and regional analysis, being most marked in frontal, paralimbic, temporal cortex, and subcortical regions. Higher ratings on muscular impairment and longer CTG expansion sizes predicted a greater volume decrease in GM and lower FA values. Age predicted global GM reduction, specifically in parietal regions. At the cognitive level, the DM1 group showed significant negative correlations between IQ estimate, visuoconstructive and executive neuropsychological scores and both global and regional volume decrease, mainly distributed in the frontal, parietal and subcortical regions.

Conclusions: In this study, we describe the structural brain signatures that delineate the involvement of the CNS in DM1. We show that specific sensory and multi-sensory - as well as frontal cortical areas - display potential vulnerability associated with the hypothesized neurodegenerative nature of DM1 brain abnormalities.
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http://dx.doi.org/10.1016/j.nicl.2019.102078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861566PMC
September 2020

Reduced limbic microstructural integrity in functional neurological disorder.

Psychol Med 2019 11 26:1-9. Epub 2019 Nov 26.

Department of Neurology, Functional Neurology Research Group, Behavioral Neurology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: Functional neurological disorder (FND) is a condition at the intersection of neurology and psychiatry. Individuals with FND exhibit corticolimbic abnormalities, yet little is known about the role of white matter tracts in the pathophysiology of FND. This study characterized between-group differences in microstructural integrity, and correlated fiber bundle integrity with symptom severity, physical disability, and illness duration.

Methods: A diffusion tensor imaging (DTI) study was performed in 32 patients with mixed FND compared to 36 healthy controls. Diffusion-weighted magnetic resonance images were collected along with patient-reported symptom severity, physical disability (Short Form Health Survey-36), and illness duration data. Weighted-degree and link-level graph theory and probabilistic tractography analyses characterized fractional anisotropy (FA) values across cortico-subcortical connections. Results were corrected for multiple comparisons.

Results: Compared to controls, FND patients showed reduced FA in the stria terminalis/fornix, medial forebrain bundle, extreme capsule, uncinate fasciculus, cingulum bundle, corpus callosum, and striatal-postcentral gyrus projections. Except for the stria terminalis/fornix, these differences remained significant adjusting for depression and anxiety. In within-group analyses, physical disability inversely correlated with stria terminalis/fornix and medial forebrain bundle FA values; illness duration negatively correlated with stria terminalis/fornix white matter integrity. A FND symptom severity composite score did not correlate with FA in patients.

Conclusions: In this first DTI study of mixed FND, microstructural differences were observed in limbic and associative tracts implicated in salience, defensive behaviors, and emotion regulation. These findings advance our understanding of neurocircuit pathways in the pathophysiology of FND.
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http://dx.doi.org/10.1017/S0033291719003386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247956PMC
November 2019

Neurofilament-lysosomal genetic intersections in the cortical network of stuttering.

Prog Neurobiol 2020 01 24;184:101718. Epub 2019 Oct 24.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. Electronic address:

The neurobiological underpinnings of stuttering, a speech disorder characterized by disrupted speech fluency, remain unclear. While recent developments in the field have afforded researchers the ability to pinpoint several genetic profiles associated with stuttering, how these specific genetic backgrounds impact neuronal circuits and how they generate or facilitate the emergence of stuttered speech remains unknown. In this study, we identified the large-scale cortical network that characterizes stuttering using functional connectivity MRI and graph theory. We performed a spatial similarity analysis that examines whether the topology of the stuttering cortical network intersects with genetic expression levels of previously reported genes for stuttering from the protein-coding transcriptome data of the Allen Human Brain Atlas. We found that GNPTG - a gene involved in the mannose-6-phosphate lysosomal targeting pathways - was significantly co-localized with the stuttering cortical network. An enrichment analysis demonstrated that the genes identified with the stuttering cortical network shared a significantly overrepresented biological functionality of Neurofilament Cytoskeleton Organization (NEFH, NEFL and INA). The relationship between lysosomal pathways, cytoskeleton organization, and stuttering, was investigated by comparing the genetic interactome between GNPTG and the neurofilament genes implicated in the current study. We found that genes of the interactome network, including CDK5, SNCA, and ACTB, act as functional links between lysosomal and neurofilament genes. These findings support the notion that stuttering is due to a lysosomal dysfunction, which has deleterious effects on the neurofilament organization of the speech neuronal circuits. They help to elucidate the intriguing, unsolved link between lysosomal mutations and the presence of stuttering.
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http://dx.doi.org/10.1016/j.pneurobio.2019.101718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938554PMC
January 2020

Corrigendum to: -PTEN activity defines an axis for plasticity at cortico-amygdala synapses and influences social behavior.

Cereb Cortex 2020 03;30(2):849

Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain.

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http://dx.doi.org/10.1093/cercor/bhz232DOI Listing
March 2020

Metastable Resting State Brain Dynamics.

Front Comput Neurosci 2019 6;13:62. Epub 2019 Sep 6.

Ikerbasque - the Basque Foundation for Science, Bilbao, Spain.

Metastability refers to the fact that the state of a dynamical system spends a large amount of time in a restricted region of its available phase space before a transition takes place, bringing the system into another state from where it might recur into the previous one. beim Graben and Hutt (2013) suggested to use the recurrence plot (RP) technique introduced by Eckmann et al. (1987) for the segmentation of system's trajectories into metastable states using recurrence grammars. Here, we apply this recurrence structure analysis (RSA) for the first time to resting-state brain dynamics obtained from functional magnetic resonance imaging (fMRI). Brain regions are defined according to the brain hierarchical atlas (BHA) developed by Diez et al. (2015), and as a consequence, regions present high-connectivity in both structure (obtained from diffusion tensor imaging) and function (from the blood-level dependent-oxygenation-BOLD-signal). Remarkably, regions observed by Diez et al. were completely time-invariant. Here, in order to compare this static picture with the metastable systems dynamics obtained from the RSA segmentation, we determine the number of metastable states as a measure of complexity for all subjects and for region numbers varying from 3 to 100. We find RSA convergence toward an optimal segmentation of 40 metastable states for normalized BOLD signals, averaged over BHA modules. Next, we build a bistable dynamics at population level by pooling 30 subjects after Hausdorff clustering. In link with this finding, we reflect on the different modeling frameworks that can allow for such scenarios: heteroclinic dynamics, dynamics with riddled basins of attraction, multiple-timescale dynamics. Finally, we characterize the metastable states both functionally and structurally, using templates for resting state networks (RSNs) and the automated anatomical labeling (AAL) atlas, respectively.
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http://dx.doi.org/10.3389/fncom.2019.00062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743347PMC
September 2019

Individual differences in social network size linked to nucleus accumbens and hippocampal volumes in functional neurological disorder: A pilot study.

J Affect Disord 2019 11 30;258:50-54. Epub 2019 Jul 30.

Department of Neurology, Cognitive Behavioral Neurology Unit, Functional Neurology Research Group, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Psychiatry, Neuropsychiatry Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. Electronic address:

Background: In the biopsychosocial formulation of functional neurological (conversion) disorder (FND), little is known about relationships between social behavior and brain anatomy. We hypothesized that social behavior would relate to brain areas implicated in affiliative behaviors and that social network size would correlate with symptom severity and predisposing vulnerabilities in FND.

Methods: This neuroimaging pilot probed how social network size, as measured by the Social Network Index, related to structural brain profiles in 23 patients with motor FND (15 woman and 8 men). FreeSurfer cortical thickness and subcortical volumetric analyses were performed correcting for multiple comparisons. Stratified analyses compared FND patients with a low social network size to matched healthy controls. Secondary exploratory analyses in an expanded sample of 38 FND patients investigated relationships between social network size, risk factors and patient-reported symptom severity.

Results: Adjusting for age and gender, neuroimaging analyses showed that social network size positively correlated with left nucleus accumbens and hippocampal volumes in patients with FND; stratified analyses did not show any group-level differences. In individuals with FND, social network size correlated with health-related quality of life, graduating college, working full-time and a non-epileptic seizure diagnosis; social network size inversely related to lifetime trauma burden, post-traumatic stress disorder severity and age.

Limitations: Only patient-reported scales were used and social network size information was not collected for healthy subjects.

Conclusions: This neuroimaging pilot adds to the literature linking affiliation network brain areas to pro-social behaviors and enhances the biopsychosocial conceptualization of FND.
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http://dx.doi.org/10.1016/j.jad.2019.07.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783807PMC
November 2019

PTEN Activity Defines an Axis for Plasticity at Cortico-Amygdala Synapses and Influences Social Behavior.

Cereb Cortex 2020 03;30(2):505-524

Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain.

Phosphatase and tensin homolog on chromosome 10 (PTEN) is a tumor suppressor and autism-associated gene that exerts an important influence over neuronal structure and function during development. In addition, it participates in synaptic plasticity processes in adulthood. As an attempt to assess synaptic and developmental mechanisms by which PTEN can modulate cognitive function, we studied the consequences of 2 different genetic manipulations in mice: presence of additional genomic copies of the Pten gene (Ptentg) and knock-in of a truncated Pten gene lacking its PDZ motif (Pten-ΔPDZ), which is required for interaction with synaptic proteins. Ptentg mice exhibit substantial microcephaly, structural hypoconnectivity, enhanced synaptic depression at cortico-amygdala synapses, reduced anxiety, and intensified social interactions. In contrast, Pten-ΔPDZ mice have a much more restricted phenotype, with normal synaptic connectivity, but impaired synaptic depression at cortico-amygdala synapses and virtually abolished social interactions. These results suggest that synaptic actions of PTEN in the amygdala contribute to specific behavioral traits, such as sociability. Also, PTEN appears to function as a bidirectional rheostat in the amygdala: reduction in PTEN activity at synapses is associated with less sociability, whereas enhanced PTEN activity accompanies hypersocial behavior.
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http://dx.doi.org/10.1093/cercor/bhz103DOI Listing
March 2020

Corticolimbic fast-tracking: enhanced multimodal integration in functional neurological disorder.

J Neurol Neurosurg Psychiatry 2019 08 8;90(8):929-938. Epub 2019 Mar 8.

Radiology, Athinoula A Martinos Center for Biomedical Imaging, Charlestown, Massachusetts, USA

Objective: Some individuals with functional neurological disorder (FND) exhibit motor and affective disturbances, along with limbic hyper-reactivity and enhanced motor-limbic connectivity. Given that the multimodal integration network (insula, dorsal cingulate, temporoparietal junction (TPJ)) is implicated in convergent sensorimotor, affective and interoceptive processing, we hypothesised that patients with FND would exhibit altered motor and amygdalar resting-state propagation to this network. Patient-reported symptom severity and clinical outcome were also hypothesised to map onto multimodal integration areas.

Methods: Between-group differences in primary motor and amygdalar nuclei (laterobasal, centromedial) were examined using graph-theory stepwise functional connectivity (SFC) in 30 patients with motor FND compared with 30 healthy controls. Within-group analyses correlated functional propagation profiles with symptom severity and prospectively collected 6-month outcomes as measured by the Screening for Somatoform Symptoms Conversion Disorder subscale and Patient Health Questionnaire-15 composite score. Findings were clusterwise corrected for multiple comparisons.

Results: Compared with controls, patients with FND exhibited increased SFC from motor regions to the bilateral posterior insula, TPJ, middle cingulate cortex and putamen. From the right laterobasal amygdala, the FND cohort showed enhanced connectivity to the left anterior insula, periaqueductal grey and hypothalamus among other areas. In within-group analyses, symptom severity correlated with enhanced SFC from the left anterior insula to the right anterior insula and TPJ; increased SFC from the left centromedial amygdala to the right anterior insula correlated with clinical improvement. Within-group associations held controlling for depression, anxiety and antidepressant use.

Conclusions: These neuroimaging findings suggest potential candidate neurocircuit pathways in the pathophysiology of FND.
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http://dx.doi.org/10.1136/jnnp-2018-319657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625895PMC
August 2019

Connectome sorting by consensus clustering increases separability in group neuroimaging studies.

Netw Neurosci 2019 1;3(2):325-343. Epub 2019 Feb 1.

Dipartimento di Fisica, Universitá degli Studi "Aldo Moro" Bari, Italy.

A fundamental challenge in preprocessing pipelines for neuroimaging datasets is to increase the signal-to-noise ratio for subsequent analyses. In the same line, we suggest here that the application of the consensus clustering approach to brain connectivity matrices can be a valid additional step for to find subgroups of subjects with reduced intragroup variability and therefore increasing the separability of the distinct subgroups when connectomes are used as a biomarker. Moreover, by partitioning the data with consensus clustering before any group comparison (for instance, between a healthy population vs. a pathological one), we demonstrate that unique regions within each cluster arise and bring new information that could be relevant from a clinical point of view.
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http://dx.doi.org/10.1162/netn_a_00074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370473PMC
February 2019

Neurogenetic contributions to amyloid beta and tau spreading in the human cortex.

Nat Med 2018 12 29;24(12):1910-1918. Epub 2018 Oct 29.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Tau and amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer's disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels. We found that tau propagation and Aβ propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as 'axon related' and the Aβ profile as 'dendrite related'. This study reveals distinct genetic profiles that may confer vulnerability to tau and Aβ in vivo propagation in the human brain.
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http://dx.doi.org/10.1038/s41591-018-0206-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518398PMC
December 2018

Sequence Alterations of Cortical Genes Linked to Individual Connectivity of the Human Brain.

Cereb Cortex 2019 08;29(9):3828-3835

Department of Radiology, Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Individual differences in humans are driven by unique brain structural and functional profiles, presumably mediated in part through differential cortical gene expression. However, the relationships between cortical gene expression profiles and individual differences in large-scale neural network organization remain poorly understood. In this study, we aimed to investigate whether the magnitude of sequence alterations in regional cortical genes mapped onto brain areas with high degree of functional connectivity variability across individuals. First, human genetic expression data from the Allen Brain Atlas was used to identify protein-coding genes associated with cortical areas, which delineated the regional genetic signature of specific cortical areas based on sequence alteration profiles. Thereafter, we identified brain regions that manifested high degrees of individual variability by using test-retest functional connectivity magnetic resonance imaging and graph-theory analyses in healthy subjects. We found that rates of genetic sequence alterations shared a distinct spatial topography with cortical regions exhibiting individualized (highly-variable) connectivity profiles. Interestingly, gene expression profiles of brain regions with highly individualized connectivity patterns and elevated number of sequence alterations are devoted to neuropeptide-signaling-pathways and chemical-synaptic-transmission. Our findings support that genetic sequence alterations may underlie important aspects of brain connectome individualities in humans. Significance Statement: The neurobiological underpinnings of our individuality as humans are still an unsolved question. Although the notion that genetic variation drives an individual's brain organization has been previously postulated, specific links between neural connectivity and gene expression profiles have remained elusive. In this study, we identified the magnitude of population-based sequence alterations in discrete cortical regions and compared them to the brain topological distribution of functional connectivity variability across an independent human sample. We discovered that brain regions with high degree of connectional individuality are defined by increased rates of genetic sequence alterations; these findings specifically implicated genes involved in neuropeptide-signaling pathways and chemical-synaptic transmission. These observations support that genetic sequence alterations may underlie important aspects of the emergence of the brain individuality across humans.
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http://dx.doi.org/10.1093/cercor/bhy262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686751PMC
August 2019

Interaction Information Along Lifespan of the Resting Brain Dynamics Reveals a Major Redundant Role of the Default Mode Network.

Entropy (Basel) 2018 Sep 28;20(10). Epub 2018 Sep 28.

Computational Neuroimaging Lab, Biocruces Health Research Institute, 48903 Barakaldo, Spain.

Interaction Information (II) generalizes the univariate Shannon entropy to triplets of variables, allowing the detection of redundant (R) or synergetic (S) interactions in dynamical networks. Here, we calculated II from functional magnetic resonance imaging data and asked whether R or S vary across brain regions and along lifespan. Preserved along lifespan, we found high overlapping between the pattern of high R and the default mode network, whereas high values of S were overlapping with different cognitive domains, such as spatial and temporal memory, emotion processing and motor skills. Moreover, we have found a robust balance between R and S among different age intervals, indicating informational compensatory mechanisms in brain networks.
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http://dx.doi.org/10.3390/e20100742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512305PMC
September 2018

Neurogenetic profiles delineate large-scale connectivity dynamics of the human brain.

Nat Commun 2018 09 24;9(1):3876. Epub 2018 Sep 24.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA.

Experimental and modeling work of neural activity has described recurrent and attractor dynamic patterns in cerebral microcircuits. However, it is still poorly understood whether similar dynamic principles exist or can be generalizable to the large-scale level. Here, we applied dynamic graph theory-based analyses to evaluate the dynamic streams of whole-brain functional connectivity over time across cognitive states. Dynamic connectivity in local networks is located in attentional areas during tasks and primary sensory areas during rest states, and dynamic connectivity in distributed networks converges in the default mode network (DMN) in both task and rest states. Importantly, we find that distinctive dynamic connectivity patterns are spatially associated with Allen Human Brain Atlas genetic transcription levels of synaptic long-term potentiation and long-term depression-related genes. Our findings support the neurobiological basis of large-scale attractor-like dynamics in the heteromodal cortex within the DMN, irrespective of cognitive state.
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http://dx.doi.org/10.1038/s41467-018-06346-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155203PMC
September 2018

Positive Connectivity Predicts the Dynamic Intrinsic Topology of the Human Brain Network.

Front Syst Neurosci 2018 30;12:38. Epub 2018 Aug 30.

Department of Radiology, Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Harvard University, Boston, MA, United States.

Functional connectivity MRI (fcMRI) has become instrumental in facilitating research of human brain network organization in terms of coincident interactions between positive and negative synchronizations of large-scale neuronal systems. Although there is a common agreement concerning the interpretation of positive couplings between brain areas, a major debate has been made in disentangling the nature of negative connectivity patterns in terms of its emergence in several methodological approaches and its significance/meaning in specific neuropsychiatric diseases. It is still not clear what information the functional negative correlations or connectivity provides or how they relate to the positive connectivity. Through implementing stepwise functional connectivity (SFC) analysis and studying the causality of functional topological patterns, this study aims to shed light on the relationship between positive and negative connectivity in the human brain functional connectome. We found that the strength of negative correlations between voxel-pairs relates to their positive connectivity path-length. More importantly, our study describes how the spatio-temporal patterns of positive connectivity explain the evolving changes of negative connectivity over time, but not the other way around. This finding suggests that positive and negative connectivity do not display equivalent forces but shows that the positive connectivity has a dominant role in the overall human brain functional connectome. This phenomenon provides novel insights about the nature of positive and negative correlations in fcMRI and will potentially help new developments for neuroimaging biomarkers.
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http://dx.doi.org/10.3389/fnsys.2018.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125351PMC
August 2018

Structure-function multi-scale connectomics reveals a major role of the fronto-striato-thalamic circuit in brain aging.

Hum Brain Mapp 2018 12 13;39(12):4663-4677. Epub 2018 Jul 13.

Biocruces Health Research Institute, Barakaldo, Spain.

Physiological aging affects brain structure and function impacting morphology, connectivity, and performance. However, whether some brain connectivity metrics might reflect the age of an individual is still unclear. Here, we collected brain images from healthy participants (N = 155) ranging from 10 to 80 years to build functional (resting state) and structural (tractography) connectivity matrices, both data sets combined to obtain different connectivity features. We then calculated the brain connectome age-an age estimator resulting from a multi-scale methodology applied to the structure-function connectome, and compared it to the chronological age (ChA). Our results were twofold. First, we found that aging widely affects the connectivity of multiple structures, such as anterior cingulate and medial prefrontal cortices, basal ganglia, thalamus, insula, cingulum, hippocampus, parahippocampus, occipital cortex, fusiform, precuneus, and temporal pole. Second, we found that the connectivity between basal ganglia and thalamus to frontal areas, also known as the fronto-striato-thalamic (FST) circuit, makes the major contribution to age estimation. In conclusion, our results highlight the key role played by the FST circuit in the process of healthy aging. Notably, the same methodology can be generally applied to identify the structural-functional connectivity patterns correlating to other biomarkers than ChA.
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http://dx.doi.org/10.1002/hbm.24312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866396PMC
December 2018

Enhanced prefrontal functional-structural networks to support postural control deficits after traumatic brain injury in a pediatric population.

Netw Neurosci 2017 1;1(2):116-142. Epub 2017 Jun 1.

Biocruces Health Research Institute, Cruces University Hospital, Barakaldo, Spain.

Traumatic brain injury (TBI) affects structural connectivity, triggering the reorganization of structural-functional circuits in a manner that remains poorly understood. We focus here on brain network reorganization in relation to postural control deficits after TBI. We enrolled young participants who had suffered moderate to severe TBI, comparing them to young, typically developing control participants. TBI patients (but not controls) recruited prefrontal regions to interact with two separated networks: (1) a subcortical network, including parts of the motor network, basal ganglia, cerebellum, hippocampus, amygdala, posterior cingulate gyrus, and precuneus; and (2) a task-positive network, involving regions of the dorsal attention system, together with dorsolateral and ventrolateral prefrontal regions. We also found that the increased prefrontal connectivity in TBI patients was correlated with some postural control indices, such as the amount of body sway, whereby patients with worse balance increased their connectivity in frontal regions more strongly. The increased prefrontal connectivity found in TBI patients may provide the structural scaffolding for stronger cognitive control of certain behavioral functions, consistent with the observations that various motor tasks are performed less automatically following TBI and that more cognitive control is associated with such actions.
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http://dx.doi.org/10.1162/NETN_a_00007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988395PMC
June 2017

Group-Level Progressive Alterations in Brain Connectivity Patterns Revealed by Diffusion-Tensor Brain Networks across Severity Stages in Alzheimer's Disease.

Front Aging Neurosci 2017 7;9:215. Epub 2017 Jul 7.

Biocruces Health Research InstituteBarakaldo, Spain.

Alzheimer's disease (AD) is a chronically progressive neurodegenerative disease highly correlated to aging. Whether AD originates by targeting a localized brain area and propagates to the rest of the brain across disease-severity progression is a question with an unknown answer. Here, we aim to provide an answer to this question at the group-level by looking at differences in diffusion-tensor brain networks. In particular, making use of data from Alzheimer's Disease Neuroimaging Initiative (ADNI), four different groups were defined (all of them matched by age, sex and education level): G ( = 36, healthy control subjects, Control), G ( = 36, early mild cognitive impairment, EMCI), G ( = 36, late mild cognitive impairment, LMCI) and G ( = 36, AD). Diffusion-tensor brain networks were compared across three disease stages: stage I (Control vs. EMCI), stage II (Control vs. LMCI) and stage III (Control vs. AD). The group comparison was performed using the multivariate distance matrix regression analysis, a technique that was born in genomics and was recently proposed to handle brain functional networks, but here applied to diffusion-tensor data. The results were threefold: First, no significant differences were found in stage I. Second, significant differences were found in stage II in the connectivity pattern of a subnetwork strongly associated to memory function (including part of the hippocampus, amygdala, entorhinal cortex, fusiform gyrus, inferior and middle temporal gyrus, parahippocampal gyrus and temporal pole). Third, a widespread disconnection across the entire AD brain was found in stage III, affecting more strongly the same memory subnetwork appearing in stage II, plus the other new subnetworks, including the default mode network, medial visual network, frontoparietal regions and striatum. Our results are consistent with a scenario where progressive alterations of connectivity arise as the disease severity increases and provide the brain areas possibly involved in such a degenerative process. Further studies applying the same strategy to longitudinal data are needed to fully confirm this scenario.
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http://dx.doi.org/10.3389/fnagi.2017.00215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500648PMC
July 2017

Brain circuit-gene expression relationships and neuroplasticity of multisensory cortices in blind children.

Proc Natl Acad Sci U S A 2017 06 12;114(26):6830-6835. Epub 2017 Jun 12.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;

Sensory deprivation reorganizes neurocircuits in the human brain. The biological basis of such neuroplastic adaptations remains elusive. In this study, we applied two complementary graph theory-based functional connectivity analyses, one to evaluate whole-brain functional connectivity relationships and the second to specifically delineate distributed network connectivity profiles downstream of primary sensory cortices, to investigate neural reorganization in blind children compared with sighted controls. We also examined the relationship between connectivity changes and neuroplasticity-related gene expression profiles in the cerebral cortex. We observed that multisensory integration areas exhibited enhanced functional connectivity in blind children and that this reorganization was spatially associated with the transcription levels of specific members of the cAMP Response Element Binding protein gene family. Using systems-level analyses, this study advances our understanding of human neuroplasticity and its genetic underpinnings following sensory deprivation.
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http://dx.doi.org/10.1073/pnas.1619121114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495230PMC
June 2017

The influence of posterior visual pathway damage on visual information processing speed in multiple sclerosis.

Mult Scler 2017 Aug 14;23(9):1276-1288. Epub 2016 Nov 14.

Department of Methods and Experimental Psychology, Faculty of Psychology and Education, Universidad de Deusto, Bilbao, Spain.

Background: The injury of visual pathway and abnormalities of visual processing speed (VPS) are frequent in MS, but their association remains unexplored.

Objective: To evaluate the impact of posterior visual pathway structural and functional integrity on VPS of MS patients.

Methods: Cross-sectional study of 30 MS patients and 28 controls, evaluating the association of a VPS tests composite (Salthouse Perceptual Comparison test, Trail Making Test A and Symbol Digit Modalities Test) with 3T MRI visual cortex thickness, optic radiations (OR) diffusion tensor imaging indexes, and medial visual component (MVC) functional connectivity (FC) (MVC-MVC FC (iFC) and MVC-brain FC (eFC)) by linear regression, removing the effect of premorbid IQ, fatigue, and depression.

Results: V2 atrophy, lower OR fractional anisotropy (FA) and MVC FC significantly influenced VPS in MS (at none or lesser extent in controls), even after removing the effect of Expanded Disability Status Scale and previous optic neuritis (V2 ( r = 0.210): β = +0.366, p = 0.046; OR FA ( r = 0.243): β = +0.378, p = 0.034; MVC iFC, for example, left cuneus ( r = 0.450): β = -0.613, p < 0.001; MVC eFC, for example, right precuneus-postcentral gyrus ( r = 0.368): β = -0.466, p = 0.002).

Conclusion: Posterior visual pathway integrity, structural (V2 thickness and OR FA) and functional (MVC FC), may explain respectively up to 24% and 45% of VPS variability in MS.
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http://dx.doi.org/10.1177/1352458516676642DOI Listing
August 2017

Patient-specific computational modeling of cortical spreading depression via diffusion tensor imaging.

Int J Numer Method Biomed Eng 2017 11 11;33(11). Epub 2017 Apr 11.

Basque Center for Applied Mathematics, Bilbao, Spain.

Cortical spreading depression, a depolarization wave originating in the visual cortex and traveling towards the frontal lobe, is commonly accepted as a correlate of migraine visual aura. As of today, little is known about the mechanisms that can trigger or stop such phenomenon. However, the complex and highly individual characteristics of the brain cortex suggest that the geometry might have a significant impact in supporting or contrasting the propagation of cortical spreading depression. Accurate patient-specific computational models are fundamental to cope with the high variability in cortical geometries among individuals, but also with the conduction anisotropy induced in a given cortex by the complex neuronal organisation in the grey matter. In this paper, we integrate a distributed model for extracellular potassium concentration with patient-specific diffusivity tensors derived locally from diffusion tensor imaging data.
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http://dx.doi.org/10.1002/cnm.2874DOI Listing
November 2017

One-Tube-Only Standardized Site-Directed Mutagenesis: An Alternative Approach to Generate Amino Acid Substitution Collections.

PLoS One 2016 22;11(8):e0160972. Epub 2016 Aug 22.

Biomarkers in Cancer Unit, Biocruces Health Research Institute, Barakaldo, Spain.

Site-directed mutagenesis (SDM) is a powerful tool to create defined collections of protein variants for experimental and clinical purposes, but effectiveness is compromised when a large number of mutations is required. We present here a one-tube-only standardized SDM approach that generates comprehensive collections of amino acid substitution variants, including scanning- and single site-multiple mutations. The approach combines unified mutagenic primer design with the mixing of multiple distinct primer pairs and/or plasmid templates to increase the yield of a single inverse-PCR mutagenesis reaction. Also, a user-friendly program for automatic design of standardized primers for Ala-scanning mutagenesis is made available. Experimental results were compared with a modeling approach together with stochastic simulation data. For single site-multiple mutagenesis purposes and for simultaneous mutagenesis in different plasmid backgrounds, combination of primer sets and/or plasmid templates in a single reaction tube yielded the distinct mutations in a stochastic fashion. For scanning mutagenesis, we found that a combination of overlapping primer sets in a single PCR reaction allowed the yield of different individual mutations, although this yield did not necessarily follow a stochastic trend. Double mutants were generated when the overlap of primer pairs was below 60%. Our results illustrate that one-tube-only SDM effectively reduces the number of reactions required in large-scale mutagenesis strategies, facilitating the generation of comprehensive collections of protein variants suitable for functional analysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160972PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993582PMC
July 2017

Brain Plasticity in Blind Subjects Centralizes Beyond the Modal Cortices.

Front Syst Neurosci 2016 8;10:61. Epub 2016 Jul 8.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Harvard Medical SchoolBoston, MA, USA; Gordon Center for Medical Imaging, Massachusetts General HospitalBoston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical SchoolCharlestown, MA, USA.

It is well established that the human brain reorganizes following sensory deprivations. In blind individuals, visual processing regions including the lateral occipital cortex (LOC) are activated by auditory and tactile stimuli as demonstrated by neurophysiological and neuroimaging investigations. The mechanisms for such plasticity remain unclear, but shifts in connectivity across existing neural networks appear to play a critical role. The majority of research efforts to date have focused on neuroplastic changes within visual unimodal regions, however we hypothesized that neuroplastic alterations may also occur in brain networks beyond the visual cortices including involvement of multimodal integration regions and heteromodal cortices. In this study, two recently developed graph-theory based functional connectivity analyses, interconnector analyses and local and distant connectivity, were applied to investigate functional reorganization in regional and distributed neural-systems in late-onset blind (LB) and congenitally blind (CB) cohorts each compared to their own group of sighted controls. While functional network alterations as measured by the degree of differential links (DDL) occurred in sensory cortices, neuroplastic changes were most prominent within multimodal and association cortices. Subjects with LB showed enhanced multimodal integration connections in the parieto-opercular, temporoparietal junction (TPJ) and ventral premotor (vPM) regions, while CB individuals exhibited increased superior parietal cortex (SPC) connections. This study reveals the critical role of recipient multi-sensory integration areas in network reorganization and cross-modal plasticity in blind individuals. These findings suggest that aspects of cross-modal neuroplasticity and adaptive sensory-motor and auditory functions may potentially occur through reorganization in multimodal integration regions.
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http://dx.doi.org/10.3389/fnsys.2016.00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937754PMC
July 2016