Alterations in prefrontal connectivity in schizophrenia assessed using diffusion magnetic resonance imaging

Background: Spatial and biological characteristics of structural frontal disconnectivity in schizophrenia remain incompletely understood. Simultaneous streamline count (SC) and fractional anisotropy (FA) analyses may yield relevant complementary information to this end. Methods: Using 3T diffusion magnetic resonance imaging both SC and FA were calculated for the tracts linking lateral and medial subregions of prefrontal cortex (PFC) to cingulate, hippocampus, caudate and thalamus in 27 schizophrenia patients (14 first‐episodes) and 27 controls. Relationships of these parameters with cognition, symptoms, treatment doses and illness duration were assessed where significant between‐groups differences were detected. Results: Patients showed lower SC and FA in the tracts linking lateral and medial PFC to thalamus (likely corresponding to anterior thalamic peduncle) and lower FA in those linking PFC to caudate (likely through internal capsule), right caudal anterior cingulate and left hippocampus (likely corresponding to hippocampal‐prefrontal pathway). Moreover, patients showed greater SC values for the tracts linking medial PFC and left caudal anterior cingulate. SC and FA values for the tracts linking PFC and caudal anterior cingulate were positively related to motor speed, executive function, problem solving and completed categories in WCST. FA for the tract linking right lateral PFC and caudate was directly related to positive symptoms and FA for the tract linking left medial PFC and left thalamus was inversely related to negative symptoms. Treatment doses were not associated with SC or FA values in any tract. Illness duration was negatively associated with SC and FA in the tracts linking PFC and subcortical areas. Conclusions: Widespread alterations in frontal structural connectivity of PFC can be found in schizophrenia, and are related to cognition, symptoms and illness duration. HighlightsWe assessed fractional anisotropy and streamline counts for the tracts linking prefrontal cortex with relevant regions.Lower fractional anisotropy were found in schizophrenia patients in most of these anatomical connections.Streamline counts were lower in the patients for the right prefrontal cortico‐thalamic tract.These alterations were related with cognition and symptoms.FA and SC were inversely associated to illness duration, but not to treatment doses.

[1]  Alan Connelly,et al.  Robust determination of the fibre orientation distribution in diffusion MRI: Non-negativity constrained super-resolved spherical deconvolution , 2007, NeuroImage.

[2]  C. Junqué,et al.  Spanish Validation Of the Brief Assessment in Cognition in Schizophrenia (Bacs) in Patients With Schizophrenia and Healthy Controls , 2011, European Psychiatry.

[3]  Arvind Caprihan,et al.  The Paradoxical Relationship between White Matter, Psychopathology and Cognition in Schizophrenia: A Diffusion Tensor and Proton Spectroscopic Imaging Study , 2015, Neuropsychopharmacology.

[4]  Paul J. Harrison The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications , 2004, Psychopharmacology.

[5]  V. Calhoun,et al.  In Search of Multimodal Neuroimaging Biomarkers of Cognitive Deficits in Schizophrenia , 2015, Biological Psychiatry.

[6]  P. DeRosse,et al.  Further neuroimaging evidence for the deficit subtype of schizophrenia: a cortical connectomics analysis. , 2015, JAMA psychiatry.

[7]  Xin Yu,et al.  Reduced white matter integrity and cognitive deficit in never-medicated chronic schizophrenia: A diffusion tensor study using TBSS , 2013, Behavioural Brain Research.

[8]  Alan Connelly,et al.  Anatomically-constrained tractography: Improved diffusion MRI streamlines tractography through effective use of anatomical information , 2012, NeuroImage.

[9]  R. Murray,et al.  White matter integrity as a predictor of response to treatment in first episode psychosis , 2013, Brain : a journal of neurology.

[10]  A. Mechelli,et al.  Dysconnectivity in schizophrenia: Where are we now? , 2011, Neuroscience & Biobehavioral Reviews.

[11]  Yufei Huang,et al.  Alteration of Fractional Anisotropy and Mean Diffusivity in Glaucoma: Novel Results of a Meta-Analysis of Diffusion Tensor Imaging Studies , 2014, PloS one.

[12]  Patrick R Hof,et al.  Diffusion tensor imaging findings in first-episode and chronic schizophrenia patients. , 2008, The American journal of psychiatry.

[13]  T. Kinoshita,et al.  Diffusion Tensor Magnetic Resonance Imaging of Disruption of Regional White Matter in Schizophrenia , 2003, Neuropsychobiology.

[14]  S. Kay,et al.  The positive and negative syndrome scale (PANSS) for schizophrenia. , 1987, Schizophrenia bulletin.

[15]  Keith H. Nuechterlein,et al.  Differential effects of typical and atypical antipsychotics on brain myelination in schizophrenia , 2007, Schizophrenia Research.

[16]  J. Gold,et al.  Short form of the WAIS-III for use with patients with schizophrenia , 2000, Schizophrenia Research.

[17]  R. Coppola,et al.  Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. , 2000, Cerebral cortex.

[18]  Feliberto de la Cruz,et al.  Structural and functional dysconnectivity of the fronto-thalamic system in schizophrenia: A DCM-DTI study , 2015, Cortex.

[19]  P. Sham,et al.  Positive symptoms and white matter microstructure in never-medicated first episode schizophrenia , 2010, Psychological Medicine.

[20]  E. Bora,et al.  Neuroanatomical abnormalities in schizophrenia: A multimodal voxelwise meta-analysis and meta-regression analysis , 2011, Schizophrenia Research.

[21]  G. Pearlson,et al.  Cortical structural abnormalities in deficit versus nondeficit schizophrenia , 2012, Schizophrenia Research.

[22]  Nancy C. Andreasen,et al.  Progressive Brain Change in Schizophrenia: A Prospective Longitudinal Study of First-Episode Schizophrenia , 2011, Biological Psychiatry.

[23]  Cheuk Y. Tang,et al.  Diffusion tensor imaging of frontal lobe white matter tracts in schizophrenia , 2006, Annals of general psychiatry.

[24]  A. James,et al.  Abnormal frontostriatal connectivity in adolescent-onset schizophrenia and its relationship to cognitive functioning , 2016, European Psychiatry.

[25]  Jungsu S. Oh,et al.  Anterior limb of the internal capsule in schizophrenia: a diffusion tensor tractography study , 2012, Brain Imaging and Behavior.

[26]  Joy A. Thomas,et al.  White matter deficits in first episode schizophrenia: An activation likelihood estimation meta-analysis , 2013, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[27]  Elia Formisano,et al.  Anatomical brain connectivity and positive symptoms of schizophrenia: A diffusion tensor imaging study , 2009, Psychiatry Research: Neuroimaging.

[28]  Ragini Verma,et al.  White matter microstructure in schizophrenia: Associations to neurocognition and clinical symptomatology , 2015, Schizophrenia Research.

[29]  T. Nakada,et al.  Diffusion tensor analysis in chronic schizophrenia A preliminary study on a high–field (3.0T) system , 2005, European Archives of Psychiatry and Clinical Neuroscience.

[30]  D. Hubl,et al.  Pathways that make voices: white matter changes in auditory hallucinations. , 2004, Archives of general psychiatry.

[31]  M. Yücel,et al.  Mapping grey matter reductions in schizophrenia: An anatomical likelihood estimation analysis of voxel-based morphometry studies , 2009, Schizophrenia Research.

[32]  D. Prvulovic,et al.  Association between white matter fiber integrity and subclinical psychotic symptoms in schizophrenia patients and unaffected relatives , 2012, Schizophrenia Research.

[33]  G. Pergola,et al.  The role of the thalamus in schizophrenia from a neuroimaging perspective , 2015, Neuroscience & Biobehavioral Reviews.

[34]  M. Difrancesco,et al.  Childhood-onset lupus with clinical neurocognitive dysfunction shows lower streamline density and pairwise connectivity on diffusion tensor imaging , 2015, Lupus.

[35]  A. Wheeler,et al.  A review of structural neuroimaging in schizophrenia: from connectivity to connectomics , 2014, Front. Hum. Neurosci..

[36]  Stephen M. Smith,et al.  A Bayesian model of shape and appearance for subcortical brain segmentation , 2011, NeuroImage.

[37]  Deanna M. Barch,et al.  Cognition in schizophrenia: core psychological and neural mechanisms , 2012, Trends in Cognitive Sciences.

[38]  J. Ruíz,et al.  Versión abreviada del WAIS-III para su uso en la evaluación de pacientes con diagnóstico de esquizofrenia , 2010 .

[39]  M. Filippi,et al.  Patterns of Brain Structural Changes in First-Contact, Antipsychotic Drug-Naïve Patients with Schizophrenia , 2014, American Journal of Neuroradiology.

[40]  Benedicto Crespo-Facorro,et al.  White matter integrity and cognitive impairment in first-episode psychosis. , 2010, The American journal of psychiatry.

[41]  B. Pollock,et al.  Neuroimaging evidence for the deficit subtype of schizophrenia. , 2013, JAMA psychiatry.

[42]  E. Bullmore,et al.  Formal characterization and extension of the linearized diffusion tensor model , 2005, Human brain mapping.

[43]  R. Kikinis,et al.  Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study , 2003, Biological Psychiatry.

[44]  P. Brambilla,et al.  Anterior cingulate volumes in schizophrenia: A systematic review and a meta-analysis of MRI studies , 2007, Schizophrenia Research.

[45]  Stephen M. Smith,et al.  Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm , 2001, IEEE Transactions on Medical Imaging.

[46]  Manzar Ashtari,et al.  Clinical and Neuropsychological Correlates of White Matter Abnormalities in Recent Onset Schizophrenia , 2008, Neuropsychopharmacology.

[47]  Massimo Filippi,et al.  A selective review of structural connectivity abnormalities of schizophrenic patients at different stages of the disease , 2015, Schizophrenia Research.

[48]  E. Bullmore,et al.  Meta-analysis of diffusion tensor imaging studies in schizophrenia , 2009, Schizophrenia Research.

[49]  Paul M. Thompson,et al.  Relationship between white matter fractional anisotropy and other indices of cerebral health in normal aging: Tract-based spatial statistics study of aging , 2007, NeuroImage.

[50]  J. Fuster Anatomy of the Prefrontal Cortex , 2008 .

[51]  L. Yao,et al.  Two Patterns of White Matter Abnormalities in Medication-Naive Patients With First-Episode Schizophrenia Revealed by Diffusion Tensor Imaging and Cluster Analysis. , 2015, JAMA psychiatry.

[52]  P. Szeszko,et al.  A meta-analysis of diffusion tensor imaging studies of the corpus callosum in schizophrenia , 2011, Schizophrenia Research.

[53]  Eleanor H. Simpson,et al.  A Possible Role for the Striatum in the Pathogenesis of the Cognitive Symptoms of Schizophrenia , 2010, Neuron.

[54]  J M Fuster,et al.  Synopsis of function and dysfunction of the frontal lobe , 1999, Acta psychiatrica Scandinavica. Supplementum.

[55]  John G. Csernansky,et al.  Anterior thalamic radiation integrity in schizophrenia: A diffusion-tensor imaging study , 2010, Psychiatry Research: Neuroimaging.

[56]  G. D. Erausquin,et al.  What does anisotropy measure? Insights from increased and decreased anisotropy in selective fiber tracts in schizophrenia , 2012, Front. Integr. Neurosci..

[57]  Stephen M Smith,et al.  Fast robust automated brain extraction , 2002, Human brain mapping.

[58]  J. Gabrieli,et al.  Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia , 2009, Proceedings of the National Academy of Sciences.

[59]  Manzar Ashtari,et al.  White matter abnormalities in early-onset schizophrenia: a voxel-based diffusion tensor imaging study. , 2005, Journal of the American Academy of Child and Adolescent Psychiatry.

[60]  Sophia Frangou,et al.  Effect of age at onset of schizophrenia on white matter abnormalities , 2009, British Journal of Psychiatry.