Hippocampal‐parietal dysconnectivity and glutamate abnormalities in unmedicated patients with schizophrenia

Abnormalities in resting state connectivity in schizophrenia (SZ) are now well established, but the biological substrates of these functional alterations remain to be elucidated. We performed a combined functional magnetic resonance imaging and magnetic resonance spectroscopy study in 22 unmedicated patients with SZ and 22 matched healthy controls (HCs) to evaluate resting state functional connectivity of the hippocampus and Glx/Cr (a combined glutamate + glutamine peak normalized to creatine) in the hippocampus and investigate functional and neurometabolic abnormalities and examine the relationship between these. Functional connectivity between the left hippocampus and bilateral precuneus was significantly decreased in unmedicated patients with SZ when compared to HCs [t(4.22), cluster extent (kE) = 751, PFDRcorr = 0.001, Montreal Neurological Institute coordinates: x = −4, y = −56, z = 44]. Glx/Cr in the hippocampus was significantly elevated in SZ (HC: mean = 0.60+/−0.10 SZ: 0.67+/−0.10; F = 5.742; P = 0.02), but was not correlated with functional connectivity deficits (P > 0.05). In this study, we found hippocampal resting state functional connectivity deficits to the precuneus in unmedicated patients with SZ and an increase of Glx/Cr in the hippocampus, but did not observe a direct relationship between these abnormalities. However, our findings do not exclude the possibility of a shared underlying pathology, which warrants further investigation. © 2014 Wiley Periodicals, Inc.

[1]  A. Frances The Diagnostic Interview for Genetic Studies , 1994 .

[2]  P. Skudlarski,et al.  Brain Connectivity Related to Working Memory Performance , 2006, The Journal of Neuroscience.

[3]  Dost Öngür,et al.  Creatine abnormalities in schizophrenia and bipolar disorder , 2009, Psychiatry Research: Neuroimaging.

[4]  N. Tzourio-Mazoyer,et al.  Automated Anatomical Labeling of Activations in SPM Using a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain , 2002, NeuroImage.

[5]  Abraham Z. Snyder,et al.  Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion , 2012, NeuroImage.

[6]  Justin L. Vincent,et al.  Precuneus shares intrinsic functional architecture in humans and monkeys , 2009, Proceedings of the National Academy of Sciences.

[7]  D. Schacter,et al.  The Brain's Default Network , 2008, Annals of the New York Academy of Sciences.

[8]  Dimitrios Kapogiannis,et al.  Posteromedial cortex glutamate and GABA predict intrinsic functional connectivity of the default mode network , 2013, NeuroImage.

[9]  Chunming Xie,et al.  Recovery of hippocampal network connectivity correlates with cognitive improvement in mild alzheimer's disease patients treated with donepezil assessed by resting‐state fMRI , 2011, Journal of magnetic resonance imaging : JMRI.

[10]  B. Biswal,et al.  Functional connectivity in the motor cortex of resting human brain using echo‐planar mri , 1995, Magnetic resonance in medicine.

[11]  John Ashburner,et al.  A fast diffeomorphic image registration algorithm , 2007, NeuroImage.

[12]  Martial Van der Linden,et al.  Self-referential reflective activity and its relationship with rest: a PET study , 2005, NeuroImage.

[13]  Niall W. Duncan,et al.  Glutamate Concentration in the Medial Prefrontal Cortex Predicts Resting-State Cortical-Subcortical Functional Connectivity in Humans , 2013, PloS one.

[14]  F. Hyder,et al.  Total neuroenergetics support localized brain activity: Implications for the interpretation of fMRI , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[15]  P. Skudlarski,et al.  Brain Connectivity Is Not Only Lower but Different in Schizophrenia: A Combined Anatomical and Functional Approach , 2010, Biological Psychiatry.

[16]  J. Nurnberger,et al.  Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. , 1994, Archives of general psychiatry.

[17]  A. Anderson,et al.  Respiratory effects in human functional magnetic resonance imaging due to bulk susceptibility changes. , 2001, Physics in medicine and biology.

[18]  Thomas T. Liu,et al.  A component based noise correction method (CompCor) for BOLD and perfusion based fMRI , 2007, NeuroImage.

[19]  M. Lowe,et al.  Functional Connectivity in Single and Multislice Echoplanar Imaging Using Resting-State Fluctuations , 1998, NeuroImage.

[20]  G. Shulman,et al.  Medial prefrontal cortex and self-referential mental activity: Relation to a default mode of brain function , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Simone Kühn,et al.  Resting-state brain activity in schizophrenia and major depression: a quantitative meta-analysis. , 2013, Schizophrenia bulletin.

[22]  A. Lahti,et al.  Regional Decoupling of N-acetyl-aspartate and Glutamate in Schizophrenia , 2012, Neuropsychopharmacology.

[23]  A. Lahti,et al.  Neurometabolites in schizophrenia and bipolar disorder — A systematic review and meta-analysis , 2012, Psychiatry Research: Neuroimaging.

[24]  A. Cavanna,et al.  The precuneus: a review of its functional anatomy and behavioural correlates. , 2006, Brain : a journal of neurology.

[25]  H. Sackeim,et al.  Parietal cortex and representation of the mental Self. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  R. Conley,et al.  Decisional capacity for informed consent in schizophrenia research. , 2000, Archives of general psychiatry.

[27]  Joaquín Goñi,et al.  Abnormal rich club organization and functional brain dynamics in schizophrenia. , 2013, JAMA psychiatry.

[28]  Guillén Fernández,et al.  The hippocampus supports encoding of between-domain associations within working memory. , 2009, Learning & memory.

[29]  B. Biswal,et al.  Functional connectivity of default mode network components: Correlation, anticorrelation, and causality , 2009, Human brain mapping.

[30]  C. Randolph,et al.  The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. , 1998, Journal of clinical and experimental neuropsychology.

[31]  Georg Northoff,et al.  Involvement of glutamate in rest‐stimulus interaction between perigenual and supragenual anterior cingulate cortex: A combined fMRI‐MRS study , 2011, Human brain mapping.

[32]  Paul J. Laurienti,et al.  An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets , 2003, NeuroImage.

[33]  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.

[34]  V. Calhoun,et al.  Modulation of temporally coherent brain networks estimated using ICA at rest and during cognitive tasks , 2008, Human brain mapping.

[35]  J. Ford,et al.  Default mode network activity and connectivity in psychopathology. , 2012, Annual review of clinical psychology.

[36]  Paul M. Matthews,et al.  Functional segmentation of the hippocampus in the healthy human brain and in Alzheimer's disease , 2013, NeuroImage.

[37]  S. Wakana,et al.  Fiber tract-based atlas of human white matter anatomy. , 2004, Radiology.

[38]  Mark S. Bolding,et al.  Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging , 2012, Schizophrenia Research.

[39]  Sabina M. Gonzales,et al.  Prefrontal activation deficits during episodic memory in schizophrenia. , 2009, The American journal of psychiatry.

[40]  Carol A. Tamminga,et al.  Subanesthetic Doses of Ketamine Stimulate Psychosis in Schizophrenia , 1995, Neuropsychopharmacology.

[41]  Chunshui Yu,et al.  Altered resting-state functional connectivity and anatomical connectivity of hippocampus in schizophrenia , 2008, Schizophrenia Research.

[42]  A. Lahti,et al.  Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia. , 2013, JAMA psychiatry.

[43]  Niall W. Duncan,et al.  Glutamate modulates resting state activity in the perigenual anterior cingulate cortex – A combined fMRI–MRS study , 2012, Neuroscience.

[44]  Huafu Chen,et al.  Default mode network abnormalities in mesial temporal lobe epilepsy: A study combining fMRI and DTI , 2011, Human brain mapping.

[45]  Anthony D Wagner,et al.  Glutamate dysfunction in hippocampus: relevance of dentate gyrus and CA3 signaling. , 2012, Schizophrenia bulletin.

[46]  F. Hyder,et al.  Cerebral energetics and spiking frequency: The neurophysiological basis of fMRI , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Edward Bullmore,et al.  From Lichtheim to rich club: brain networks and psychiatry. , 2013, JAMA psychiatry.

[48]  G L Shulman,et al.  INAUGURAL ARTICLE by a Recently Elected Academy Member:A default mode of brain function , 2001 .

[49]  Jürgen Gallinat,et al.  Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla , 2004, NeuroImage.

[50]  K. Hugdahl,et al.  Resting-state glutamate level in the anterior cingulate predicts blood-oxygen level-dependent response to cognitive control , 2012, Proceedings of the National Academy of Sciences.

[51]  O. Sporns,et al.  High-cost, high-capacity backbone for global brain communication , 2012, Proceedings of the National Academy of Sciences.

[52]  A. Belger,et al.  NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development , 2003, Psychopharmacology.

[53]  Scott T. Grafton,et al.  Wandering Minds: The Default Network and Stimulus-Independent Thought , 2007, Science.

[54]  Vanhamme,et al.  Improved method for accurate and efficient quantification of MRS data with use of prior knowledge , 1997, Journal of magnetic resonance.

[55]  R. Freedman,et al.  Intrinsic hippocampal activity as a biomarker for cognition and symptoms in schizophrenia. , 2014, The American journal of psychiatry.

[56]  Joshua Carp,et al.  Optimizing the order of operations for movement scrubbing: Comment on Power et al. , 2013, NeuroImage.

[57]  Stephen Lawrie,et al.  Functional Specialization within Rostral Prefrontal Cortex (Area 10): A Meta-analysis , 2006, Journal of Cognitive Neuroscience.

[58]  P. Boesiger,et al.  Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action , 2012, PloS one.

[59]  Craig J. Brozinsky,et al.  Functional connectivity with the hippocampus during successful memory formation , 2005, Hippocampus.

[60]  John C Gore,et al.  Resting state functional connectivity of the hippocampus associated with neurocognitive function in left temporal lobe epilepsy , 2014, Human brain mapping.

[61]  A. Flemenbaum,et al.  Inter- and Intra-Rater Reliability of the Brief Psychiatric Rating Scale , 1973, Psychological reports.

[62]  Vinod Menon,et al.  Functional connectivity in the resting brain: A network analysis of the default mode hypothesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.