Altered Cerebral Response During Cognitive Control: A Potential Indicator of Genetic Liability for Schizophrenia

Aberrant activity in brain regions underlying various aspects of executive cognition has been reported in patients with schizophrenia and in their healthy relatives, suggesting an association with genetic liability. The aim of this study was to investigate brain responses to selective aspects of cognitive control in unaffected siblings who are at increased genetic risk of schizophrenia. Altogether, 65 non-affected siblings, 70 patients with schizophrenia spectrum disorders, and 235 normal controls participated in this study. Blood-oxygen-Ievel-dependent functional magnetic resonance imaging was conducted while participants performed a cognitive control task (‘flanker task’) to identify brain activity and connectivity associated with response inhibition and conflict monitoring, and suppression. Behaviorally, similar to patients with schizophrenia, siblings were less accurate when inhibiting prepotent responses relative to normal controls. During response inhibition, again similar to patients with schizophrenia, siblings showed decreased activity in the anterior cingulate (ACC), along with increased functional coupling with the dorsolateral prefrontal cortex (PFC) when compared to normal controls. Our findings show altered ACC activity and PFC connectivity in unaffected siblings and patients with schizophrenia during response inhibition. These results suggest that such changes in the neural activity underlying aspects of cognitive control may represent a potential intermediate phenotype for the investigation of the genetic basis of schizophrenia.

[1]  P. Michie,et al.  Acts of control in schizophrenia: dissociating the components of inhibition , 2002, Psychological Medicine.

[2]  Fabio Sambataro,et al.  Altered cortical network dynamics: a potential intermediate phenotype for schizophrenia and association with ZNF804A. , 2011, Archives of general psychiatry.

[3]  David Badre,et al.  Selection, Integration, and Conflict Monitoring Assessing the Nature and Generality of Prefrontal Cognitive Control Mechanisms , 2004, Neuron.

[4]  V. Calhoun,et al.  Brain network dynamics during error commission , 2009, Human brain mapping.

[5]  Colm McDonald,et al.  Functional magnetic resonance imaging (fMRI) of attention processes in presumed obligate carriers of schizophrenia: preliminary findings , 2008, Annals of general psychiatry.

[6]  Keiji Tanaka,et al.  Conflict-induced behavioural adjustment: a clue to the executive functions of the prefrontal cortex , 2009, Nature Reviews Neuroscience.

[7]  D. Carmelli,et al.  Evidence for genetic mediation of executive control: a study of aging male twins. , 2002, The journals of gerontology. Series B, Psychological sciences and social sciences.

[8]  T. Goldberg,et al.  Genetic risk of neuropsychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder , 1995, Schizophrenia Research.

[9]  R. Hübner,et al.  On-the-fly adaptation of selectivity in the flanker task , 2008, Psychonomic bulletin & review.

[10]  Jin Fan,et al.  Effective Connectivity of the Fronto-parietal Network during Attentional Control , 2010, Journal of Cognitive Neuroscience.

[11]  C. Carter,et al.  Anterior cingulate cortex activity and impaired self-monitoring of performance in patients with schizophrenia: an event-related fMRI study. , 2001, The American journal of psychiatry.

[12]  J. Callicott,et al.  Normal aging modulates prefrontoparietal networks underlying multiple memory processes , 2012, The European journal of neuroscience.

[13]  Klaus P. Ebmeier,et al.  fMRI correlates of state and trait effects in subjects at genetically enhanced risk of schizophrenia. , 2003, Brain : a journal of neurology.

[14]  Michal Mikl,et al.  Effective connectivity in target stimulus processing: A dynamic causal modeling study of visual oddball task , 2007, NeuroImage.

[15]  H. Barbas,et al.  Synapses with Inhibitory Neurons Differentiate Anterior Cingulate from Dorsolateral Prefrontal Pathways Associated with Cognitive Control , 2009, Neuron.

[16]  Tyrone D. Cannon,et al.  Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers. , 1994, Archives of general psychiatry.

[17]  A. Turken,et al.  Dissociation between conflict detection and error monitoring in the human anterior cingulate cortex , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Daniel R Weinberger,et al.  Impaired intellect and memory: a missing link between genetic risk and schizophrenia? , 2010, Archives of general psychiatry.

[19]  Gian Luca Romani,et al.  Altered brain response without behavioral attention deficits in healthy siblings of schizophrenic patients An event-related fMRI study , 2010, NeuroImage.

[20]  T. Robbins,et al.  Impaired conscious and preserved unconscious inhibitory processing in recent onset schizophrenia , 2008, Psychological Medicine.

[21]  Daniel A. Miller,et al.  Individuals with schizophrenia present hypo- and hyperactivation during implicit cueing in an inhibitory task , 2006, NeuroImage.

[22]  Daniel R. Weinberger,et al.  Prefrontal neurons and the genetics of schizophrenia , 2001, Biological Psychiatry.

[23]  Martin J. Herrmann,et al.  Brain electrical dysfunction of the anterior cingulate in schizophrenic patients , 2003, Psychiatry Research: Neuroimaging.

[24]  Vishnu P. Murty,et al.  Catechol-O-Methyltransferase Valine158Methionine Polymorphism Modulates Brain Networks Underlying Working Memory Across Adulthood , 2009, Biological Psychiatry.

[25]  Katya Rubia,et al.  An fMRI study of reduced left prefrontal activation in schizophrenia during normal inhibitory function , 2001, Schizophrenia Research.

[26]  R. Kahn,et al.  Striatal Dysfunction in Schizophrenia and Unaffected Relatives , 2006, Biological Psychiatry.

[27]  S. Rauch,et al.  Test-retest reliability of a functional MRI working memory paradigm in normal and schizophrenic subjects. , 2001, The American journal of psychiatry.

[28]  T. Goldberg,et al.  Brain regions underlying response inhibition and interference monitoring and suppression , 2006, The European journal of neuroscience.

[29]  Jonathan D. Cohen,et al.  Anterior Cingulate Conflict Monitoring and Adjustments in Control , 2004, Science.

[30]  John L. Bradshaw,et al.  Associations between laboratory measures of executive inhibitory control and self-reported impulsivity , 2006 .

[31]  T. Goldberg,et al.  Probing prefrontal function in schizophrenia with neuropsychological paradigms. , 1988, Schizophrenia bulletin.

[32]  Jill M Goldstein,et al.  Functional magnetic resonance imaging during auditory verbal working memory in nonpsychotic relatives of persons with schizophrenia: a pilot study , 2004, Biological Psychiatry.

[33]  C. Carter,et al.  Functional Magnetic Resonance Imaging Study of Cognitive Control in the Healthy Relatives of Schizophrenia Patients , 2006, Biological Psychiatry.

[34]  M. Minzenberg,et al.  Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. , 2009, Archives of general psychiatry.

[35]  Klaus P. Ebmeier,et al.  Altered cerebral perfusion measured by SPECT in relatives of patients with schizophrenia , 1999, British Journal of Psychiatry.

[36]  I. Gottesman,et al.  The endophenotype concept in psychiatry: etymology and strategic intentions. , 2003, The American journal of psychiatry.

[37]  P. Liddle,et al.  Cognitive deficits in early-onset schizophrenia spectrum patients and their non-psychotic siblings: A comparison with ADHD , 2008, Schizophrenia Research.

[38]  G. Glover,et al.  Acquiring and inhibiting prepotent responses in schizophrenia: event-related brain potentials and functional magnetic resonance imaging. , 2004, Archives of general psychiatry.

[39]  M. Egan,et al.  Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. , 2003, The American journal of psychiatry.

[40]  J. Anton,et al.  Blunted activation in right ventrolateral prefrontal cortex during motor response inhibition in schizophrenia , 2007, Schizophrenia Research.

[41]  C. Carter,et al.  Prefrontal Dysfunction in First-Degree Relatives of Schizophrenia Patients during a Stroop Task , 2008, Neuropsychopharmacology.

[42]  R. Kahn,et al.  Reduced Proactive Inhibition in Schizophrenia Is Related to Corticostriatal Dysfunction and Poor Working Memory , 2011, Biological Psychiatry.

[43]  J. Callicott,et al.  Intermediate phenotypes in schizophrenia genetics redux: is it a no brainer? , 2008, Molecular Psychiatry.

[44]  T. Paus,et al.  Functional connectivity of the anterior cingulate cortex within the human frontal lobe: a brain-mapping meta-analysis , 2000, Experimental Brain Research.