Functional dysconnectivity in schizophrenia associated with attentional modulation of motor function

University of Cambridge, Department of Psychiatry, Cambridge, UK.
Brain (Impact Factor: 9.2). 12/2005; 128(Pt 11):2597-611. DOI: 10.1093/brain/awh632
Source: PubMed


It is not known whether there is a core abnormality that occurs in all cases of schizophrenia. The cognitive dysmetria hypothesis proposes that there is such an abnormality which is characterized cognitively by a disruption in control and coordination processes, and functionally by abnormal inter-regional connectivity within the cortico-cerebellar-thalamo-cortical circuit (CCTCC). In the current study, we used functional MRI (fMRI) to investigate these two key aspects of the hypothesis. Since patients with schizophrenia show deficits in attention which have been characterized extensively using the continuous performance task (CPT) and since functional imaging studies have also demonstrated that this task engages the CCTCC, we used this task to investigate whether two patient groups with distinct symptom profiles would show functional dysconnectivity within this network. Three groups of subjects participated in the study: healthy volunteers (n = 12), schizophrenia patients with both negative and positive symptoms (n = 11) and schizophrenia patients with primarily positive symptoms (n = 11). Patient groups were matched for age of illness onset and medication, and to the control group for age, gender and handedness. Subjects were scanned using fMRI whilst they performed a modified version of the CPT, involving both degraded and non-degraded stimuli. Stimulus degradation has been shown to produce decrements in sensitivity, which is thought to reflect increased demands on the limited capacity of visual attention. Between-group comparisons revealed that patients with schizophrenia, irrespective of symptomatology, showed attenuation of the anterior cingulate and cerebellar response to stimulus degradation in comparison with control subjects. We also observed disruptions of inter-regional brain integration in schizophrenia. A task-specific relationship between the medial superior frontal gyrus and both anterior cingulate and the cerebellum was disrupted in both patient groups in comparison with controls. In addition, patients with negative symptoms showed impaired behavioural performance, and abnormal task-related connectivity between anterior cingulate and supplementary motor area. These findings are consistent with theoretical accounts of schizophrenia as a disorder of functional integration, and with the cognitive dysmetria hypothesis, which posits a disconnection within the CCTCC as a fundamental abnormality in schizophrenia, independent of diagnostic subtype. Furthermore, these data show evidence of additional functional deficits in patients with negative symptoms, deficits which may explain the accompanying attentional impairment.

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    • "Sensory and motor impairments are nevertheless indicated by multiple lines of research (Butler et al., 2008; Javitt, 2009; Walther and Strik, 2012). Motor cortex, like prefrontal cortex, has lower neuronal density in schizophrenia when measured post-mortem (Benes et al., 1986) and imaging studies have shown alterations in cortical and subcortical motor areas (Dazzan et al., 2004; Honey et al., 2005). Previous behavioural studies have documented motor abnormalities in anti-psychotic naı¨ve patients (Wolff and O'Driscoll, 1999; Whitty et al., 2009), particularly as a neurodevelopmental sign (Walker et al., 1994). "
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    ABSTRACT: Schizophrenia is increasingly recognized as a neurodevelopmental disorder with altered connectivity among brain networks. In the current study we examined large-scale network interactions in childhood-onset schizophrenia, a severe form of the disease with salient genetic and neurobiological abnormalities. Using a data-driven analysis of resting-state functional magnetic resonance imaging fluctuations, we characterized data from 19 patients with schizophrenia and 26 typically developing controls, group matched for age, sex, handedness, and magnitude of head motion during scanning. This approach identified 26 regions with decreased functional correlations in schizophrenia compared to controls. These regions were found to organize into two function-related networks, the first with regions associated with social and higher-level cognitive processing, and the second with regions involved in somatosensory and motor processing. Analyses of across- and within-network regional interactions revealed pronounced across-network decreases in functional connectivity in the schizophrenia group, as well as a set of across-network relationships with overall negative coupling indicating competitive or opponent network dynamics. Critically, across-network decreases in functional connectivity in schizophrenia predicted the severity of positive symptoms in the disorder, such as hallucinations and delusions. By contrast, decreases in functional connectivity within the social-cognitive network of regions predicted the severity of negative symptoms, such as impoverished speech and flattened affect. These results point toward the role that abnormal integration of sensorimotor and social-cognitive processing may play in the pathophysiology and symptomatology of schizophrenia.
    Brain 10/2015; DOI:10.1093/brain/awv306 · 9.20 Impact Factor
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    • "Additionally, they are again consistent with the relationship between schizotypy in healthy subjects and the schizophrenia continuum. Consistently, previous studies have indicated that patients with schizophrenia have abnormal prefrontal activity and worse behavioral performance during attentional processing (Weiss et al., 2003; Honey et al., 2005; Kerns et al., 2005; Laurens et al., 2005; MacDonald et al., 2005; Gur et al., 2007). Furthermore, evidence of abnormal prefrontal activity has been reported during cognitive processing in patients with schizophrenia carrying the rs1076560 T allele (Bertolino et al., 2009a,b, 2010; Blasi et al., 2010). "
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    ABSTRACT: "Schizotypy" is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the Schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [(123)I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum.
    Frontiers in Behavioral Neuroscience 07/2014; 8(235):eCollection2014. DOI:10.3389/fnbeh.2014.00235 · 3.27 Impact Factor
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    • "(2013), and Park, 2005; Honey and Fletcher, 2006; Reichenberg and Harvey, 2007). WM is associated with the cortical–subcortical–cerebellar system that involves cortical areas including the inferior frontal gyrus (IFG), and subcortical regions, including the thalamus and pons, and cerebellum (Desmond et al., 1997; Chen and Desmond, 2005ab; Passamonti et al., 2011; Strick et al., 2009); these regions were often altered in schizophrenia (Andreasen et al., 1996; Honey et al., 2005; Rusch et al., 2007; Andreasen and Pierson, 2008; Mouchet-Mages et al., 2011). We employed an established Sternberg VWM paradigm of fMRI (Desmond et al., 1997; Chen and Desmond, 2005ab; Marvel and Desmond, 2010); a prolonged maintenance of WM in the paradigm was advantageous because it required intensive cognitive resources including parallel processing, which were altered in schizophrenia (Andreasen et al., 1998). "
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    ABSTRACT: A dysfunction in working memory (WM) is a core cognitive impairment in schizophrenia that involves the cortical-subcortical-cerebellar network. We propose that in addition to other often-referred markers, the signal reduction in the network during verbal working memory (VWM) is a stable and intrinsic indicator of illness. We presented a Sternberg VWM task to 46 patients with schizophrenia and 46 healthy controls matched on performance accuracy during functional magnetic resonance imaging (fMRI). Reduced activation was demonstrated in the thalamus, cerebellar vermis, pons and the triangular part of the inferior frontal gyrus (IFG) in the patient group. We also found a "failure of deactivation" in the default mode network (DMN) in patients as represented by a low versus high load VWM. In addition, a reduced left lateralization in the triangular and opercular parts of the IFG was observed in the patient group replicating previous "failure of lateralization" findings in schizophrenia. A comparison of long (10 to 19years) and short (3 to 9years) durations of illness (DoIs) demonstrated that the DoI was only associated with the activation changes in the middle frontal gyrus and lateral temporal cortex but not with the IFG-subcortico-cerebellar regions observed. These alterations were consistent with the cognitive dysmetria described in the cortical-subcortical-cerebellar network in schizophrenia. In conclusion, the combination of reduced activation in the cortical-subcortical-cerebellar network during VWM in particular, reduced deactivation in the DMN and reduced lateralization in the IFG is thought to be stable neuroimaging signatures of schizophrenia.
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