Functional dysconnectivity in schizophrenia associated with attentional modulation of motor function

University of Cambridge, Department of Psychiatry, Cambridge, UK.
Brain (Impact Factor: 10.23). 12/2005; 128(Pt 11):2597-611. DOI: 10.1093/brain/awh632
Source: PubMed

ABSTRACT 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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Available from: Edward T Bullmore, Aug 17, 2015
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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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    • "The high accuracy of different classifiers in this study consolidates the disconnection hypothesis in schizophrenia patients (Friston and Frith, 1995; Frith et al., 1995; Josin and Liddle, 2001; Bokde et al., 2006; Mikula and Niebur, 2006; Salvador et al., 2010). Using FC methods, researchers have shown disrupted connectivity patterns in schizophrenia patients during rest and task in several brain regions (Meyer-Lindenberg et al., 2001; Boksman et al., 2005; Honey et al., 2005; Liang et al., 2006; Jafri et al., 2008). In our experiment, connectivity between two DMN nodes (IC #12 and 13) was found to be significantly lower in schizophrenia patients compared to healthy controls (Figure 4). "
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    • "Such ideas have been embedded in more specific theories such as cognitive dysmetria (Andreasen and Paradiso, 1998; Andreasen et al., 1999), cerebral asymmetry (Crow, 2008), and the reduced neuropil hypothesis (Selemon and Goldman-Rakic, 1999), each implicating aberrant connectivity as the structural substrate for functional abnormalities. These theories have been supported by a wealth of independent evidence ranging from abnormal functional connectivity (Honey et al., 2005; Micheloyannis et al., 2006), loss of asymmetry in minicolumn separation and cortical volumes (Bilder et al., 1994; Turetsky et al., 1995), and reduced inter-neuronal spacing (Buxhoeveden et al., 2000). However, a striking aspect of the findings from brain imaging studies of schizophrenia is the heterogeneity of observations, with many studies failing to replicate findings or even producing conflicting results (Chua and McKenna, 1995; Shenton et al., 2001). "
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