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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Available from: Edward T Bullmore, Oct 06, 2015
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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.
    Schizophrenia Research 11/2013; 151(1-3). DOI:10.1016/j.schres.2013.10.028 · 3.92 Impact Factor
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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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    ABSTRACT: There is a growing interest in automatic classification of mental disorders based on neuroimaging data. Small training data sets (subjects) and very large amount of high dimensional data make it a challenging task to design robust and accurate classifiers for heterogeneous disorders such as schizophrenia. Most previous studies considered structural MRI, diffusion tensor imaging and task-based fMRI for this purpose. However, resting-state data has been rarely used in discrimination of schizophrenia patients from healthy controls. Resting data are of great interest, since they are relatively easy to collect, and not confounded by behavioral performance on a task. Several linear and non-linear classification methods were trained using a training dataset and evaluate with a separate testing dataset. Results show that classification with high accuracy is achievable using simple non-linear discriminative methods such as k-nearest neighbors (KNNs) which is very promising. We compare and report detailed results of each classifier as well as statistical analysis and evaluation of each single feature. To our knowledge our effects represent the first use of resting-state functional network connectivity (FNC) features to classify schizophrenia.
    Frontiers in Neuroscience 07/2013; 7(7):133. DOI:10.3389/fnins.2013.00133 · 3.66 Impact Factor
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