This is quite interesting work. I feel strongly that more multimodal imaging work is needed in the field to give us a more complete picture of the complex functional and structural changes associated with schizophrenia (and, of course, this kind of work is relevant for other diseases as well). I do notice that the authors imply in the paper that their findings are at odds with our own findings using joint independent component analysis on structural MRI and oddball fMRI data. I would like to point out that since the authors use a working memory task (whereas we used oddball), and they look at convergence based upon separate analyses, whereas we study regions showing a similar co-variation among subjects for both modalities, it is not surprising that the findings would be different. The convergent finding the authors report is quite important, especially given the evidence of significant disease-related changes in the default mode in schizophrenia. Future work is needed to examine this finding in more detail.

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The default-mode network is characterized by spontaneous, low frequency coherence (<0.1 Hz) across the precuneus/posterior cingulate cortex; the medial prefrontal cortex; and the medial, lateral, and inferior parietal cortex (Raichle et al., 2001). Recently, increasing scientific interest has turned to default-mode dysfunction in a number of mental disorders including Alzheimer disease, autism spectrum disorder (ASD), attention-deficit and hyperactivity disorder (ADHD), and schizophrenia (for a review, see Broyd et al., 2009). In this work the authors examine evidence for altered brain structure and function in 32 chronic schizophrenia patients and matched controls by applying three different neuroimaging techniques: voxel-based morphometry (VBM), functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI). Pomarol-Clotet and colleagues found convergent evidence across all three whole brain voxel-based imaging techniques for altered structure and function of the medial frontal cortex in patients. This is a particularly interesting finding as recent research suggests that the medial prefrontal cortex is an important node in the default-mode network and thought to be related to self-referential and social cognition and emotional processing (Gusnard et al., 2001).

Reduced deactivation of the medial prefrontal cortex in schizophrenic patients and possible association with default-mode dysfunction in the same sample has been previously noted by Pomarol-Clotet et al. (2008). Further, Whitfield-Gabrieli and colleagues have reported reduced task-related suppression of the medial prefrontal cortex in patients with schizophrenia and their first-degree relatives, even when they controlled for working memory task performance. These authors suggest that the reduced deactivation of default-mode activity may result in an increased focus and redirection of attention from the external environment (including task-related events) to introspective and self-referential thought processes (Whitfield-Gabrieli et al., 2009). Indeed, the evidence from Pomarol-Clotet and other neuroimaging research (e.g., Whitfield-Gabrieli et al., 2009) brings biological plausibility to the notion of an overzealous focus on internal thought in patients with schizophrenia. Despite inconsistencies in literature as to the role of the default-mode network in schizophrenia (see Bluhm et al., 2007), a key strength of the current paper is inclusion of multimodal imaging techniques which consistently highlighted the important role of the medial prefrontal cortex in schizophrenia.

In ADHD, another disorder which is characterized by attentional deficits and aberrant default-mode activity (for examples, see Sonuga-Barke and Castellanos, 2007; Castellanos et al., 2008; Uddin et al., 2008), we have chosen to exploit the superior temporal resolution of the electroencephalogram (EEG) relative to other neuroimaging techniques, and its direct association with neuronal activity to explore very low frequency oscillations (VLFOs) in brain activity during rest and task performance (Helps et al., 2008; Helps et al., in press-a; Helps et al., 2010). Similar to fMRI research in schizophrenia, we have shown reduced power in resting-state VLFO activity and task-related attenuation in a group of non-clinical high ADHD scorers (Helps et al., in press-a) and adolescent boys with ADHD (Helps et al., 2010) in a network that is spatially and temporally similar to the default-mode network described in fMRI and other neuroimaging research. Here we provide preliminary support for the utility and value of electrophysiological research within the framework of default-mode network research. Importantly, Pomarol-Clotet and colleagues offer very clear evidence for the scientific merit and efficacy of incorporating multiple imaging modalities. Future research should endeavor to adopt a similar approach in the further investigation of aberrant default-mode activity in schizophrenia.

References:

Bluhm, R.L., Miller, J., Lanius, R.A., Osuch, E.A., Boksman, K., Neufeld, R.W.J., Théberge, J., Schaefer, B., and Williamson, P. (2007). Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: Anomalies in the default network. Schizophrenia Bulletin, 33, 1004-1012. Abstract

Broyd, S.J., Demanuele, D., Debener, S., Helps, S.K., James, C.J., and Sonuga-Barke, E.J.S. (2009). Default-mode brain dysfunction in mental disorders: a systematic review. Neuroscience and Biobehavioural Reviews, 33, 279-296. Abstract

Castellanos, F.X., Margulies, D.S., Kelly, A.M.C., Uddin, L.Q., Ghaffari, M., Kirsch, A., Shaw, D., Shehzad, Z., Di Martino, A., Biswal, B.B., Sonuga-Barke, E.J.S., Rotrosen, J., Adler, L.A., and Milham, M.P. (2008). Cingulate-precuneus interactions: A new locus of dysfunction in adult attention-deficit/hyperactivity disorder. Biological Psychiatry, 63, 332-337. Abstract

Gusnard, D.A., Akbudak, E., Shulman, G.L., and Raichle, M.E. (2001). Medial prefrontal cortex and self-referential mental activity: Relation to a default mode of brain function. Proceedings of the National Academy of Sciences of the United States of America, 98, 4259-4264. Abstract

Helps, S., James, C., Debener, S., Karl, A., and Sonuga-Barke, E.J.S. (2008). Very low frequency EEG oscillations and the resting brain in young adults: A preliminary study of localisation, stability and association with symptoms of inattention. Journal of Neural Transmission, 115, 279-285. Abstract

Helps, S.K., Broyd, S.J., James, C.J., Karl, A., and Sonuga-Barke, E.J.S. (in press-a). The attenuation of very low frequency brain oscillations in transitions from a rest state to active attention. Journal of Psychophysiology.

Helps, S.K., Broyd, S.J., James, C.J., Karl, A., Chen, W. and Sonuga-Barke, E.J.S. Altered spontaneous low frequency brain activity in Attention Deficit/Hyperactivity Disorder. Brain Res. 2010 Jan 28. Abstract

Pomarol-Clotet, E., Salvador, R., Sarro, S., Gomar, J., Vila, F., Martinez, A., Guerrero, A.,Ortiz-Gil, J., Sans-Sansa, B., Capdevila, A., Cebemanos, J.M., McKenna, P.J., 2008. Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default-mode network? Psychological Medicine, 38, 1185-1193. Abstract

Raichle, M.E., MacLeod, A.M., Snyder, A.Z., Powers, W.J., Gusnard, D.A., and Shulman, G.L. (2001). A default mode of brain function. Proceedings of the National Academy of Sciences of the United States of America, 98, 676-682. Abstract

Sonuga-Barke, E.J.S., and Castellanos, F.X. (2007). Spontaneous attentional fluctuations in impaired states and pathological conditions: A neurobiological hypothesis. Neuroscience and Biobehavioural Reviews, 31, 977-986. Abstract

Uddin, L.Q., Kelly, A.M.C., Biswal, B.B., Margulies, D.S., Shehzad, Z., Shaw, D., Ghaffari, M., Rotrosen, J., Adler, L.A., Castellanos, F.X., and Milham, M.P. (2008). Network homogeneity reveals decreased integrity of default-mode network in ADHD. Journal of Neuroscience Methods, 169, 249-254. Abstract

Whitfield-Gabrieli, S., Thermenos, H., Milanovic, S., Tsuang, M., Faraone, S., McCarley, R., Shenton, M., Green, A., LaViolette, P., Wojcik, J., Gabrieli, J.D.E., Seidman, L. (2009). Hyperactivity and Hyperconnectivity of the Default Network in Schizophrenia and in First Degree Relatives of Persons with Schizophrenia, Proceedings of the National Academy of Sciences of the United States of America, 106(4): 1279-1284. Abstract

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