Dysconnectivity, large-scale networks and neuronal dynamics in schizophrenia

Uhlhaas, Peter J.

doi:10.1016/j.conb.2012.11.004

Cited by 159 publications

(157 citation statements)

References 60 publications

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“…Local cortical computations, and in turn large-scale neural connectivity, are profoundly altered in SCZ (13). One outcome of such dysconnectivity could be an alteration in the distributed gray matter BOLD signal, reflected in increased variance/power.…”

Section: Discussionmentioning

confidence: 99%

Altered global brain signal in schizophrenia

Yang

Murray

Repovš

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

364

336

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Neuropsychiatric conditions like schizophrenia display a complex neurobiology, which has long been associated with distributed brain dysfunction. However, no investigation has tested whether schizophrenia shows alterations in global brain signal (GS), a signal derived from functional MRI and often discarded as a meaningless baseline in many studies. To evaluate GS alterations associated with schizophrenia, we studied two large chronic patient samples (n = 90, n = 71), comparing them to healthy subjects (n = 220) and patients diagnosed with bipolar disorder (n = 73). We identified and replicated increased cortical power and variance in schizophrenia, an effect predictive of symptoms yet obscured by GS removal. Voxel-wise signal variance was also increased in schizophrenia, independent of GS effects. Both findings were absent in bipolar patients, confirming diagnostic specificity. Biologically informed computational modeling of shared and nonshared signal propagation through the brain suggests that these findings may be explained by altered net strength of overall brain connectivity in schizophrenia.resting-state | global signal | psychiatric illness T he brain of humans and other mammalian species is organized into large-scale systems that exhibit coherent functional relationships across space and time (1). This organizational principle was discovered in the human brain primarily through examination of correlated spontaneous fluctuations in the bloodoxygenation level-dependent (BOLD) signal, which reflects blood flow and is interpreted as a surrogate marker for regional brain metabolic activity (2-4). Such resting-state functional connectivity (rs-fcMRI) analyses further revealed the functional architecture of the brain (1, 3) and its alterations in pathological states, wherein disruptions of brain function may be restricted to certain regions, or extend globally because of widespread neurotransmitter abnormalities (5, 6), possibly affecting widespread global signals (GS) (7). Schizophrenia (SCZ) has been described as a disorder of distributed brain "dysconnectivity" (8), emerging from complex biological alterations (9) that may involve extensive disturbances in the NMDA glutamate receptor, altering the balance of excitation and inhibition (10). The symptoms of SCZ are correspondingly pervasive (11), leading to a lifetime of disability for most patients (12) at profound economic cost. Understanding the properties of neural disturbances in SCZ constitutes an important research goal, to identify pathophysiological mechanisms and advance biomarker development. Given noted hypotheses for brain-wide disturbances in cortical and subcortical computations (13), we hypothesized that SCZ might be associated with GS alterations. However, most rs-fcMRI studies discard the GS to better isolate functional networks. Such removal may fundamentally obscure meaningful brain-wide GS alterations in SCZ. It is currently unknown whether prevalent implementation of such methods affects our understanding of BOLD signal abnormalities in ...

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Section: Discussionmentioning

confidence: 99%

Altered global brain signal in schizophrenia

Yang

Murray

Repovš

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

364

336

View full text Add to dashboard Cite

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“…Aberrant neural oscillations have been suggested to represent a core feature of the pathophysiology of schizophrenia (Uhlhaas andSinger, 2006, 2010;Sun et al, 2011), although the direction and extent of changes in power and covariance across theta and gamma frequencies are highly dependent upon patient, brain region, and behavioral context. Reductions in gamma synchrony among disparate brain areas have been observed in patient populations Mulert et al, 2011) and have been proposed as a framework for understanding inappropriate sensory binding Uhlhaas and Singer, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…We investigated spectral responses in mPFC and dorsal hippocampus in the theta and gamma frequency ranges, as oscillations at these frequencies and in these structures are consistently implicated in schizophrenia-and have been previously shown to be modified by ketamine (Lazarewicz et al, 2010;Uhlhaas, 2013). Ketamine administration simultaneously (1) enhanced gamma activity, with effects observed throughout the network but with greater power changes in mPFC ( Figure 2a) and (2) reduced theta activity throughout the network, particularly in the hippocampal formation, culminating in profoundly reduced dCA1-mPFC crossspectral density in the theta frequency range (Figure 2b).…”

Section: Model Structure For Theta and Gamma Cross-spectramentioning

confidence: 99%

Losing Control Under Ketamine: Suppressed Cortico-Hippocampal Drive Following Acute Ketamine in Rats

Moran

Jones

Blockeel

et al. 2014

Neuropsychopharmacol

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Systemic doses of the psychotomimetic ketamine alter the spectral characteristics of hippocampal and prefrontal cortical network activity. Using dynamic causal modeling (DCM) of cross-spectral densities, we quantify the putative synaptic mechanisms underlying ketamine effects in terms of changes in directed, effective connectivity between dorsal hippocampus and medial prefrontal (dCA1-mPFC) cortex of freely moving rats. We parameterize dose-dependent changes in spectral signatures of dCA1-mPFC local field potential recordings, using neural mass models of glutamatergic and GABAergic circuits. Optimizing DCMs of theta and gamma frequency range responses, model comparisons suggest that both enhanced gamma and depressed theta power result from a reduction in top-down connectivity from mPFC to the hippocampus, mediated by postsynaptic NMDA receptors (NMDARs). This is accompanied by an alteration in the bottom-up pathway from dCA1 to mPFC, which exhibits a distinct asymmetry: here, feed-forward drive at AMPA receptors increases in the presence of decreased NMDAR-mediated inputs. Setting these findings in the context of predictive coding suggests that NMDAR antagonism by ketamine in recurrent hierarchical networks may result in the failure of top-down connections from higher cortical regions to signal predictions to lower regions in the hierarchy, which consequently fail to respond consistently to errors. Given that NMDAR dysfunction has a central role in pathophysiological theories of schizophrenia and that theta and gamma rhythm abnormalities are evident in schizophrenic patients, the approach followed here may furnish a framework for the study of aberrant hierarchical message passing (of prediction errors) in schizophrenia-and the false perceptual inferences that ensue.

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“…Discordant data from the MRI literature demonstrated that changes in brain functioning may be characterized by either abnormally reduced, or increased interactions in extended frontal and parietal cortical circuits, respectively (Woodward et al 2012). These impaired interactions between brain regions support the notion of a disconnectivity syndrome in schizophrenia, which suggests dysfunctional coordination or synchronization of neuronal oscillations in large-scale networks (Uhlhaas 2013). Alterations of neuronal synchrony parameters of these brain regions have also been demonstrated to be implicated in the pathophysiological processes of the disorder (Uhlhaas et al 2008;Roach et al 2013;Skåtun et al 2016).…”

Section: Introductionmentioning

confidence: 55%

“…Similar neurophysiological gamma oscillations profiles were reported in first-episode psychosis (FEP), as well as schizophrenia patients (Leicht et al 2015;Basar 2013;Symond et al 2005). Earlier reports demonstrated a reduction of phase and dysfunctional long-range synchrony during various cognitive paradigms (Pittman-Polletta et al 2015; for review, Uhlhaas andSinger 2011, 2012;Basar 2013), thus highlighting a deficit in sensory processing in psychotic patients. Moreover, a global decrease, as well as a latency increase, of gamma synchrony in initial phases of encoding (\150 ms post-stimulus) were also described for relevant stimuli in a conventional oddball paradigm in FEP (Lee et al 2003;Perez et al 2013).…”

Section: Introductionmentioning

confidence: 56%

Differences of temporal dynamics and signal complexity of gamma band oscillations in first-episode psychosis during a working memory task

et al. 2017

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Gamma band oscillations participate in the temporal binding needed to synchronize cortical networks, involved in early sensory and short term memory processes. In earlier studies, alterations of these neurophysiological parameters have been found in psychotic disorders. To date no study has explored the temporal dynamics and signal complexity of gamma band oscillations in first episode psychosis (FEP). To address this issue, gamma band analysis was performed in 15 FEP patients and 18 healthy controls who successfully performed an adapted 2-back working memory task. Multiple linear and logistic regression models were computed to explore the relationship between the cognitive status and gamma oscillation changes over time. Based on regression model results, phase diagrams were constructed and their complexity was estimated using fractal dimension, a mathematical tool that describes shapes as numeric values. When adjusted for gamma values at time lags -3 to -4 ms and -15 to -16 ms, FEP patients displayed significantly higher time-dependent changes than controls, independently of the nature of the task. The present results are consistent with a discoordination of the activity of cortical generators engaged by the stimulus apparition in FEP patients, leading to a global binding deficit. In addition, fractal analysis showing higher complexity of gamma signal, confirmed this deficit. Our results provide evidence for recruitment of supplementary cortical generators as compensating mechanisms and yield further understanding for the pathophysiology cognitive impairments in FEP.

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Dysconnectivity, large-scale networks and neuronal dynamics in schizophrenia

Cited by 159 publications

References 60 publications

Altered global brain signal in schizophrenia

Altered global brain signal in schizophrenia

Losing Control Under Ketamine: Suppressed Cortico-Hippocampal Drive Following Acute Ketamine in Rats

Differences of temporal dynamics and signal complexity of gamma band oscillations in first-episode psychosis during a working memory task

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