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 ...

IMPORTANCESevere neuropsychiatric conditions, such as schizophrenia, affect distributed neural computations. One candidate system profoundly altered in chronic schizophrenia involves the thalamocortical networks. It is widely acknowledged that schizophrenia is a neurodevelopmental disorder that likely affects the brain before onset of clinical symptoms. However, no investigation has tested whether thalamocortical connectivity is altered in individuals at risk for psychosis or whether this pattern is more severe in individuals who later develop full-blown illness.OBJECTIVES To determine whether baseline thalamocortical connectivity differs between individuals at clinical high risk for psychosis and healthy controls, whether this pattern is more severe in those who later convert to full-blown illness, and whether magnitude of thalamocortical dysconnectivity is associated with baseline prodromal symptom severity. DESIGN, SETTING, AND PARTICIPANTSIn this multicenter, 2-year follow-up, case-control study, we examined 397 participants aged 12-35 years of age (243 individuals at clinical high risk of psychosis, of whom 21 converted to full-blown illness, and 154 healthy controls). The baseline scan dates were January 15, 2010, to April 30, 2012. MAIN OUTCOMES AND MEASURESWhole-brain thalamic functional connectivity maps were generated using individuals' anatomically defined thalamic seeds, measured using resting-state functional connectivity magnetic resonance imaging.RESULTS Using baseline magnetic resonance images, we identified thalamocortical dysconnectivity in the 243 individuals at clinical high risk for psychosis, which was particularly pronounced in the 21 participants who converted to full-blown illness. The pattern involved widespread hypoconnectivity between the thalamus and prefrontal and cerebellar areas, which was more prominent in those who converted to full-blown illness (t 173 = 3.77, P < .001, Hedge g = 0.88). Conversely, there was marked thalamic hyperconnectivity with sensory motor areas, again most pronounced in those who converted to full-blown illness (t 173 = 2.85, P < .001, Hedge g = 0.66). Both patterns were significantly correlated with concurrent prodromal symptom severity (r = 0.27, P < 3.6 × 10 −8 , Spearman ρ = 0.27, P < 4.75 × 10 −5 , 2-tailed).CONCLUSIONS AND RELEVANCE Thalamic dysconnectivity, resembling that seen in schizophrenia, was evident in individuals at clinical high risk for psychosis and more prominently in those who later converted to psychosis. Dysconnectivity correlated with symptom severity, supporting the idea that thalamic connectivity may have prognostic implications for risk of conversion to full-blown illness.

Recent theoretical accounts have proposed excitation (E) and inhibition (I) imbalance as a possible mechanistic, network-level hypothesis underlying neural and behavioral dysfunction across neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and schizophrenia (SCZ). These two disorders share some overlap in their clinical presentation as well as convergence in their underlying genes and neurobiology. However, there are also clear points of dissociation in terms of phenotypes and putatively affected neural circuitry. Here we highlight emerging work from the clinical neuroscience literature examining neural correlates of E/I imbalance across children and adults with ASD and adults with both chronic and early-course SCZ. We discuss findings from diverse neuroimaging studies across distinct modalities, conducted with EEG, MEG, 1H-MRS, and fMRI, including effects observed both during task and at rest. Throughout this review we discuss points of convergence and divergence in the ASD and SCZ literature, with a focus on disruptions in neural E/I balance. We also consider these findings in relation to predictions generated by theoretical neuroscience, particularly computational models predicting E/I imbalance across disorders. Finally, we discuss how human non-invasive neuroimaging can benefit from pharmacological challenge studies to reveal mechanisms in ASD and SCZ. Collectively, we attempt to shed light on shared and divergent neuroimaging effects across disorders with the goal of informing future research examining the mechanisms underlying the E/I imbalance hypothesis across neurodevelopmental disorders. We posit that such translational efforts are vital to facilitate development of neurobiologically informed treatment strategies across neuropsychiatric conditions.