Functional hierarchy underlies preferential connectivity disturbances in schizophrenia

Abstract

Schizophrenia may involve an elevated excitation/inhibition (E/I) ratio in cortical microcircuits. It remains unknown how this regulatory disturbance maps onto neuroimaging findings. To address this issue, we implemented E/I perturbations within a neural model of large-scale functional connectivity, which predicted hyperconnectivity following E/I elevation. To test predictions, we examined restingstate functional MRI in 161 schizophrenia patients and 164 healthy subjects. As predicted, patients exhibited elevated functional connectivity that correlated with symptom levels, and was most prominent in association cortices, such as the fronto-parietal control network. This pattern was absent in patients with bipolar disorder (n = 73). To account for the pattern observed in schizophrenia, we integrated neurobiologically plausible, hierarchical differences in association vs. sensory recurrent neuronal dynamics into our model. This in silico architecture revealed preferential vulnerability of association networks to E/I imbalance, which we verified empirically. Reported effects implicate widespread microcircuit E/I imbalance as a parsimonious mechanism for emergent inhomogeneous dysconnectivity in schizophrenia.functional connectivity | schizophrenia | computational modeling S chizophrenia (SCZ) is a disabling psychiatric disease associated with widespread neural disturbances. These involve abnormal neurodevelopment (1-3), neurochemistry (4-7), neuronal gene expression (8-11), and altered microscale neural architecture (2). Such deficits are hypothesized to impact excitation-inhibition (E/I) balance in cortical microcircuits (12). Clinically, SCZ patients display a wide range of symptoms, including delusions, hallucinations (13, 14), higher-level cognitive deficits (15, 16), and lower-level sensory alterations (17). This display is consistent with a widespread neuropathology (18), such as the E/I imbalance suggested by the NMDA receptor (NMDAR) hypofunction model (19-21). However, emerging resting-state functional magnetic resonance imaging (rs-fMRI) studies implicate more networkspecific abnormalities in SCZ. Typically, these alterations are localized to higher-order association regions, such as the frontoparietal control network (FPCN) (18,22) and the default mode network (DMN) (23, 24), with corresponding disturbances in thalamo-cortical circuits connecting to association regions (25,26). It remains unknown how to reconcile widespread cellularlevel neuropathology in SCZ (20,21,27,28) with preferential association network disruptions (29,30).Currently a tension exists between two competing frameworks: global versus localized neural dysfunction in SCZ. Association network alterations in SCZ, identified via neuroimaging, may arise from a localized dysfunction (3,9,31,32). Alternatively, they may represent preferential abnormalities arising emergently from a nonspecific global microcircuit disruption (20, 33). Mechanistically, an emergent preferential effect could occur because of intrinsic differences between cortical ...

Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function

“…The temporal coordination of node allegiances to neural systems is at the core of the quantified network flexibility measure, and our node-wise supplemental analyses highlighted a systemwide (rather than a regionally confined) increase in network flexibility in the patients and relatives. However, these findings do not argue against a differential or preferential involvement of certain brain areas at different hierarchical levels (34). For the proposed excitatory-inhibitory imbalance of neural networks in schizophrenia, altered NMDA receptor-depending input to fast-spiking γ-aminobutyric acid (GABA) interneurons has been repeatedly highlighted as a key molecular candidate mechanism for schizophrenia (5,25,35,36).…”

“…Here, further research is warranted, including pharmacological experiments in schizophrenia patients and their healthy first-degree relatives. Fourth, although the idea of an excitatoryinhibitory imbalance is a popular concept in current psychiatric neuroscience (34,46), the biological mechanisms require further clarification. Specifically, although the ubiquitous presence of glutamatergic neurons and NMDA receptors across the brain makes distributed genetic risk effects at the neural network level plausible, further translational research is needed to dissolve some of the ambiguities of this pathophysiological concept.…”

Toward understanding thalamocortical dysfunction in schizophrenia through computational models of neural circuit dynamics

“…As a step in this direction, such an extension has been explored in heterogeneity of local recurrent connectivity across cortical hierarchy. Yang et al (2016) found that elevated E/I ratio in a homogenous model yielded elevated mean functional connectivity, as measured by covariance of the BOLD signal. In line with this model prediction, analysis of resting-state fMRI revealed that this connectivity is increased in SCZ, but that this increase is preferential in association cortex relative to sensory cortex (Fig.…”

“…Thus far these models have primarily applied to cortex only, without inclusion of thalamus or other subcortical structures. In a series of studies, we applied these models to study the large-scale impact of alterations in the excitation-inhibition (E/I) ratio in cortical circuits, relating these effects to rs-fcMRI biomarkers in SCZ (Yang et al, 2014; Anticevic et al, 2015b; Yang et al, 2016). Yang et al (2014) found that increasing the effective strength of connectivity at either the local or long-range level, resulting in an elevated E/I ratio, can capture the elevated local and global neural variability observed in SCZ.…”

Mapping the Consequences of Impaired Synaptic Plasticity in Schizophrenia through Development: An Integrative Model for Diverse Clinical Features

“…For example, schizophrenia patients show altered electroencephalograph (EEG) event related potentials (ERPs) in response to auditory and visual stimuli, as well as altered neural activation in sensory cortices during fMRI studies of sensory processing [105,119,120]. Schizophrenia patients also show altered activation across many individual brain regions and altered connectivity within large-scale brain networks during a variety of sensory and cognitive tasks, although, relative to sensory regions, activation and connectivity involving association cortices may be more disrupted [121-123]. Similarly, schizophrenia patients show altered neural oscillations, as measured by EEG and magnetoencephalography (MEG), during sensory and cognitive tasks, as well as at rest [123,124], with gamma-band oscillations thought to show particular disturbance.…”