Aberrant Network Activity in Schizophrenia

Abstract

Brain dynamic changes associated with schizophrenia are largely equivocal, with interpretation complicated by many factors, such as the presence of therapeutic agents and the complex nature of the syndrome itself. Evidence for a brain-wide change in individual network oscillations, shared by all patients, is largely equivocal, but stronger for lower (delta) than for higher (gamma) bands. However, region-specific changes in rhythms across multiple, interdependent, nested frequencies may correlate better with pathology. Changes in synaptic excitation and inhibition in schizophrenia disrupt delta rhythm-mediated cortico-cortical communication, while enhancing thalamocortical communication in this frequency band. The contrasting relationships between delta and higher frequencies in thalamus and cortex generate frequency mismatches in inter-regional connectivity, leading to a disruption in temporal communication between higher-order brain regions associated with mental time travel.

Keywords: cross-frequency coupling; default mode network; delta rhythm; gamma rhythm; thalamocortical communication; theta rhythm.

Figure 1. Gamma Frequency Oscillations Respond to Reduced NMDA Receptor-Mediated Excitation Differently Depending on Brain Region and Mechanisms of Generation

Data from in vitro experiments using isolated slices of individual cortical regions (indicated by the circles in the top panel). Gamma oscillations were evoked by either kainate (gluR-driven gamma) or carbachol (AchR-driven gamma) except in perirhinal and medial or ‘ormital’ = orbitalital cortices, where neither excitation-generated gamma rhythms occurred (red circles). Data show the power of local field potential gamma rhythms in the presence of ketamine relative to control gamma power. Note the overt regional differences in the effect of ketamine in each condition and the contrasting effects of ketamine in auditory cortex depending on the method of gamma rhythm generation. Adapted from [83].

Figure 2. Gamma, Theta and Delta Rhythms Nest Robustly in Local Circuits of Neocortex but Are Mutually Exclusive in Thalamocortical Neurons

(A) Example thalamocortical neuronal recordings under different neuromodulatory conditions and levels of excitation. Delta rhythms are generated by thalamocortical cells in the absence of cholinergic neuromodulation. Theta rhythms occur under the influence of metabotropic glutamate or acetylcholine receptor activation. Fast rhythmic bursting (FRB) at gamma frequencies arises from these neurons under conditions of reduced BK channel activity in a similar manner to FRB activity underlying persistent gamma rhythms in neocortex [84]. (B) Example neuronal recordings during spontaneous delta rhythms in neocortical slices under dopamine receptor blockade. In these conditions, delta rhythms arise from deep layer (5a) intrinsically bursting neurons (dIB). By contrast, deep layer regular-spiking neurons (dRS) generate packets of theta frequency output temporally aligned (nested) with the dIB cell bursts. dRS neuron theta frequency outputs generate theta frequency and compound excitatory postsynaptic currents (EPSPs) in superficial fast-spiking neurons (sFS), leading to bursts of gamma-frequency output. (C) The coexistence of gamma, theta, and delta rhythms seen in vitro (B) is also commonly seen in invasive recordings from awake, behaving non-human primates. Reproduced, with permission, from [7,44] (A) and [46] (B). Adapted, with permission, from [92] (C).

Figure 3. Gamma and Theta Rhythms Nest Robustly in Hippocampus

(A) In vitro recordings from neurons in rodent hippocampal area CA1 during pharmacologically induced theta rhythms. Note epochs of loosely timed gamma frequency spikes from fast-spiking (FS) interneurons (perisomatic-targeting interneurons) precede spikes on oriens lacunosum moleculare (OLM) interneurons (dendrite-targeting interneurons) and pyramidal cells. Individual intracellular recordings are shown time-locked to the filtered local field potential (LFP) theta rhythm (lower panel). (B) In vivo recordings in awake behaving rats during a spatial learning task showing distinct theta-nested gamma oscillations in two distinct frequency bands. Raw LFP data and a spectrogram are shown relative to the theta-filtered LFP average. Reproduced, with permission, from [54] (A) and [58] (B).

Figure 4. Frequency Mismatches in Core Default Mode Network (DMN) Regions and Related Sub- and Temporal Cortical Areas May Disrupt Internal Memory Recall/’Mental Time Travel’ Networks

(A) Cartoon suggesting the core large-scale dynamic connectivity pathways and the relative contributions of locally generated delta (1–4 Hz, red lines), theta (5–8 Hz, green lines), and gamma (30–80 Hz, blue lines) rhythms to their functional interactions. The main neocortical regions of note form the core anterior and posterior components of the DMN (bilaterally represented), coupled predominantly with delta rhythms (see main text). In addition, the connectivity of these nodes with archi- and periallocortical areas (hippocampus and entorhinal cortex), and relevant thalamic nuclei (anterior and midline) is shown. Note the overall balance between gamma/theta-mediated interactions and the dominance of ipsilateral cortico-cortical delta-mediated interactions. (B) Cartoon summarising the precedented functional connectivity changes and local network oscillation changes in the network summarised in (A). Note the overall deficit in direct cortico-cortical interaction frequencies in favour of indirect interactions mediated by excessive thalamic delta rhythm generation. Interhemispheric interactions are shown losing their faster frequency components in line with the deficits in NR2A receptors in schizophrenia, the higher temporal precision and selective role of this subunit in inter- versus intrahemispheric connectivity [28], and the observation of interhemispheric delta phase-modulated coupling during hallucinations [85]. Reported changes in primary sensory and attentional network are not illustrated here for clarity and brevity. Abbreviations: ERC, entorhinal cortex; Hipp, hippocampus; PFC, prefrontal cortex (cPFC, contralateral); Par/PCC, parietal cortex/posterior cingulate cortex (cPAR/PCC, contralateral); Thal, thalamus.

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