Information processing and self-awareness are dependent on functional connectivity within thalamo-limbic and prefrontal–parietal cortex neural networks that participate in mediating the perception of a ‘subjective experience’ and a sense of self-agency, which are significantly disrupted at the onset of schizophrenia (SZ) 1, 2, 3. During information processing and maintenance, frontotemporal or frontoparietal cortex long-range tuning, required to suppress irrelevant cortical ‘noise’, appears to be deficient in SZ. This abnormal connectivity state reduces the capacity of related neural assemblies to represent domain-specific memory information 4, 5. Deficits in this form of corticocortical inhibition have been implicated in the failure of individuals diagnosed with SZ to recognize their own thoughts as internally generated. More specifically, spatial context tuning in hippocampal networks facilitates band-specific neural oscillations (i.e. the firing of hippocampal place cells in the gamma-frequency) and directly impacts higher order functional properties (i.e. frontal theta oscillations) related to their domain general memory processing and episodic memory storage 4, 5. Spatial tuning impairments in SZ are mandatory and seem to be related to fast-spiking gamma oscillation synchronicity disruptions, giving rise to deficits in the recruitment of neural ensembles (e.g. reduced theta-gamma cross-frequency coupling) when performing higher order memory operations, which could result in the generation of false memories or delusions. In parallel, the failure to suppress default mode activity during the activation of the executive control network (prefrontal cortex networks) seems to underlie elevated cortical global connectivity and disruption of cross-frequency coupling in SZ [5].
Domains of awareness in SZ, such as insight of symptoms and self-certainty, significantly obscure the sense of self-agency and seem to represent a gateway to first-rank symptoms or may signal the onset of debilitating positive symptoms, such as experiencing delusions of external forces controlling their thoughts and actions 1, 6. Neural oscillations recorded from the scalps of humans represent rhythmic brain mechanisms that can organize temporal synchronicity of locally activated brain networks within structural patterns of large-scale brain networks that facilitate information processing and awareness in humans 7, 8••. Neural oscillatory activity obtained via Electroencephalography (EEG) during awake resting conditions consistently demonstrates a decrease in theta-frequency amplitude and increased amplitude of gamma-frequency oscillations in patients with SZ versus healthy controls 9, 10, 11. Furthermore, in SZ, clinical and biological features are associated with EEG power abnormalities 10, 11, 12. In regard to neural oscillations, diminished delta- or alpha-band power is significantly related to neuroanatomical abnormalities in SZ and other psychiatric disorders [10]. Changes in neural oscillations can occur spontaneously at rest or be evoked by a sensory or cognitive stimulation 13, 14. Most importantly, frequency-specific neural oscillations, such as frontal midline theta oscillations, are related to ‘active retention’ of context-relevant information and are believed to play a role in encoding, memory, attention, and self-awareness 6, 15, 16, 17•. In patients with SZ, compromised temporary memory storage precision (i.e. active retention interval) can lead to false attributions [5], cultivating a disturbed sense of self-agency and poor insight. In conjunction, gamma oscillations are hypothesized to play an important role in the attention processes underlying stimulus selection. Finely tuned gamma synchrony is critical for processing multiple stimulus modalities represented by multimodal cortical populations 5, 18. Additionally, dopaminergic modulation may help select the relevant information to be stored before response selection. Thus, aberrant baseline gamma power in SZ and excessive limbic dopaminergic activity can interfere with fast precise cortical processing needed during multimodal information storage, which directly affects immediate attention and access to self-referential memory. These sensory integration processing deficits associated with disrupted gamma synchrony could indirectly impact self-boundary perceptions, resulting in altered self-awareness 19, 20.
Disturbances in self-awareness that characterize SZ spectrum disorders versus other psychiatric populations are manifested in a basic alteration of self-consciousness [20]. Essentially, the ‘minimal self’, which is described as a prereflective and primitive level of selfhood and the core of self-awareness, has been implicated to be discretely impaired in SZ directly affecting sense of self, body ownership, and sense of agency. In support, a systematic meta-analysis investigating 25 studies of 690 patients with SZ and 979 healthy controls indicated a prominent impairment in minimal self and moderate deficits in body ownership and sense of agency [20]. In relevance, it has been reported individuals living with SZ have difficulty with the boundary between self and others. Although the core sense of self, reflected by body ownership and sense of agency awareness, has been consistently supported by neurocognitive and psychopathological evidence, patients with SZ show most pronounced deficits in the sense of the minimal self, which is usually expressed in exaggerated self-consciousness rather than a diminished sense of self, which is more prevalent in the prodromal stages of SZ or in high-risk groups at risk for entering a psychotic state. The default mode network (DMN) seems to play a significant role in the sense of self. Altered connectivity in the DMN may lead to deficits in self-referential processing and disturbances in self-awareness observed in psychosis. Overall, disturbed basic sense of self seems to reflect a psychopathological trait marker of psychosis vulnerability. In terms of affected neural oscillations, altered evoked gamma oscillations in prefrontal networks might play a role in corollary discharge disturbances, resulting in altered motor-sensory preparatory cortical activation preceding a motor response 20, 21. This is could indirectly lead to impaired self-agency, where patients with SZ report strange external forces as mediating their actions reflecting a conflict between the self and the external world, aligning with Freud’s definition of psychosis. Intracortical prefrontal gamma synchrony noted a resting or baseline periods, reflective of inhibitory activity of interneurons while the brain is in ‘default mode’ resting periods [13], influences DMN activity and appears to play a significant role in the sense of self. Specifically, in SZ, characterized by elevated baseline gamma power [19], paranoid delusions related to disturbed sense of self are exacerbated by upregulation of dopaminergic signaling in the amygdala. This baseline state apparently induces ‘noisy’ frontal gamma activity, resulting in altered DMN activation within medial temporal lobe structures (e.g. hippocampus) and compromised prefrontal inhibitory control. However, gamma power alterations are not specific to SZ [22]. Similar deficits in baseline and evoked gamma power have been reported in preclinical and clinical studies investigating autistic spectrum disorders (ASD) and in different psychiatric disorders [19]. In accordance, it has been suggested that neurophysiological abnormalities (e.g. disrupted gamma aminobutyric acidergic [GABAergic] interneuron activity) related to gamma synchrony alterations reflect common neuronal circuit insults with overlapping phenotypic deficits (e.g. social withdrawal) observed in different neurodevelopmental disorders (e.g. Attention deficit hyperactivity disorder, ASD).
Insight into self-agency and metacognition can be significantly impaired in SZ and both represent the ‘feeling of knowing’ and the feeling of ‘self’ may stem from common abnormalities in neurobiological mechanisms, such as reduced N-methyl-D-aspartate (NMDA) receptor activity within prefrontal cortex (PFC) networks, associated with reduced working memory (WM) span and distorted mnemonic representations of information 1, 5, 6, 17•, 23. Consistent research findings 7, 9 imply that neural oscillation activity under specific frontal-central electrodes could represent primary ‘neural synchrony’ or network connectivity disease biomarkers for understanding SZ pathophysiology and possibly for predicting SZ symptom severity scores within specific psychopathological dimensions in prodromal (before disease onset) and drug-free patients (at disease onset). Some studies report that resting-state activity in patients with SZ is accompanied by elevated gamma band activity, and some suggest reduced gamma power depending on the resting-state paradigm 10, 13, 14. More so, recent findings show that changes in gamma band activity correlate with liability to SZ [24]. Importantly, visually induced gamma oscillations drive the acute sensory detection of visual stimuli in the environment. Furthermore, primary visual cortex (V1) gamma activity is sensitive to contrast, orientation, spatial frequency, and temporal frequency, all of which compose our immediate visual perception of reality. Deficits in synaptic connectivity within the V1 primary visual cortex seem to be related to the occurrence of pathological gamma activity, which may directly contribute to the development of hallucinations and other positive symptoms in SZ [5], resulting in compromised self-awareness and abnormal perceptions of self-agency in many cases that remain hospitalized and dependent on their family and immediate community.
In the current research review, consistent with previous findings, we adopted the theoretical approach that clinical and biological concomitants of frequency-specific band power abnormalities in SZ are inherent and may indicate the presence of thalamic and frontal lobe dysfunctions 3, 10. However, to support these deviant patterns of neural synchrony in evaluating self-awareness in SZ, it is critical to evaluate in which specific EEG frequency band and under which electrode derivations absolute power (i.e. mean amplitude of gamma-frequency band) may be significantly associated with poor insight and how this activity is modulated under different sensory-driven states. Specifically, the current research review will aim to examine whether neural oscillatory activity (e.g. mean gamma power under parietal electrodes) may predict SZ symptom severity and abnormal states of self-awareness or the onset of a psychotic active state that could exacerbate positive symptoms, such as delusions and auditory verbal hallucinations.
Delusions and positive symptom severity could indicate states of altered consciousness in patients with SZ. In relevance, these mental states (e.g. disrupted self-agency percept) may cause patients to conceptualize thoughts and actions as controlled by external forces. This altered self-agency phenomenon in SZ may result from inaccurate internal mental models generated by pathological activity in sensory-motor preparatory networks comparing predictions with actual sensory input that precedes a specific response or self-perception [1]. Importantly, conscious perception may be dependent mainly on disparity arising from the difference between neural sensory activity and incidental perceived prediction. It has been suggested that perceptual predictions based on sensory references are disrupted in SZ and are likely to result from compromised thalamocortical network connectivity 3, 17•. Positive symptoms such as delusions can be generated, as frontal-parietal lobe dysconnectivity emerges during disease pathogenesis [5], which alters the predictive input, generating poor insight and compromised self-awareness in SZ. 1, 3, 6. The subjective experience of action in SZ is not based on the same predictive mechanisms as in healthy volunteers. Unlike healthy controls, patients with SZ display impaired action prediction along pathological perceptions of the impact of one’s own agency (e.g. grandiosity delusions).
Patients with SZ reveal synchronization and connectivity deficits in multiple brain neural network functional hubs (e.g. thalamo-striatal-cortical networks) related to sensory processing, WM function, and behavioral regulation [3]. EEG studies have shown the increased relative power of slow EEG rhythms may serve as reliable clinical diagnostic markers of SZ [13]. Other EEG studies have indicated excessive amplitude of fast wave oscillations in the gamma-frequency during resting periods of opened and closed eyes conditions in patients with SZ [11]. These changes in open–close eyes resting EEG paradigms involve shifting from a state without visual stimuli input to a state allowing visual input bottom-up processing (‘close eyes’ vs ‘open eyes’ conditions) at rest reflects relaxed awake states denoting a slight shift in the ‘conscious experience’ that can influence the generation of internal representations of ‘nonreal’ perceptions during the absence of input-driven visual processes (e.g. in eyes closed periods vs eyes open periods).
Excessive alpha over frontal lobe regions may represent an incremental shift in ‘alpha functional inhibition’ in open eyes versus closed eyes conditions, linked to prefrontal cortex regions that regulate awareness toward target visual stimuli 25, 26. Accordingly, elevated coherence between the frontal gyrus and the rest of the brain in alpha frequency and higher frontoparietal connectivity is associated with poor illness outcome in SZ [27]. Increased predictive biasing in sensory prefrontal mechanisms in SZ may result from inflexible synchronization in the alpha band, which shapes the excitability of sensory areas and immediate perception. As a result of disrupted frontal alpha synchrony, people living with SZ may be overloaded with ambiguous information due to altered alpha functional inhibition of irrelevant sensory networks, leading to self-agency perceptual impairments that may trigger the formation of ‘conspiracy’ delusions [27]. The current review will focus mainly on prefrontal-sensory neural network interactions (e.g. prefrontal gamma oscillations), including DMN connectivity and prefrontal mediated functional inhibition underlying self-awareness deficits and involved in generating fragile sense of self-agency in SZ.
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