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BACKGROUND: The integration of various domains or levels of analysis (clinical, neurobiological, genetic, etc.) has been a challenge in schizophrenia research. A promising approach is to use the core phenomenological features of the disorder as an organising principle for other levels of analysis. Minimal self-disturbance (fragility in implicit first-person perspective, presence and agency) is emerging as a strong candidate to play this role. This approach was adopted in a previously described theoretical neurophenomenological model that proposed that source monitoring deficits and aberrant salience may be neurocognitive/neurobiological processes that correlate with minimal self-disturbance on the phenomenological level, together playing an aetiological role in the onset of schizophrenia spectrum disorders. The current paper presents full cross-sectional data from the first empirical test of this model. METHODS: Fifty ultra-high risk for psychosis patients, 39 first episode psychosis patients and 34 healthy controls were assessed with a variety of clinical measures, including the Examination of Anomalous Self-Experience (EASE), and neurocognitive and neurophysiological (EEG) measures of source monitoring deficits and aberrant salience. RESULTS: Linear regression indicated that source monitoring (composite score across neurocognitive and neurophysiological measures), with study group as an interaction term, explained 39.8% of the variance in EASE scores (R2 = 0.41, F(3,85) = 14.78, p < 0.001), whereas aberrant salience (composite score) explained only 6% of the variance in EASE scores (R2 = 0.06, F(3,85) = 1.44, p = 0.93). Aberrant salience measures were more strongly related to general psychopathology measures, particularly to positive psychotic symptoms, than to EASE scores. DISCUSSION: A neurophenomenological model of minimal self-disturbance in schizophrenia spectrum disorders may need to be expanded from source monitoring deficits to encompass other relevant constructs such as temporal processing, intermodal/multisensory integration, and hierarchical predictive processing. The cross-sectional data reported here will be expanded with longitudinal analysis in subsequent reports. These data and other related recent research show an emerging picture of neuro-features of core phenomenological aspects of schizophrenia spectrum disorders beyond surface-level psychotic symptoms.

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BACKGROUND: Self-monitoring biases and overconfidence in incorrect judgments have been suggested as playing a role in schizophrenia spectrum disorders. Little is known about whether self-monitoring biases may contribute to early risk factors for psychosis. In this study, action self-monitoring (i.e., discrimination between imagined and performed actions) was investigated, along with confidence in judgments among ultra-high risk (UHR) for psychosis individuals and first-episode psychosis (FEP) patients. METHODS: Thirty-six UHR for psychosis individuals, 25 FEP patients and 33 healthy controls (CON) participated in the study. Participants were assessed with the Action memory task. Simple actions were presented to participants verbally or non-verbally. Some actions were required to be physically performed and others were imagined. Participants were asked whether the action was presented verbally or non-verbally (action presentation type discrimination), and whether the action was performed or imagined (self-monitoring). Confidence self-ratings related to self-monitoring responses were obtained. RESULTS: The analysis of self-monitoring revealed that both UHR and FEP groups misattributed imagined actions as being performed (i.e., self-monitoring errors) significantly more often than the CON group. There were no differences regarding performed actions as being imagined. UHR and FEP groups made their false responses with higher confidence in their judgments than the CON group. There were no group differences regarding discrimination between the types of actions presented (verbal vs non-verbal). CONCLUSIONS: A specific type of self-monitoring bias (i.e., misattributing imagined actions with performed actions), accompanied by high confidence in this judgment, may be a risk factor for the subsequent development of a psychotic disorder.

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Phenomenological research indicates that disturbance of the basic sense of self may be a core phenotypic marker of schizophrenia spectrum disorders. Basic self-disturbance refers to disruption of the sense of ownership of experience and agency of action and is associated with a variety of anomalous subjective experiences. Little is known about the neurocognitive underpinnings of basic self-disturbance. In these two theoretical papers (of which this is Part 2), we review some recent phenomenological and neurocognitive research and point to a convergence of these approaches around the concept of self-disturbance. Specifically, we propose that subjective anomalies associated with basic self-disturbance may be associated with: 1. source monitoring deficits, which may contribute particularly to disturbances of "ownership" and "mineness" (the phenomenological notion of presence or self-affection) and 2. aberrant salience, and associated disturbances of memory, prediction and attention processes, which may contribute to hyper-reflexivity, disturbed "grip" or "hold" on perceptual and conceptual fields, and disturbances of intuitive social understanding ("common sense"). In this paper (Part 2) we focus on aberrant salience. Part 1 (this issue) addressed source monitoring deficits. Empirical studies are required in a variety of populations in order to test these proposed associations between phenomenological and neurocognitive aspects of self-disturbance in schizophrenia. An integration of findings across the phenomenological and neurocognitive "levels" would represent a significant advance in the understanding of schizophrenia and possibly enhance early identification and intervention strategies.

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The normal human brain is characterized by a pattern of gross anatomical asymmetry. This pattern, known as the "torque", is associated with a sexual dimorphism: The male brain tends to be more asymmetric than that of the female. This fact, along with well-known sex differences in brain development (faster in females) and onset of psychosis (earlier with worse outcome in males), has led to the theory that schizophrenia is a disorder in which sex-dependent abnormalities in the development of brain torque, the correlate of the capacity for language, cause alterations in interhemispheric connectivity, which are causally related to psychosis (Crow TJ, Paez P, Chance SE. 2007. Callosal misconnectivity and the sex difference in psychosis. Int Rev Psychiatry. 19(4):449-457.). To provide evidence toward this theory, we analyze the geometry of interhemispheric white matter connections in adolescent-onset schizophrenia, with a particular focus on sex, using a recently introduced framework for white matter geometry computation in diffusion tensor imaging data (Savadjiev P, Kindlmann GL, Bouix S, Shenton ME, Westin CF. 2010. Local white geometry from diffusion tensor gradients. Neuroimage. 49(4):3175-3186.). Our results reveal a pattern of sex-dependent white matter geometry abnormalities that conform to the predictions of Crow's torque theory and correlate with the severity of patients' symptoms. To the best of our knowledge, this is the first study to associate geometrical differences in white matter connectivity with torque in schizophrenia.

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Phenomenological research indicates that disturbance of the basic sense of self may be a core phenotypic marker of schizophrenia spectrum disorders. Basic self-disturbance refers to disruption of the sense of ownership of experience and agency of action and is associated with a variety of anomalous subjective experiences. Little is known about the neurocognitive underpinnings of basic self-disturbance. In these two theoretical papers (of which this is Part 1), we review some recent phenomenological and neurocognitive research and point to a convergence of these approaches around the concept of self-disturbance. Specifically, we propose that subjective anomalies associated with basic self-disturbance may be associated with: 1. source monitoring deficits, which may contribute particularly to disturbances of "ownership" and "mineness" (the phenomenological notion of presence or self-affection) and 2. aberrant salience, and associated disturbances of memory, prediction and attention processes, which may contribute to hyper-reflexivity, disturbed "grip" or "hold" on the perceptual and conceptual field, and disturbances of intuitive social understanding ("common sense"). In this paper (Part 1) we focus on source monitoring deficits. Part 2 (this issue) addresses aberrant salience. Empirical studies are required in a variety of populations in order to test these proposed associations between phenomenological and neurocognitive aspects of self-disturbance in schizophrenia. An integration of findings across the phenomenological and neurocognitive "levels" would represent a significant advance in the understanding of schizophrenia and possibly enhance early identification and intervention strategies.

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BACKGROUND: Patients with schizophrenia (SZ) characteristically exhibit supranormal levels of cortical activity to self-induced sensory stimuli, ostensibly because of abnormalities in the neural signals (corollary discharges, CDs) normatively involved in suppressing the sensory consequences of self-generated actions. The nature of these abnormalities is unknown. This study investigated whether SZ patients experience CDs that are abnormally delayed in their arrival at the sensory cortex. METHOD: Twenty-one patients with SZ and 25 matched control participants underwent electroencephalography (EEG). Participants' level of cortical suppression was calculated as the amplitude of the N1 component evoked by a button press-elicited auditory stimulus, subtracted from the N1 amplitude evoked by the same stimulus presented passively. In the three experimental conditions, the auditory stimulus was delivered 0, 50 or 100 ms subsequent to the button-press. Fifteen SZ patients and 17 healthy controls (HCs) also underwent diffusion tensor imaging (DTI), and the fractional anisotropy (FA) of participants' arcuate fasciculus was used to predict their level of cortical suppression in the three conditions. RESULTS: While the SZ patients exhibited subnormal N1 suppression to undelayed, self-generated auditory stimuli, these deficits were eliminated by imposing a 50-ms, but not a 100-ms, delay between the button-press and the evoked stimulus. Furthermore, the extent to which the 50-ms delay normalized a patient's level of N1 suppression was linearly related to the FA of their arcuate fasciculus. CONCLUSIONS: These data suggest that SZ patients experience temporally delayed CDs to self-generated auditory stimuli, putatively because of structural damage to the white-matter (WM) fasciculus connecting the sites of discharge initiation and destination.

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A segment of mitochondrial DNA encoding the bovine cytochrome c oxidase subunit III gene was isolated and inserted into an Escherichia coli plasmid vector. A 556 base pair fragment of the insert DNA representing about 70% of the 3'-end of the subunit III gene was used to search for homology with bacterial DNA from strains that contain heme aa3-type cytochrome c oxidases. Bacillus subtilis, Thermus thermophilus, and PS3 DNAs all showed strong hybridization to the probe, whereas Paracoccus denitrificans and Rhodopseudomonas sphaeroides DNAs showed only weak hybridization to the probe, even under low stringency conditions.

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Periodate-oxidized inosine (Inox; NSC 118994) and periodate-oxidized 5'-inosinic acid (PI-IMP) were prepared and studied for their effects on ribonucleotide reductase activity in partially purified extracts from Ehrlich tumor cells and on nucleic acid synthesis in intact tumor cells in culture. Ribonucleotide reductase activity in cell-free extracts from Ehrlich tumor cells was inhibited by Inox and PI-IMP. PI-IMP was more inhibitory to the reductase activity than was Inox. Furthermore, the inhibition of ribonucleotide reductase activity by Inox and PI-IMP was greater for cytidine-5'-diphosphate reductase activity than for adenosine-5'-diphosphate reductase activity. The ribonucleotide reductase activity in cell-free extracts prepared from Ehrlich tumor cells treated with Inox or PI-IMP in culture was decreased compared with the activity in the extracts from untreated cells. Incorporation of labeled cytidine into the RNA and DNA of Ehrlich tumor cells in culture was inhibited by both Inox and PI-IMP. The conversion of cytidine to deoxycytidine nucleotides in the acid-soluble pool was likewise inhibited. These data indicate that Inox and PI-IMP inhibit the ribonucleotide reductase step as one of the sites of action of these compounds. However, the inhibition of RNA synthesis indicates that there must be additional sites of action of these nucleoside analogs.

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Transfer RNA nucleotidyl transferase from Ehrlich tumor cells was inhibited by proflavine sulfate and ethidium bromide but not by actinomycin D, chromomycin, rifamycin SV, rifampin, daunomycin, or alpha-amanitin. Complete inhibition of nucleotidyl transferase activity was attained at a final concentration of 1 mmol/1 proflavine sulfate, while 2 mmol/1 ethidium bromide was required to completely inhibit the enzyme. CMP incorporation into tRNA was more sensitive to both proflavine sulfate and ethidium bromide than was AMP incorporation.

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