Speech based natural language profile before, during and after the onset of psychosis: A cluster analysis.

BACKGROUND AND HYPOTHESIS: Speech markers are digitally acquired, computationally derived, quantifiable set of measures that reflect the state of neurocognitive processes relevant for social functioning. "Oddities" in language and communication have historically been seen as a core feature of schizophrenia. The application of natural language processing (NLP) to speech samples can elucidate even the most subtle deviations in language. We aim to determine if NLP based profiles that are distinctive of schizophrenia can be observed across the various clinical phases of psychosis. DESIGN: Our sample consisted of 147 participants and included 39 healthy controls (HC), 72 with first-episode psychosis (FEP), 18 in a clinical high-risk state (CHR), 18 with schizophrenia (SZ). A structured task elicited 3 minutes of speech, which was then transformed into quantitative measures on 12 linguistic variables (lexical, syntactic, and semantic). Cluster analysis that leveraged healthy variations was then applied to determine language-based subgroups. RESULTS: We observed a three-cluster solution. The largest cluster included most HC and the majority of patients, indicating a 'typical linguistic profile (TLP)'. One of the atypical clusters had notably high semantic similarity in word choices with less perceptual words, lower cohesion and analytical structure; this cluster was almost entirely composed of patients in early stages of psychosis (EPP - early phase profile). The second atypical cluster had more patients with established schizophrenia (SPP - stable phase profile), with more perceptual but less cognitive/emotional word classes, simpler syntactic structure, and a lack of sufficient reference to prior information (reduced givenness). CONCLUSION: The patterns of speech deviations in early and established stages of schizophrenia are distinguishable from each other and detectable when lexical, semantic and syntactic aspects are assessed in the pursuit of 'formal thought disorder'.

Speech markers to predict and prevent recurrent episodes of psychosis: A narrative overview and emerging opportunities.

Preventing relapse in schizophrenia improves long-term health outcomes. Repeated episodes of psychotic symptoms shape the trajectory of this illness and can be a detriment to functional recovery. Despite early intervention programs, high relapse rates persist, calling for alternative approaches in relapse prevention. Predicting imminent relapse at an individual level is critical for effective intervention. While clinical profiles are often used to foresee relapse, they lack the specificity and sensitivity needed for timely prediction. Here, we review the use of speech through Natural Language Processing (NLP) to predict a recurrent psychotic episode. Recent advancements in NLP of speech have shown the ability to detect linguistic markers related to thought disorder and other language disruptions within 2-4 weeks preceding a relapse. This approach has shown to be able to capture individual speech patterns, showing promise in its use as a prediction tool. We outline current developments in remote monitoring for psychotic relapses, discuss the challenges and limitations and present the speech-NLP based approach as an alternative to detect relapses with sufficient accuracy, construct validity and lead time to generate clinical actions towards prevention.

More than words: Speech production in first-episode psychosis predicts later social and vocational functioning.

Background: Several disturbances in speech are present in psychosis; however, the relationship between these disturbances during the first-episode of psychosis (FEP) and later vocational functioning is unclear. Demonstrating this relationship is critical if we expect speech and communication deficits to emerge as targets for early intervention. Method: We analyzed three 1-min speech samples using automated speech analysis and Bayes networks in an antipsychotic-naive sample of 39 FEP patients and followed them longitudinally to determine their vocational status (engaged or not engaged in employment education or training-EET vs. NEET) after 6-12 months of treatment. Five baseline linguistic variables with prior evidence of clinical relevance (total and acausal connectives use, pronoun use, analytic thinking, and total words uttered in a limited period) were included in a Bayes network along with follow-up NEET status and Social and Occupational Functioning Assessment Scale (SOFAS) scores to determine dependencies among these variables. We also included clinical (Positive and Negative Syndrome Scale 8-item version (PANSS-8)), social (parental socioeconomic status), and cognitive features (processing speed) at the time of presentation as covariates. Results: The Bayes network revealed that only total words spoken at the baseline assessment were directly associated with later NEET status and had an indirect association with SOFAS, with a second set of dependencies emerging among the remaining linguistic variables. The primary (speech-only) model outperformed models including parental socioeconomic status, processing speed or both as latent variables. Conclusion: Impoverished speech, even at subclinical levels, may hold prognostic value for functional outcomes and warrant consideration when providing measurement based care for first-episode psychosis.

Aberrant frontal lobe "U"-shaped association fibers in first-episode schizophrenia: A 7-Tesla Diffusion Imaging Study.

Schizophrenia is believed to be a developmental disorder with one hypothesis suggesting that symptoms arise due to abnormal interactions (or disconnectivity) between different brain regions. While some major deep white matter pathways have been extensively studied (e.g. arcuate fasciculus), studies of short-ranged, "U"-shaped tracts have been limited in patients with schizophrenia, in part due to the sheer abundance of tracts present and due to the spatial variations across individuals that defy probabilistic characterization in the absence of reliable templates. In this study, we use diffusion magnetic resonance imaging (dMRI) to investigate frontal lobe superficial white matter that are present in the majority of study participants, comparing healthy controls and minimally treated patients with first-episode schizophrenia (<3 median days of lifetime treatment). Through group comparisons, 3 out of 63 frontal lobe "U"-shaped tracts were found to demonstrate localized aberrations affecting the microstructural tissue properties (via diffusion tensor metrics) in this early stage of disease. No associations were found in patients between aberrant segments of affected tracts and clinical or cognitive variables. Aberrations in the frontal lobe "U"-shaped tracts in early untreated stages of psychosis occur irrespective of symptom burden, and are distributed across critical functional networks associated with executive function and salience processing. While we limited the investigation to the frontal lobe, a framework has been developed to study such connections in other brain regions, enabling further extensive investigations jointly with the major deep white matter pathways.

Active Inference, Epistemic Value, and Uncertainty in Conceptual Disorganization in First-Episode Schizophrenia.

BACKGROUND AND HYPOTHESIS: Active inference has become an influential concept in psychopathology. We apply active inference to investigate conceptual disorganization in first-episode schizophrenia. We conceptualize speech production as a decision-making process affected by the latent "conceptual organization"-as a special case of uncertainty about the causes of sensory information. Uncertainty is both minimized via speech production-in which function words index conceptual organization in terms of analytic thinking-and tracked by a domain-general salience network. We hypothesize that analytic thinking depends on conceptual organization. Therefore, conceptual disorganization in schizophrenia would be both indexed by low conceptual organization and reflected in the effective connectivity within the salience network. STUDY DESIGN: With 1-minute speech samples from a picture description task and resting state fMRI from 30 patients and 30 healthy subjects, we employed dynamic causal and probabilistic graphical models to investigate if the effective connectivity of the salience network underwrites conceptual organization. STUDY RESULTS: Low analytic thinking scores index low conceptual organization which affects diagnostic status. The influence of the anterior insula on the anterior cingulate cortex and the self-inhibition within the anterior cingulate cortex are elevated given low conceptual organization (ie, conceptual disorganization). CONCLUSIONS: Conceptual organization, a construct that explains formal thought disorder, can be modeled in an active inference framework and studied in relation to putative neural substrates of disrupted language in schizophrenia. This provides a critical advance to move away from rating-scale scores to deeper constructs in the pursuit of the pathophysiology of formal thought disorder.

Syntactic complexity of spoken language in the diagnosis of schizophrenia: A probabilistic Bayes network model.

In the clinical linguistics of schizophrenia, syntactic complexity has received much attention. In this study, we address whether syntactic complexity deteriorates within the six months following the first episode of psychosis in those who develop a diagnosis of schizophrenia. We collected data from a cohort of twenty-six first-episode psychosis and 12 healthy control subjects using the Thought and Language Index interview in response to three pictures from the Thematic Apperception Test at first assessment and after six months (the time of consensus diagnosis). An automated labeling (part-of-speech tagging) for specific syntactic elements calculated large and granular syntactic complexity indices with a focus on clause complexity as a particular case from this spoken language data. Probabilistic reasoning leveraging the conditional independence properties of Bayes networks revealed that consensus diagnosis of schizophrenia predicted a decrease in nominal subjects per clause among individuals with first episode psychosis. From the entire sample, we estimate a 95.4 % probability that a 50 % decrease in mean nominal subjects per clause after six months is explained by the presence of first episode psychosis. Among those with psychosis, a 30 % decrease in this clause-complexity index after six months of experiencing the first episode predicted with 95 % probability a consensus diagnosis of schizophrenia, representing a conditional relationship between a longitudinal decrease in syntactic complexity and a diagnosis of schizophrenia. We conclude that an early drift towards linguistic disorganization/impoverishment of clause complexity-at the granular level of nominal subject per clause-is a distinctive feature of schizophrenia that decreases longitudinally, thus differentiating schizophrenia from other psychotic illnesses with shared phenomenology.

Microstructural imaging and transcriptomics of the basal forebrain in first-episode psychosis.

Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, <2 defined daily dose of antipsychotics) and used magnetic resonance spectroscopy (MRS) and transcriptomic data to support our findings. We used a cytoarchitectonic atlas of the BF to map the nuclei and obtained measures of myelin (quantitative T1, or qT1 as myelin surrogate) and microstructure (axial diffusion; AxD). In a clinical sample (n = 85; 29 healthy controls, 56 first-episode psychosis), we found significant correlations between qT1 of Ch1-3, left NBM and MRS-based dorsal anterior cingulate choline in healthy controls while this relationship was disrupted in FEP (p > 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia.

Widespread cortical thinning, excessive glutamate and impaired linguistic functioning in schizophrenia: A cluster analytic approach.

Introduction: Symptoms of schizophrenia are closely related to aberrant language comprehension and production. Macroscopic brain changes seen in some patients with schizophrenia are suspected to relate to impaired language production, but this is yet to be reliably characterized. Since heterogeneity in language dysfunctions, as well as brain structure, is suspected in schizophrenia, we aimed to first seek patient subgroups with different neurobiological signatures and then quantify linguistic indices that capture the symptoms of "negative formal thought disorder" (i.e., fluency, cohesion, and complexity of language production). Methods: Atlas-based cortical thickness values (obtained with a 7T MRI scanner) of 66 patients with first-episode psychosis and 36 healthy controls were analyzed with hierarchical clustering algorithms to produce neuroanatomical subtypes. We then examined the generated subtypes and investigated the quantitative differences in MRS-based glutamate levels [in the dorsal anterior cingulate cortex (dACC)] as well as in three aspects of language production features: fluency, syntactic complexity, and lexical cohesion. Results: Two neuroanatomical subtypes among patients were observed, one with near-normal cortical thickness patterns while the other with widespread cortical thinning. Compared to the subgroup of patients with relatively normal cortical thickness patterns, the subgroup with widespread cortical thinning was older, with higher glutamate concentration in dACC and produced speech with reduced mean length of T-units (complexity) and lower repeats of content words (lexical cohesion), despite being equally fluent (number of words). Conclusion: We characterized a patient subgroup with thinner cortex in first-episode psychosis. This subgroup, identifiable through macroscopic changes, is also distinguishable in terms of neurochemistry (frontal glutamate) and language behavior (complexity and cohesion of speech). This study supports the hypothesis that glutamate-mediated cortical thinning may contribute to a phenotype that is detectable using the tools of computational linguistics in schizophrenia.

Progressive changes in descriptive discourse in First Episode Schizophrenia: a longitudinal computational semantics study.

Computational semantics, a branch of computational linguistics, involves automated meaning analysis that relies on how words occur together in natural language. This offers a promising tool to study schizophrenia. At present, we do not know if these word-level choices in speech are sensitive to the illness stage (i.e., acute untreated vs. stable established state), track cognitive deficits in major domains (e.g., cognitive control, processing speed) or relate to established dimensions of formal thought disorder. In this study, we collected samples of descriptive discourse in patients experiencing an untreated first episode of schizophrenia and healthy control subjects (246 samples of 1-minute speech; n = 82, FES = 46, HC = 36) and used a co-occurrence based vector embedding of words to quantify semantic similarity in speech. We obtained six-month follow-up data in a subsample (99 speech samples, n = 33, FES = 20, HC = 13). At baseline, semantic similarity was evidently higher in patients compared to healthy individuals, especially when social functioning was impaired; but this was not related to the severity of clinically ascertained thought disorder in patients. Across the study sample, higher semantic similarity at baseline was related to poorer Stroop performance and processing speed. Over time, while semantic similarity was stable in healthy subjects, it increased in patients, especially when they had an increasing burden of negative symptoms. Disruptions in word-level choices made by patients with schizophrenia during short 1-min descriptions are sensitive to interindividual differences in cognitive and social functioning at first presentation and persist over the early course of the illness.

Central Oxidative Stress and Early Vocational Outcomes in First Episode Psychosis: A 7-Tesla Magnetic Resonance Spectroscopy Study of Glutathione.

BACKGROUND AND HYPOTHESIS: Following the first episode of psychosis, some patients develop poor social and occupational outcomes, while others display a pattern of preserved functioning. Evidence from preclinical, genetic, and biochemical studies suggest a role for high oxidative stress in poor functional outcomes among patients. The measurement of intracortical glutathione (GSH) using magnetic resonance spectroscopy (MRS) enables investigating the relationship between central antioxidant tone and functional outcomes at the time of first-episode psychosis (FEP). We hypothesized that patients with higher central antioxidant tone at first presentation will have better functional outcomes in early stages of illness. STUDY DESIGN: We scanned 57 patients with FEP and 30 matched healthy controls and estimated GSH resonance using 7-Tesla MRS. We minimized the confounding effects of illness chronicity, long-term treatment exposure, and metabolic complications by recruiting patients with <2 weeks of lifetime antipsychotic exposure on average and followed up this cohort for the next 1 year to determine functional outcomes. STUDY RESULTS: Patients who achieved employment/education or training status (EET) in the first year, had higher GSH at the baseline than healthy controls. Social and occupational functioning assessment scale (SOFAS) scores were also significantly higher in patients with higher GSH levels at the outset, after adjusting for various confounds including baseline SOFAS. Patients who were not in EET did not differ from healthy subjects in their GSH levels. CONCLUSION: Our observations support a key role for the central antioxidant tone in the functional outcomes of early psychosis.

The trajectory of putative astroglial dysfunction in first episode schizophrenia: a longitudinal 7-Tesla MRS study.

Myo-inositol is mainly found in astroglia and its levels has been shown to be reduced in the anterior cingulate cortex (ACC) of patients with schizophrenia. We investigate the status of astroglial integrity indexed by ACC myo-inositol at the onset and over the first 6 months of treatment of first episode schizophrenia. We employed 7 T magnetic resonance spectroscopy (1H-MRS) and quantified myo-inositol spectra at the dorsal ACC in 31 participants; 21 patients with schizophrenia with median lifetime antipsychotic exposure of less than 3 days, followed up after 6 months of treatment, and 10 healthy subjects scanned twice over the same period. We studied the time by group interaction for myo-inositol after adjusting for gender and age. We report significant reduction in myo-inositol concentration in the ACC in schizophrenia at an early, untreated state of acute illness that becomes insignificant over time, after instituting early intervention. This trajectory indicates that dynamic astroglial changes are likely to operate in the early stages of schizophrenia. MRS myo-inositol may be a critical marker of amelioration of active psychosis in early stages of schizophrenia.

Progressive Changes in Glutamate Concentration in Early Stages of Schizophrenia: A Longitudinal 7-Tesla MRS Study.

Progressive reduction in glutamatergic transmission has been proposed as an important component of the illness trajectory of schizophrenia. Despite its popularity, to date, this notion has not been convincingly tested in patients in early stages of schizophrenia. In a longitudinal 7T magnetic resonance spectroscopy (1H-MRS), we quantified glutamate at the dorsal anterior cingulate cortex in 21 participants with a median lifetime antipsychotic exposure of less than 3 days and followed them up after 6 months of treatment. Ten healthy controls were also scanned at 2 time points. While patients had significantly lower overall glutamate levels than healthy controls (F(1,27) = 5.23, P = .03), we did not observe a progressive change of glutamate concentration in patients (F(1,18) = 0.47, P = .50), and the group by time interaction was not significant (F(1,27) = 0.86, P = .36). On average, patients with early psychosis receiving treatment showed a 0.02 mM/y increase, while healthy controls showed a 0.06 mM/y reduction of MRS glutamate levels. Bayesian analysis of our observations does not support early, post-onset glutamate loss in schizophrenia. Interestingly, it provides evidence in favor of a lack of progressive glutamate change in our schizophrenia sample-indicating that the glutamate level at the onset of illness was the best predictor of the levels 6 months after treatment. A more nuanced view of glutamatergic physiology, linked to early cortical maturation, may be required to understand glutamate-mediated dynamics in schizophrenia.

Glutathione as a Molecular Marker of Functional Impairment in Patients with At-Risk Mental State: 7-Tesla 1H-MRS Study.

A substantial number of individuals with clinical high-risk (CHR) mental state do not transition to psychosis. However, regardless of future diagnostic trajectories, many of these individuals develop poor social and occupational functional outcomes. The levels of glutathione, a crucial cortical antioxidant, may track variations in functional outcomes in early psychosis and prodromal states. Thirteen clinical high-risk and 30 healthy control volunteers were recruited for a 7-Tesla magnetic resonance spectroscopy scan with a voxel positioned within the dorsal anterior cingulate cortex (ACC). Clinical assessment scores were collected to determine if any association was observable with glutathione levels. The Bayesian Spearman's test revealed a positive association between the Social and Occupational Functioning Assessment Scale (SOFAS) and the glutathione concentration in the clinical high-risk group but not in the healthy control group. After accounting for variations in the SOFAS scores, the CHR group had higher GSH levels than the healthy subjects. This study is the first to use 7-Tesla magnetic resonance spectroscopy to test whether ACC glutathione levels relate to social and occupational functioning in a clinically high-risk group and offers preliminary support for glutathione levels as a clinically actionable marker of prognosis in emerging adults presenting with risk features for various severe mental illnesses.

Small Words That Matter: Linguistic Style and Conceptual Disorganization in Untreated First-Episode Schizophrenia.

This study aimed to shed light on the linguistic style affecting the communication discourse in first-episode schizophrenia (FES) by investigating the analytic thinking index in relation to clinical scores of conceptual and thought disorganization (Positive and Negative Syndrome Scale, PANSS-P2 and Thought and Language Index, TLI). Using robust Bayesian modeling, we report three major findings: (1) FES subjects showed reduced analytic thinking, exhibiting a less categorical linguistic style than healthy control (HC) subjects (Bayes factor, BF10 > 1000), despite using the same proportion of function and content words as HCs; (2) the lower the analytic thinking score, the higher the symptoms scores of conceptual disorganization (PANSS-P2, BF = 22.66) and global disorganization of thinking (TLI, BF10 = 112.73); (3) the linguistic style is a better predictor of conceptual disorganization than the cognitive measure of processing speed in schizophrenia (SZ). These findings provide an objectively detectable linguistic style with a focus on Natural Language Processing Analytics of transcribed speech samples of patients with SZ that require no clinical judgment. These findings also offer a crucial insight into the primacy of linguistic structural disruption in clinically ascertained disorganized thinking in SZ. Our work contributes to an emerging body of literature on the psychopathology of SZ using a first-order lexeme-level analysis and a hypothesis-driven approach. At a utilitarian level, this has implications for improving educational and social outcomes in patients with SZ.

Hippocampal neuroanatomy in first episode psychosis: A putative role for glutamate and serotonin receptors.

Disrupted serotonergic and glutamatergic signaling interact and contribute to the pathophysiology of schizophrenia, which is particularly relevant for the hippocampus where diverse expression of serotonin receptors is noted. Hippocampal atrophy is a well-established feature of schizophrenia, with select subfields hypothesized as particularly vulnerable due to variation in glutamate receptor densities. We investigated hippocampal anomalies in first-episode psychosis (FEP) in relation to receptor distributions by leveraging 4 sources of data: (1) ultra high-field (7-Tesla) structural neuroimaging, and (2) proton magnetic resonance spectroscopy (1H-MRS) of glutamate from 27 healthy and 41 FEP subjects, (3) gene expression data from the Allen Human Brain Atlas and (4) atlases of the serotonin receptor system. Automated methods delineated the hippocampus to map receptor density across subfields. We used gene expression data to correlate serotonin and glutamate receptor genes across the hippocampus. Measures of individual hippocampal shape-receptor alignment were derived through normative modelling and correlations to receptor distributions, termed Receptor-Specific Morphometric Signatures (RSMS). We found reduced hippocampal volumes in FEP, while CA4-dentate gyrus showed greatest reductions. Gene expression indicated 5-HT1A and 5-HT4 to correlate with AMPA and NMDA expression, respectively. Magnitudes of subfield volumetric reduction in FEP correlated most with 5-HT1A (R = 0.64, p = 4.09E-03) and 5-HT4 (R = 0.54, p = 0.02) densities as expected, and replicated using previously published data from two FEP studies. Right-sided 5-HT4-RSMS was correlated with MRS glutamate (R = 0.357, p = 0.048). We demonstrate a putative glutamate-driven hippocampal variability in FEP through a serotonin receptor-density gated mechanism, thus outlining a mechanistic interplay between serotonin and glutamate in determining the hippocampal morphology in schizophrenia.

Conceptual disorganization and redistribution of resting-state cortical hubs in untreated first-episode psychosis: A 7T study.

Network-level dysconnectivity has been studied in positive and negative symptoms of schizophrenia. Conceptual disorganization (CD) is a symptom subtype that predicts impaired real-world functioning in psychosis. Systematic reviews have reported aberrant connectivity in formal thought disorder, a construct related to CD. However, no studies have investigated whole-brain functional correlates of CD in psychosis. We sought to investigate brain regions explaining the severity of CD in patients with first-episode psychosis (FEPs) compared with healthy controls (HCs). We computed whole-brain binarized degree centrality maps of 31 FEPs, 25 HCs, and characterized the patterns of network connectivity in the 2 groups. In FEPs, we related these findings to the severity of CD. We also studied the effect of positive and negative symptoms on altered network connectivity. Compared to HCs, reduced centrality of a right superior temporal gyrus (rSTG) cluster was observed in the FEPs. In patients exhibiting high CD, increased centrality of a medial superior parietal (mSPL) cluster was observed, compared to patients exhibiting low CD. This cluster was strongly correlated with CD scores but not with other symptom scores. Our observations are congruent with previous findings of reduced but not increased centrality. We observed increased centrality of mSPL suggesting that cortical reorganization occurs to provide alternate routes for information transfer. These findings provide insight into the underlying neural processes mediating the presentation of symptoms in untreated FEP. Longitudinal tracking of the symptom course will be useful to assess the mechanisms underlying these compensatory changes.

Linguistic determinants of formal thought disorder in first episode psychosis.

AIM: Thought disorder is a core feature of schizophrenia but assessment of disordered thinking is challenging, which may contribute to the paucity of mechanistic understanding of disorganization in early psychosis. We studied the use of linguistic connectives in relation to clinically quantified dimensions of thought disorder using automated speech analysis in untreated, first episode psychosis (FEPs) and healthy controls (HCs). METHODS: 39 treatment-naïve, actively psychotic FEPs and 23 group matched HCs were recruited. Three one-minute speech samples were induced in response to photographs from the Thematic Apperception Test and speech was analysed using COH-METRIX software. Five connectives variables from the Coh-Metrix software were reduced using principle component analysis, resulting in two linguistic connectives factors. Thought disorder was assessed using the Thought Language Index (TLI) and the PANSS-8. RESULTS: Connective factors predicted disorganization, but not impoverishment suggesting aberrant use of connectives is specific to positive thought disorder. An independent t test comparing low and high disorganization FEPs showed higher load of acausal temporal connectives in high disorganization FEPs compared to low disorganization FEPs (mean [SD] in high vs low disorganization FEPs = 0.64 (1.1) vs -0.37 (1.02); t = 2.91, P = .006). Acausal-temporal connectives were not correlated with severity of symptoms or cognition suggesting connective use is a specific index of disorganized thinking rather than overall illness status. CONCLUSIONS: Clinical assessment of disorganization in psychosis is likely linked to the aberrant use of connectives resulting in an intuitive sense of incoherence. In early psychosis, thought disorder may be reliably quantifiable using automated syntax analysis.

Frontal-striatal connectivity and positive symptoms of schizophrenia: implications for the mechanistic basis of prefrontal rTMS.

Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high-frequency rTMS of the LDLPFC might increase the dopaminergic neurotransmission by driving the activity of the left striatum in the basal ganglia (LSTR)-increasing striatal dopaminergic activity. This hypothesis relies on the assumption that either the frontal-striatal connection or the intrinsic frontal and/or striatal connections covary with the severity of positive symptoms. The current work aimed to evaluate this assumption by studying the association between positive and negative symptoms severity and the effective connectivity within the frontal and striatal network using dynamic causal modeling of resting state fMRI in a sample of 19 first episode psychosis subjects. We found that the total score of positive symptoms of schizophrenia is strongly associated with the frontostriatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as decreased bidirectional excitatory influence between the LDLPFC and the LSTR is related to the severity of positive symptoms, especially delusions. We interpret that an increase in striatal dopaminergic tone that underlies positive symptoms is likely associated with increased prefrontal inhibitory tone, strengthening the frontostriatal 'brake'. Furthermore, based on our model, we propose that lessening of positive symptoms could be achieved by means of continuous theta-burst or low-frequency (1 Hz) rTMS of the prefrontal area.

Deviant cortical sulcation related to schizophrenia and cognitive deficits in the second trimester.

OBJECTIVES: Aberrant cortical development, inferred from cortical folding, is linked to the risk of schizophrenia. Cortical folds develop in a time-locked fashion during fetal growth. We leveraged this temporal specificity of sulcation to investigate the timing of the prenatal insult linked to schizophrenia and the cognitive impairment seen in this illness. METHODS: Anatomical MRI scans from 68 patients with schizophrenia and 72 controls were used to evaluate the sulcal depth of five major invariable primary sulci representing lobar development (calcarine sulcus, superior temporal sulcus, superior frontal sulcus, intraparietal sulcus and inferior frontal sulcus) with formation representing the distinct developmental periods. RESULTS: A repeated-measure ANOVA with five sulci and two hemispheres as the within-subject factors and gender, age and intracranial volume as covariates revealed a significant effect of diagnosis (F[1,134] = 14.8, p = 0.0002). Control subjects had deeper bilateral superior temporal, right inferior frontal and left calcarine sulci. A deeper superior frontal sulcus predicted better cognitive scores among patients. CONCLUSION: Our results suggest that the gestational disruption underlying schizophrenia is likely to predate, if not coincide with the appearance of calcarine sulcus (early second trimester). Nevertheless, the burden of cognitive deficits may relate specifically to the aberrant superior frontal development apparent in late second trimester.

Glutamate and Dysconnection in the Salience Network: Neurochemical, Effective Connectivity, and Computational Evidence in Schizophrenia.

BACKGROUND: Functional dysconnection in schizophrenia is underwritten by a pathophysiology of the glutamate neurotransmission that affects the excitation-inhibition balance in key nodes of the salience network. Physiologically, this manifests as aberrant effective connectivity in intrinsic connections involving inhibitory interneurons. In computational terms, this produces a pathology of evidence accumulation and ensuing inference in the brain. Finally, the pathophysiology and aberrant inference would partially account for the psychopathology of schizophrenia as measured in terms of symptoms and signs. We refer to this formulation as the 3-level hypothesis. METHODS: We tested the hypothesis in core nodes of the salience network (the dorsal anterior cingulate cortex [dACC] and the anterior insula) of 20 patients with first-episode psychosis and 20 healthy control subjects. We established 3-way correlations between the magnetic resonance spectroscopy measures of glutamate, effective connectivity of resting-state functional magnetic resonance imaging, and correlations between measures of this connectivity and estimates of precision (inherent in evidence accumulation in the Stroop task) and psychopathology. RESULTS: Glutamate concentration in the dACC was associated with higher and lower inhibitory connectivity in the dACC and in the anterior insula, respectively. Crucially, glutamate concentration correlated negatively with the inhibitory influence on the excitatory neuronal population in the dACC of subjects with first-episode psychosis. Furthermore, aberrant computational parameters of the Stroop task performance were associated with aberrant inhibitory connections. Finally, the strength of connections from the dACC to the anterior insula correlated negatively with severity of social withdrawal. CONCLUSIONS: These findings support a link between glutamate-mediated cortical disinhibition, effective-connectivity deficits, and computational performance in psychosis.