Clinical outcomes vary among youths at clinical high risk for psychosis (CHR-P), with approximately 20% progressing to full-blown psychosis over 2 to 3 years and 30% achieving remission. Recent ...research efforts have focused on identifying biomarkers that precede psychosis onset and enhance the accuracy of clinical outcome prediction in CHR-P individuals, with the ultimate goal of developing staged treatment approaches based on the individual’s level of risk. Identifying such biomarkers may also facilitate progress toward understanding pathogenic mechanisms underlying psychosis onset, which may support the development of mechanistically informed early interventions for psychosis. In recent years, electroencephalography-based event-related potential measures with established sensitivity to schizophrenia have gained traction in the study of CHR-P and its clinical outcomes. In this review, we describe the evidence for event-related potential abnormalities in CHR-P and discuss how they inform our understanding of information processing deficits as vulnerability markers for emerging psychosis and as indicators of future outcomes. Among the measures studied, P300 and mismatch negativity are notable because deficits predict conversion to psychosis and/or CHR-P remission. However, the accuracy with which these and other measures predict outcomes in CHR-P has been obscured in the prior literature by the tendency to only report group-level differences, underscoring the need for inclusion of individual predictive accuracy metrics in future studies. Nevertheless, both P300 and mismatch negativity show promise as electrophysiological markers of risk for psychosis, as target engagement measures for clinical trials, and as potential translational bridges between human studies and animal models focused on novel drug development for early psychosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective:Although patients with schizophrenia exhibit impaired suppression of the P50 event-related brain potential in response to the second of two identical auditory stimuli during a ...paired-stimulus paradigm, uncertainty remains over whether this deficit in inhibitory gating of auditory sensory processes has relevance for patients’ clinical symptoms or cognitive performance. The authors examined associations between P50 suppression deficits and several core features of schizophrenia to address this gap.Method:P50 was recorded from 52 patients with schizophrenia and 41 healthy comparison subjects during a standard auditory paired-stimulus task. Clinical symptoms were assessed with the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. The MATRICS Consensus Cognitive Battery was utilized to measure cognitive performance in a subsample of 39 patients. Correlation and regression analyses were conducted to examine P50 suppression in relation to clinical symptom and cognitive performance measures.Results:Schizophrenia patients demonstrated a deficit in P50 suppression when compared with healthy subjects, replicating prior research. Within the patient sample, impaired P50 suppression covaried reliably with greater difficulties in attention, poorer working memory, and reduced processing speed.Conclusions:Impaired suppression of auditory stimuli was associated with core pathological features of schizophrenia, increasing confidence that P50 inhibitory processing can inform the development of interventions that target cognitive impairments in this chronic and debilitating mental illness.
P300 in schizophrenia: Then and now Hamilton, Holly K.; Mathalon, Daniel H.; Ford, Judith M.
Biological psychology,
March 2024, 2024-Mar, 2024-03-00, 20240301, Volume:
187
Journal Article
Peer reviewed
The 1965 discovery of the P300 component of the electroencephalography (EEG)-based event-related potential (ERP), along with the subsequent identification of its alteration in people with ...schizophrenia, initiated over 50 years of P300 research in schizophrenia. Here, we review what we now know about P300 in schizophrenia after nearly six decades of research. We describe recent efforts to expand our understanding of P300 beyond its sensitivity to schizophrenia itself to its potential role as a biomarker of risk for psychosis or a heritable endophenotype that bridges genetic risk and psychosis phenomenology. We also highlight efforts to move beyond a syndrome-based approach to understand P300 within the context of the clinical, cognitive, and presumed pathophysiological heterogeneity among people diagnosed with schizophrenia. Finally, we describe several recent approaches that extend beyond measuring the traditional P300 ERP component in people with schizophrenia, including time-frequency analyses and pharmacological challenge studies, that may help to clarify specific cognitive mechanisms that are disrupted in schizophrenia. Moreover, we discuss several promising areas for future research, including studies of animal models that can be used for treatment development.
•The 1965 discovery of P300 led to nearly six decades of P300 studies in schizophrenia.•P300 deficits show trait-like stability but fluctuate with clinical severity.•Deficits precede the illness and occur in relatives, but the genetic basis is unclear.•The relationship between P300 deficits and clinical symptoms remains elusive.•Promising new approaches include time-frequency analysis and animal model studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Mismatch negativity (MMN) and P300 event-related potential (ERP) reductions in schizophrenia (SZ) reflect preattentive and attention-mediated auditory processing deficits, respectively. ...Although both have been linked to cognitive deficits in SZ, their relative contributions to real-world functioning are unclear. We sought to determine the functional significance of disrupted auditory processing in SZ by examining MMN and P300 in typically disabled low-functioning patients and in patients with high levels of independent role functioning. MMN to auditory deviants and P300 to infrequent auditory target and nontarget novel stimuli were assessed in 20 high-functioning SZ patients (HF-SZ), 17 low-functioning patients (LF-SZ), and 35 healthy comparison (HC) subjects. There was a group effect on MMN and P300 amplitudes across stimulus types. MMN was significantly diminished in LF-SZ compared to HF-SZ and HC, and HF-SZ demonstrated comparable MMN to HC. In contrast, P300 was significantly reduced in both LF-SZ and HF-SZ compared to HC. Logistic regression suggested independent sensitivity of MMN to functioning in SZ over and above P300 measures. Neither MMN nor P300 were associated with positive or negative symptom severity. Results replicate MMN and P300 abnormalities in SZ, and also suggest that the neural mechanisms associated with the preattentive detection of auditory deviance are most compromised in patients with functional disability. MMN may index pathophysiological processes that are critical for optimal functioning in SZ.
IMPORTANCE: Although clinical criteria for identifying youth at risk for psychosis have been validated, they are not sufficiently accurate for predicting outcomes to inform major treatment decisions. ...The identification of biomarkers may improve outcome prediction among individuals at clinical high risk for psychosis (CHR-P). OBJECTIVE: To examine whether mismatch negativity (MMN) event–related potential amplitude, which is deficient in schizophrenia, is reduced in young people with the CHR-P syndrome and associated with outcomes, accounting for effects of antipsychotic medication use. DESIGN, SETTING, AND PARTICIPANTS: MMN data were collected as part of the multisite case-control North American Prodrome Longitudinal Study (NAPLS-2) from 8 university-based outpatient research programs. Baseline MMN data were collected from June 2009 through April 2013. Clinical outcomes were assessed throughout 24 months. Participants were individuals with the CHR-P syndrome and healthy controls with MMN data. Participants with the CHR-P syndrome who developed psychosis (ie, converters) were compared with those who did not develop psychosis (ie, nonconverters) who were followed up for 24 months. Analysis took place between December 2019 and December 2021. MAIN OUTCOMES AND MEASURES: Electroencephalography was recorded during a passive auditory oddball paradigm. MMN elicited by duration-, pitch-, and duration + pitch double-deviant tones was measured. RESULTS: The CHR-P group (n = 580; mean SD age, 19.24 4.39 years) included 247 female individuals (42.6%) and the healthy control group (n = 241; mean age, 20.33 4.74 years) included 114 female individuals (47.3%). In the CHR-P group, 450 (77.6%) were not taking antipsychotic medication at baseline. Baseline MMN amplitudes, irrespective of deviant type, were deficient in future CHR-P converters to psychosis (n = 77, unmedicated n = 54) compared with nonconverters (n = 238, unmedicated n = 190) in both the full sample (d = 0.27) and the unmedicated subsample (d = 0.33). In the full sample, baseline medication status interacted with group and deviant type indicating that double-deviant MMN, compared with single deviants, was reduced in unmedicated converters compared with nonconverters (d = 0.43). Further, within the unmedicated subsample, deficits in double-deviant MMN were most strongly associated with earlier conversion to psychosis (hazard ratio, 1.40 95% CI, 1.03-1.90; P = .03, which persisted over and above positive symptom severity. CONCLUSIONS AND RELEVANCE: This study found that MMN amplitude deficits were sensitive to future psychosis conversion among individuals at risk of CHR-P, particularly those not taking antipsychotic medication at baseline, although associations were modest. While MMN shows limited promise as a biomarker of psychosis onset on its own, it may contribute novel risk information to multivariate prediction algorithms and serve as a translational neurophysiological target for novel treatment development in a subgroup of at-risk individuals.
Saliva is an attractive specimen type for asymptomatic surveillance of COVID-19 in large populations due to its ease of collection and its demonstrated utility for detecting RNA from SARS-CoV-2. ...Multiple saliva-based viral detection protocols use a direct-to-RT-qPCR approach that eliminates nucleic acid extraction but can reduce viral RNA detection sensitivity. To improve test sensitivity while maintaining speed, we developed a robotic nucleic acid extraction method for detecting SARS-CoV-2 RNA in saliva samples with high throughput. Using this assay, the Free Asymptomatic Saliva Testing (IGI FAST) research study on the UC Berkeley campus conducted 11,971 tests on supervised self-collected saliva samples and identified rare positive specimens containing SARS-CoV-2 RNA during a time of low infection prevalence. In an attempt to increase testing capacity, we further adapted our robotic extraction assay to process pooled saliva samples. We also benchmarked our assay against nasopharyngeal swab specimens and found saliva methods require further optimization to match this gold standard. Finally, we designed and validated a RT-qPCR test suitable for saliva self-collection. These results establish a robotic extraction-based procedure for rapid PCR-based saliva testing that is suitable for samples from both symptomatic and asymptomatic individuals.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: In most patients, a prodromal period precedes the onset of schizophrenia. Although clinical criteria for identifying the psychosis risk syndrome (PRS) show promising predictive validity, ...assessment of neurophysiologic abnormalities in at-risk individuals may improve clinical prediction and clarify the pathogenesis of schizophrenia. OBJECTIVE: To determine whether P300 event-related potential amplitude, which is deficient in schizophrenia, is reduced in the PRS and associated with clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Auditory P300 data were collected as part of the multisite, case-control North American Prodrome Longitudinal Study (NAPLS-2) at 8 university-based outpatient programs. Participants included 552 individuals meeting PRS criteria and 236 healthy controls with P300 data. Auditory P300 data of participants at risk who converted to psychosis (n = 73) were compared with those of nonconverters who were followed up for 24 months and continued to be symptomatic (n = 135) or remitted from the PRS (n = 90). Data were collected from May 27, 2009, to September 17, 2014, and were analyzed from December 3, 2015, to May 1, 2019. MAIN OUTCOMES AND MEASURES: Baseline electroencephalography was recorded during an auditory oddball task. Two P300 subcomponents were measured: P3b, elicited by infrequent target stimuli, and P3a, elicited by infrequent nontarget novel stimuli. RESULTS: This study included 788 participants. The PRS group (n = 552) included 236 females (42.8%) (mean SD age, 19.21 4.38 years), and the healthy control group (n = 236) included 111 females (47.0%) (mean SD age, 20.44 4.73 years). Target P3b and novelty P3a amplitudes were reduced in at-risk individuals vs healthy controls (d = 0.37). Target P3b, but not novelty P3a, was significantly reduced in psychosis converters vs nonconverters (d = 0.26), and smaller target P3b amplitude was associated with a shorter time to psychosis onset in at-risk individuals (hazard ratio, 1.45; 95% CI, 1.04-2.00; P = .03). Participants with the PRS who remitted had baseline target P3b amplitudes that were similar to those of healthy controls and greater than those of converters (d = 0.51) and at-risk individuals who remained symptomatic (d = 0.41). CONCLUSIONS AND RELEVANCE: In this study, deficits in P300 amplitude appeared to precede psychosis onset. Target P3b amplitudes, in particular, may be sensitive to clinical outcomes in the PRS, including both conversion to psychosis and clinical remission. Auditory target P3b amplitude shows promise as a putative prognostic biomarker of clinical outcome in the PRS.
Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity mediated by glutamatergic transmission at N-methyl-D-aspartate receptors (NMDARs). Impaired neuroplasticity has been ...implicated in the pathophysiology of schizophrenia, possibly due to underlying NMDAR hypofunction. Analogous to the high frequency electrical stimulation used to induce LTP
and
in animal models, repeated high frequency presentation of a visual stimulus in humans
has been shown to induce enduring LTP-like neuroplastic changes in electroencephalography (EEG)-based visual evoked potentials (VEPs) elicited by the stimulus. Using this LTP-like visual plasticity paradigm, we previously showed that visual high-frequency stimulation (VHFS) induced sustained changes in VEP amplitudes in healthy controls, but not in patients with schizophrenia. Here, we extend this prior work by re-analyzing the EEG data underlying the VEPs, focusing on neuroplastic changes in stimulus-evoked EEG oscillatory activity following VHFS. EEG data were recorded from 19 patients with schizophrenia and 21 healthy controls during the visual plasticity paradigm. Event-related EEG oscillations (total power, intertrial phase coherence; ITC) elicited by a standard black and white checkerboard stimulus (~0.83 Hz, several 2-min blocks) were assessed before and after exposure to VHFS with the same stimulus (~8.9 Hz, 2 min). A cluster-based permutation testing approach was applied to time-frequency data to examine LTP-like plasticity effects following VHFS. VHFS enhanced theta band total power and ITC in healthy controls but not in patients with schizophrenia. The magnitude and phase synchrony of theta oscillations in response to a visual stimulus were enhanced for at least 22 min following VHFS, a frequency domain manifestation of LTP-like visual cortical plasticity. These theta oscillation changes are deficient in patients with schizophrenia, consistent with hypothesized NMDA receptor dysfunction.
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