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Auditory-based targeted cognitive training (TCT) is an effective and well-validated intervention for the treatment of cognitive impairment in schizophrenia patients. Improvements in higher-order cognition, reductions in symptom severity, and increases in psychosocial functioning secondary to TCT are thought to be driven by “bottom-up” enhancement of early auditory information processing (EAIP). Despite strong evidence of efficacy at the group level, there is significant variability in response to TCT, with few well-delineated biomarkers for predicting individual benefit. EEG biomarkers of EAIP are indicators of early-treatment sensitivity that predict full-course TCT outcome; however, further characterization is necessary for biomarker-guided clinical trials. The current study examined baseline and early-treatment sensitivity (i.e., change from baseline after 1 h) in theta band oscillatory activity to deviant stimuli as moderators of full course (30 h) TCT response in treatment-refractory schizophrenia patients randomly assigned to receive either treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 30). Theta evoked power and phase locking at baseline predicted patient improvements in global cognitive function after 30 h of TCT. Decrease in theta activity to deviant stimuli after 1 h of TCT predicted improvements in verbal learning after 30 h. Exploratory analyses using EEG composite scores had high levels of sensitivity and specificity for identifying patients most likely to benefit from TCT. The integrity of baseline neurophysiologic activity associated with EAIP, as well as the sensitivity of the underlying circuity to change, likely reflects an intermediate therapeutic process underlying the effectiveness of TCT that can be used to predict patient response to treatment.

Cognitive impairments are pervasive and disabling features of schizophrenia. Targeted cognitive training (TCT) is a “bottom-up” cognitive remediation intervention with efficacy for neurocognitive outcomes in schizophrenia, yet individual responses are variable. Gamma oscillatory measures are leading candidate biomarkers in the development of biologically informed pro-cognitive therapeutics. Forty-two schizophrenia patients were recruited from a long-term residential treatment facility. Participants were randomized to receive either 1 h of cognitive training (TCT, n = 21) or computer games (TAU, n = 21). All participants received standard-of-care treatment; the TCT group additionally completed 30 h of cognitive training. The auditory steady-state response paradigm was used to elicit gamma oscillatory power and synchrony during electroencephalogram recordings. Detailed clinical and cognitive assessments were collected at baseline and after completion of the study. Baseline gamma power predicted cognitive gains after a full course of TCT (MCCB, R2 = 0.31). A change in gamma power after 1-h TCT exposure predicted improvement in both positive (SAPS, R2 = 0.40) and negative (SANS, R2 = 0.30) symptoms. These relationships were not observed in the TAU group (MCCB, SAPS, and SANS, all R2

In clinical trials, standardized assessment conducted by research staff facilitates identification of treatment benefit. Narrative notes completed by clinicians offer a novel source to characterize and contextualize outcomes. In this study, we examine qualitative analysis of clinical notes as a method to augment quantitative outcome measures and supply meaningful context in clinical trials. Two hundred eighty-four clinical progress notes from 19 participants with schizophrenia or schizoaffective disorder assigned to receive either auditory-targeted cognitive training or treatment as usual were included. Qualitative analysis of weekly progress notes written by clinicians involved in ongoing care of the participants was used to identify overall outcome trajectories and specific changes in program participation, social functioning, and symptom severity. Trajectories were compared with the parent study's 2 primary outcome measures. Qualitative analysis identified personalized and complex trajectories for individual participants. Approximately half the participants improved overall. Most participants displayed improved program participation and social functioning, whereas most participants experienced symptom deterioration. Engagement in targeted cognitive training did not impact change in trajectories. Qualitative trajectories were congruent (e.g., both indicated improvement) with the 2 primary outcome measures for 26-36% of the participants depending on the comparison. Including qualitative analysis of clinician progress notes provides useful context and identifies underlying processes not captured in quantitative data. However, they cannot replace quantitative outcome measurement. Better alignment with clinician- and patient-targeted outcomes may strengthen clinical trials. Qualitative analysis of routinely collected data can benefit research and programmatic decision making in usual care settings. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Deficits in early auditory information processing contribute to cognitive and psychosocial disability; this has prompted development of interventions that target low-level auditory processing, which may alleviate these disabilities. The frequency following response (FFR) is a constellation of event-related potential and frequency characteristics that reflect the processing of simple acoustic stimuli at the level of the brainstem and ascending portions of the auditory pathway. While FFR is a promising candidate biomarker of response to auditory-based cognitive training interventions, the psychometric properties of FFR in schizophrenia patients have not been studied. Here we assessed the internal consistency characteristics and magnitude of group differences across 18 different FFR parameters to determine which, if any, of these parameters demonstrate adequate internal consistency for use in intervention studies. Electroencephalography from 40 schizophrenia patients and 40 nonpsychiatric comparison subjects was recorded during rapid presentation of an auditory speech stimulus (6,000 trials). Patients showed normal response amplitudes but longer latencies for most FFR peaks and lower signal-to-noise ratios (SNRs) than healthy subjects. Analysis of amplitude and latency estimates of peaks, however, indicated a need for a substantial increase in task length to obtain internal consistency estimates above .80. In contrast, excellent internal consistency (> .95) was shown for FFR sustained responses. Only SNR scores reflecting the FFR sustained response yielded significant group differences and excellent internal consistency, suggesting that this measure is a viable candidate for use in clinical treatment studies. The present study highlights the use of internal consistency estimates of FFR to guide future intervention studies interested in individual differences among patients.

Chronic psychotic disorders, including schizophrenia (SZ), are highly heterogeneous at many levels of analysis, from genetics to clinical presentation and treatment sensitivity. This heterogeneity reflects both a divergence of shared biological pathways moving from over a hundred “risk genes” to many different clinical phenotypes, and the convergence of distinct biological pathways to a shared “phenocopies” of chronic psychosis. Successful strategies for developing “next generation” interventions in SZ – including “pro-cognitive” medications, cognitive remediation, neurostimulation and combinations thereof – will address these pathways to clinical heterogeneity by using biological signals, or “biomarkers” that characterize treatment-sensitive subpopulations. Identifying and detecting these meaningful signals in the complex biology of SZ is a vexing scientific challenge. We propose that rational starting points are neurophysiological measures of early auditory information processing (EAIP), based on their functional importance as strong mediators of both cognition and function in SZ, their plasticity in response to both pharmacologic and non-pharmacologic therapeutic “challenge”, and their experimental characteristics as highly quantitative, robust and reliable measures of brain activity. Here we describe some of our current approaches to developing neurophysiological biomarkers for “next generation” therapeutic sensitivity in SZ, and some potentially novel experimental strategies that we envision on the near horizon.

Cognitive impairment is a core feature of schizophrenia and a strong predictor of psychosocial disability. Auditory-based targeted cognitive training (TCT) aims to enhance verbal learning and other domains of cognitive functioning through “bottom-up” tuning of the neural systems underlying early auditory information processing (EAIP). Although TCT has demonstrated efficacy at the group level, individual response to TCT varies considerably, with nearly half of patients showing little-to-no benefit. EEG measures of EAIP, mismatch negativity (MMN) and P3a, are sensitive to the neural systems engaged by TCT exercises and might therefore predict clinical outcomes after a full course of treatment. This study aimed to determine whether initial malleability of MMN and P3a to 1-h of auditory-based TCT predicts improvements in verbal learning and clinical symptom reduction following a full (30-h) course of TCT. Treatment refractory patients diagnosed with schizophrenia were randomly assigned to receive treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 23). Results indicated that malleability (i.e., change from baseline after the initial 1-h dose of TCT) of MMN and P3a predicted improvements in verbal learning as well as decreases in the severity of positive symptoms. Examination of MMN and P3a malleability in patients after their first dose of TCT can be used to predict clinical response to a full course of treatment and shows promise for future biomarker-informed treatment assignment.

Targeted cognitive training (TCT) has been reported to improve verbal learning deficits in patients with schizophrenia (SZ). Despite positive findings, it is not clear whether demographic factors and clinical characteristics contribute to the success of TCT on an individual basis. Medication-associated anticholinergic burden has been shown to impact TCT-associated verbal learning gains in SZ outpatients, but the role of anticholinergic medication burden on TCT gains in treatment refractory SZ patients has not been described. In this study, SZ patients mandated to a locked residential rehabilitation center were randomized to treatment as usual (TAU; n = 22) or a course of TAU augmented with TCT (n = 24). Anticholinergic medication burden was calculated from medication data at baseline and follow-up using the Anticholinergic Cognitive Burden (ACB) Scale. MATRICS Consensus Cognitive Battery Verbal Learning domain scores were used as the primary outcome variable. The TAU and TCT groups were matched in ACB at baseline and follow-up. While baseline ACB was not associated with verbal learning in either group, increases in ACB over the course of the study were significantly associated with deterioration of verbal learning in the TAU group (r = −0.51, p = 0.02). This was not seen in subjects randomized to TCT (r = −0.13, p = 0.62). Our results suggest that TCT may blunt anticholinergic medication burden associated reduction in verbal learning in severely disabled SZ inpatients.

BACKGROUND: Cognitive training is effective for improving cognitive performance among people with schizophrenia. An individual’s perception of their own cognition is dissociable from performance on objective cognitive tests. Since subjective cognitive benefit may impact engagement, motivation, and satisfaction with time-intensive cognitive interventions, this study aimed to determine whether subjective cognitive difficulties improve in conjunction with cognitive gains following 30h of cognitive training. METHODS: Patients with schizophrenia or schizoaffective disorder (N=46) were randomized to treatment as usual (TAU) or TAU augmented with auditory-targeted cognitive training (TCT). All participants completed assessment batteries at baseline and follow-up. As previously reported, the TCT group showed significant improvements in verbal learning and memory and reductions in auditory hallucinations relative to the TAU group. RESULTS: Subjective cognitive difficulties did not significantly improve following TCT, even among TCT participants who showed improvements in cognitive performance (all ps>0.05). Subjective cognitive difficulties were significantly associated with severity of depressive symptoms and hallucinations (r=0.48 and r=0.28, p0.05). DISCUSSION: Patients with schizophrenia do not detect change in their cognition following cognitive training, even among patients who showed robust gains in cognitive performance. Failure to detect improvement may undermine treatment engagement, motivation, and satisfaction. Translating score improvements on the cognitive exercises into tangible metrics, and providing ongoing, clinician-delivered feedback on performance may facilitate patient ability to detect improvements and improve motivation to engage with cognitive training interventions.

Computerized targeted cognitive training (TCT) of auditory processing has been shown to improve verbal learning in several clinical trials of schizophrenia outpatients. Less is known, however, about the effectiveness of this promising intervention in more chronic, treatment-refractory patients who are treated in non-academic settings. This study aimed to determine whether TCT improves auditory processing, verbal learning, and clinical symptoms in SZ patients mandated to receive care at a locked residential rehabilitation center. Secondarily, potential factors that moderate TCT's effectiveness including age, symptom severity, antipsychotic medication load, and duration of illness were examined. Schizophrenia patients were randomized to treatment as usual (TAU; n = 22) or TAU augmented with TCT (TAU + TCT; n = 24). Outcomes included a measure of auditory perception (Word-In-Noise test, WIN), verbal learning domain scores from the MATRICS Consensus Cognitive Battery (MCCB), and clinical symptoms (Scale for the Assessment of Positive Symptoms, SAPS; Scale for the Assessment of Negative Symptoms, SANS). TCT produced significant improvements in auditory perception (d = 0.67) and verbal learning (d = 0.65); exploratory analyses revealed a statistically significant reduction in auditory hallucinations (d = −0.64). TCT's effects were only weakly, and mostly non-significantly, moderated by age, clinical symptoms, medication, and illness duration. These findings indicate that even highly symptomatic, functionally disabled patients with chronic illness benefit from this emerging treatment. Ongoing studies will examine the predictive utility of neurophysiological biomarkers and other characteristics assessed at baseline.

Background: The auditory brain stem response to complex sounds (cABR) is an event-related potential (ERP) biomarker that quantifies sound encoding in the brain stem and midbrain. Although it has not yet been thoroughly investigated in schizophrenia (SZ), the cABR has demonstrated sufficient sensitivity for predicting response to at least one form of auditory-targeted cognitive training. We therefore aimed to examine whether the efficiency and accuracy of auditory encoding would be associated with the perception of speech-in-noise (SIN) and other higher order cognitive abilities that are commonly impaired in SZ. Methods: Thirty-one SZ patients in a transitional care facility underwent electroencephalography (EEG) testing with the cABR paradigm which consisted of 40 msec /da/ speech stimulus, presented binaurally with a 50 msec interstimulus interval (ISI). cABR onset (Peak A) latency and stimulus-to-response cross-correlations were calculated as an index of speech encoding timing and accuracy. Participants also completed the MATRICS Consensus Cognitive Battery (MCCB) and a modified version of QuickSIN, a measure of speech-in-noise perception. Results: Faster cABR peak A latency (mean = 7.93, SD = 1.41 msec) was associated with better speech-in-noise discriminability (r = −.47), CPT-IP attention (r = −.40), working memory (r = −.54 to r = −.62), and global cognition (r = −.44). Stimulus-to-response cABR encoding was positively associated with verbal learning and memory performance (r = .38, P < .05); its relationship with speech-in-noise discriminability trended toward significance (r = .33, P = .07). Conclusion: The cABR provides important information about the accuracy and efficiency of sound encoding within the brain stem. Its amplitude and timing appear to reflect functioning of the neural networks underlying speech perception and other functionally significant cognitive domains in SZ. Ongoing studies will assess whether these and other cABR parameters can be used to predict and monitor response to procognitive interventions in SZ.

Background Salivary immunoglobulin A (SIgA) together with innate defenses such as α-amylase, provides the ‘first line of defense’ against pathogens present at mucosal surfaces. This study aimed to evaluate salivary α-amylase and immunoglobulin A (IgA) in whole saliva of spastic cerebral palsy (CP) individuals. Methods Whole saliva was collected from 22 CP and 24 sibling volunteers with no neurological damage control groups (CG) (aged 7–14 years). The salivary flow rate, total protein and SIgA concentrations, and α-amylase activity were determined. Results The CP group presented higher salivary flow rate (35%) and lower total protein concentration (18%) compared with the CG (P ≤ 0.05). CPG had higher absolute (68%, μg SIgA/ml) and relative (55%, μg SIgA/mg prot and 108%, μg SIgA/min) concentrations of IgA compared with the CG (P ≤ 0.05). CPG had lower relative α-amylase activity (15% mg malt/mg prot and 33%, mg malt/min) compared with the CG (P ≤ 0.05). Conclusion This study concluded that CP individuals presented alterations in the profile of salivary proteins involved in the defense system of the oral cavity.

Background: Disturbances of auditory perception are characteristic features of schizophrenia (SZ) and contribute to cognitive and functional disability. Targeted Cognitive Training (TCT) of the auditory system has shown great promise for remediating cognitive impairments in SZ, but training-associated gains vary across individuals and are difficult to predict in the early stages of treatment. The Auditory Steady State Response (ASSR) to gamma-frequency stimulation is increasingly used as a functional biomarker of central auditory system plasticity in translational neuroscience. Here, we aimed to determine whether gamma evoked power and phase synchronization measures are sensitive to and predict the amount of perceptual learning that occurs during initial exposure to TCT.