Neurophysiologic measures of target engagement predict response to auditory-based cognitive training in treatment refractory schizophrenia.
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ABSTRACT:
SUBMITTER: Hochberger WC
PROVIDER: S-EPMC6333927 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Individuals with schizophrenia who engage in targeted cognitive training (TCT) of the auditory system show generalized cognitive improvements. The high degree of variability in cognitive gains maybe due to individual differences in the level of engagement of the underlying neural system target.131 individuals with schizophrenia underwent 40 hours of TCT. We identified target engagement of auditory system processing efficiency by modeling subject-specific trajectories of auditory processing speed (APS) over time. Lowess analysis, mixed models repeated measures analysis, and latent growth curve modeling were used to examine whether APS trajectories were moderated by age and illness duration, and mediated improvements in cognitive outcome measures.We observed significant improvements in APS from baseline to 20 hours of training (initial change), followed by a flat APS trajectory (plateau) at subsequent time-points. Participants showed interindividual variability in the steepness of the initial APS change and in the APS plateau achieved and sustained between 20 and 40 hours. We found that participants who achieved the fastest APS plateau, showed the greatest transfer effects to untrained cognitive domains.There is a significant association between an individual's ability to generate and sustain auditory processing efficiency and their degree of cognitive improvement after TCT, independent of baseline neurocognition. APS plateau may therefore represent a behavioral measure of target engagement mediating treatment response. Future studies should examine the optimal plateau of auditory processing efficiency required to induce significant cognitive improvements, in the context of interindividual differences in neural plasticity and sensory system efficiency that characterize schizophrenia. (PsycINFO Database Record
| S-EPMC5088059 | biostudies-literature
Project description: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 < 0.06). The results indicate that the capacity to support gamma oscillations, as well as the plasticity of the underlying ASSR circuitry after acute exposure to 1 h of TCT, reflect neural mechanisms underlying the efficacy of TCT, and may be used to predict individualized treatment outcomes. These findings suggest that gamma oscillatory biomarkers applied within the context of experimental medicine designs can be used to personalize individual treatment options for pro-cognitive interventions in patients with schizophrenia.
| S-EPMC7684295 | biostudies-literature
Project description: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.
| S-EPMC7035985 | biostudies-literature
Project description: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.
| S-EPMC7409526 | biostudies-literature
Project description:BackgroundSensory processing abnormalities are common in schizophrenia (SZ) and impact everyday functions, such as speech perception in noisy environments. Auditory-based targeted cognitive training (TCT) is a "bottom up" cognitive remediation intervention designed to enhance the speed and accuracy of low-level auditory information processing. However, the effects of TCT on behavioral measures of central auditory processing (CAP) and the role of CAP function on verbal learning outcomes in SZ are unknown.MethodsSZ (n = 42) and healthy subjects (CTL; n = 18) underwent comprehensive clinical, neurocognitive, and auditory assessments, including tests of hearing sensitivity and speech recognition (Words-in-Noise (WIN), Quick Speech-in-Noise (SIN)). SZ patients were randomized to receive either treatment-as-usual (TAU); or 30-h of TCT + TAU using a stratified, parallel design. SZ patients repeated assessments ~10-12 weeks later.ResultsPatients exhibited deficits in both WIN (p < 0.05, d = 0.50) and SIN (p < 0.01, d = 0.63). A treatment × time interaction on WIN (p < 0.05, d = 0.74), but not SIN discriminability, was seen in the TCT group relative to TAU. Specific enhancements in the 4-dB over background range drove gains in WIN performance. Moreover, SZ patients with greater CAP deficits experienced robust gains in verbal learning after 30-h of TCT relative to SZ patients without CAP impairment (p < 0.01, d = 1.28).ConclusionFindings demonstrate that intensive auditory training enhances the fidelity of auditory processing and perception, such that specific CAP deficits were 'normalized' and were predictive of gains in verbal learning after TCT. It is conceivable that patients with deficiencies in CAP measures may benefit most from TCT and other interventions targeting auditory dysfunction in SZ.
| S-EPMC9259506 | biostudies-literature
Project description:ObjectiveSocial cognitive deficits are an important treatment target in schizophrenia, but it is unclear to what degree they require specialized interventions and which specific components of behavioral interventions are effective. In this pilot study, we explored the effects of a novel computerized neuroplasticity-based auditory training delivered in conjunction with computerized social cognition training (SCT) in patients with schizophrenia.MethodsNineteen clinically stable schizophrenia subjects performed 50 hours of computerized exercises that place implicit, increasing demands on auditory perception, plus 12 hours of computerized training in emotion identification, social perception, and theory of mind tasks. All subjects were assessed with MATRICS-recommended measures of neurocognition and social cognition, plus a measure of self-referential source memory before and after the computerized training.ResultsSubjects showed significant improvements on multiple measures of neurocognition. Additionally, subjects showed significant gains on measures of social cognition, including the MSCEIT Perceiving Emotions, MSCEIT Managing Emotions, and self-referential source memory, plus a significant decrease in positive symptoms.ConclusionsComputerized training of auditory processing/verbal learning in schizophrenia results in significant basic neurocognitive gains. Further, addition of computerized social cognition training results in significant gains in several social cognitive outcome measures. Computerized cognitive training that directly targets social cognitive processes can drive improvements in these crucial functions.
| S-EPMC6939987 | biostudies-literature
Project description:Schizophrenia is characterized by dysfunction in basic auditory processing, as well as higher-order operations of verbal learning and executive functions. We investigated whether targeted cognitive training of auditory processing improves neural responses to speech stimuli, and how these changes relate to higher-order cognitive functions. Patients with schizophrenia performed an auditory syllable identification task during magnetoencephalography before and after 50 hours of either targeted cognitive training or a computer games control. Healthy comparison subjects were assessed at baseline and after a 10 week no-contact interval. Prior to training, patients (N = 34) showed reduced M100 response in primary auditory cortex relative to healthy participants (N = 13). At reassessment, only the targeted cognitive training patient group (N = 18) exhibited increased M100 responses. Additionally, this group showed increased induced high gamma band activity within left dorsolateral prefrontal cortex immediately after stimulus presentation, and later in bilateral temporal cortices. Training-related changes in neural activity correlated with changes in executive function scores but not verbal learning and memory. These data suggest that computerized cognitive training that targets auditory and verbal learning operations enhances both sensory responses in auditory cortex as well as engagement of prefrontal regions, as indexed during an auditory processing task with low demands on working memory. This neural circuit enhancement is in turn associated with better executive function but not verbal memory.
| S-EPMC4681549 | biostudies-literature
Project description:Background:Motivation and engagement are important factors associated with therapeutic outcomes in cognitive training for schizophrenia. The goals of the present report were to examine relations between objective treatment engagement (number of sessions attended, amount of homework completed) and self-reported motivation (intrinsic motivation and perceived competence to complete cognitive training) with neurocognitive and functional outcomes from cognitive training. Methods:Data from a clinical trial comparing two cognitive training approaches in schizophrenia-spectrum disorders were utilized in the current report (n?=?38). Relations were examined between baseline intrinsic motivation, perceived competence, homework completion, and session attendance with improvements in neurocognition, functional competence, and community functioning. Results:Number of sessions attended (r?=?0.38) and time doing homework (r?=?0.51) were significantly associated with improvements in neurocognition. Homework completion was associated with change in community functioning at a trend-level (r?=?0.30). Older age was associated with greater treatment engagement (??=?0.37) and male biological sex was associated with greater self-reported motivation (??=?0.43). Homework completion significantly mediated the relationship between session attendance and neurocognitive treatment outcomes. Conclusions:Objective measures of treatment engagement were better predictors of treatment outcomes than subjective measures of motivation. Homework completion was most strongly related to treatment outcomes and mediated the relationship between session attendance and treatment outcomes, suggesting continued engagement with cognitive stimulation may be an especially important component of cognitive remediation programs. Future research should examine methods to improve homework completion and session attendance to maximize therapeutic outcomes.
| S-EPMC6889769 | biostudies-literature
Project description:BackgroundFragile X syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS.MethodsIn this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABAB selective agonist racemic baclofen (RBAC).ResultsIn Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted.ConclusionsOverall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field.Trial registrationThe human experiments are registered under NCT02998151.
| S-EPMC9513876 | biostudies-literature
Project description:Poor treatment engagement is an enduring problem in the care of patients with schizophrenia. Evidence suggests that targeted cognitive training (TCT) improves cognition and functional outcomes, but this time-consuming intervention might reduce patients' engagement in other treatment activities when implemented in real-world settings. This is especially true of residential care programs which encourage patients to engage in group therapies, self-care, and a wide variety of structured social, work, and other rehabilitation activities. This study aimed to determine whether TCT negatively impacts engagement in other psychosocial treatments. Patients with schizophrenia were recruited from a community-based residential care program and randomized to one of two intervention arms: treatment as usual (TAU; n = 22) or TAU augmented with TCT (n = 24). Psychosocial treatment engagement was tracked over 20 weeks. Treatment groups did not significantly differ on baseline variables or psychosocial treatment engagement in the 5 weeks prior to randomization. TCT had a positive effect on engagement (β = 0.112, p = 0.003), but there was no treatment-by-time interaction (β = -0.029, p = 0.672). Participants in TCT engaged in an average of 1.34 additional group therapies, 0.58 additional activities of daily living, and 0.84 additional rehabilitation activities per week in comparison to TAU participants. Baseline cognition was also a significant predictor of psychosocial treatment engagement. Overall, results suggest that TCT can be implemented in real-world settings without negatively impacting engagement in other psychosocial treatments. Additional studies are needed to determine what role nonspecific factors play in the positive impact of TCT.
| S-EPMC7409521 | biostudies-literature