Amphetamine increases motivation of humans and mice as measured by breakpoint, but does not affect an Electroencephalographic biomarker.

Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.

Early auditory processing abnormalities alter individual learning trajectories and sensitivity to computerized cognitive training in schizophrenia.

BACKGROUND: Auditory system plasticity is a promising target for neuromodulation, cognitive rehabilitation and therapeutic development in schizophrenia (SZ). Auditory-based targeted cognitive training (TCT) is a 'bottom up' intervention designed to enhance the speed and accuracy of auditory information processing, which has been shown to improve neurocognition in certain SZ patients. However, the dynamics of TCT learning as a function of training exercises and their impact on neurocognitive functioning and therapeutic outcomes are unknown. METHODS: Forty subjects (SZ, n = 21; healthy subjects (HS), n = 19) underwent comprehensive clinical, cognitive, and auditory assessments, including measurements of auditory processing speed (APS) at baseline and after 1-h of TCT. SZ patients additionally completed 30-hours of TCT and repeated assessments ~10-12 weeks later. RESULTS: SZ patients were deficient in APS at baseline (d = 0.96, p < 0.005) relative to HS. After 1-h of TCT, analyses revealed significant main effects of diagnosis (d = 1.75, p = 0.002) and time (d = 1.04, p < 0.001), and a diagnosis × time interaction (d = 0.85, p = 0.02) on APS. APS learning effects were robust after 1-h in SZ patients (d = 1.47, p < 0.001) and persisted throughout the 30-h of training. Baseline APS was associated with verbal learning gains after 30-h of TCT (r = 0.51, p = 0.02) in SZ. CONCLUSIONS: TCT learning metrics may have prognostic utility and aid in the prospective identification of individuals likely to benefit from TCT. Future experimental medicine studies may advance predictive algorithms that enhance TCT-related clinical, cognitive and functional outcomes.

The viability of the frequency following response characteristics for use as biomarkers of cognitive therapeutics in schizophrenia.

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 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 psychometric reliability and magnitude of group differences across 18 different FFR parameters to determine which of these parameters demonstrate adequate internal consistency. Electroencephalography from 40 schizophrenia patients and 40 nonpsychiatric comparison subjects was recorded during rapid presentation of an auditory speech stimulus (6000 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 0.80. In contrast, excellent internal consistency (>0.95) 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 to select FFR characteristics for use in future intervention studies interested in individual differences among patients.

EEG reveals that dextroamphetamine improves cognitive control through multiple processes in healthy participants.

The poor translatability between preclinical and clinical drug trials has limited pro-cognitive therapeutic development. Future pro-cognitive drug trials should use translatable cross-species cognitive tasks with biomarkers (1) relevant to specific cognitive constructs, and (2) sensitive to drug treatment. Here, we used a difficulty-modulated variant of a cross-species cognitive control task with simultaneous electroencephalography (EEG) to identify neurophysiological biomarkers sensitive to the pro-cognitive effects of dextroamphetamine (d-amp) (10 or 20 mg) in healthy adults (n = 23), in a randomized, placebo-controlled, counterbalanced, double blind, within-subject study, conducted across three test days each separated by one week. D-amp boosted d-prime, sped reaction time, and increased frontal P3a amplitude to non-target correct rejections independent of task difficulty. Task difficulty did however, moderate d-amp effects on EEG during target performance. D-amp suppressed frontal theta power during easy target responses which negatively correlated with drug-induced improvement in hit rate while d-amp-induced changes in P3b amplitude during hard target trials strongly correlated with drug-induced improvement in hit rate. In summary, d-amp affected both behavioral and neurophysiological measures of cognitive control elements. Under low-demand, d-amp diminished cognitive control by suppressing theta, yet under high-demand it boosted control in concert with higher P3b amplitudes. These findings thus appear to reflect a gain-sharpening effect of d-amp: during high-demand processes were boosted while during low-demand processes were neglected. Future studies will use these neurophysiological measures of cognitive control as biomarkers to predict d-amp sensitivity in people with cognitive control deficits, including schizophrenia.

Amphetamine alters an EEG marker of reward processing in humans and mice.

The bench-to-bedside development of pro-cognitive therapeutics for psychiatric disorders has been mired by translational failures. This is, in part, due to the absence of pharmacologically sensitive cognitive biomarkers common to humans and rodents. Here, we describe a cross-species translational marker of reward processing that is sensitive to the aminergic agonist, d-amphetamine. Motivated by human electroencephalographic (EEG) findings, we recently reported that frontal midline delta-band power is an electrophysiological biomarker of reward surprise in humans and in mice. In the current series of experiments, we determined the impact of parametric doses of d-amphetamine on this reward-related EEG response from humans (n = 23) and mice (n = 28) performing a probabilistic learning task. In humans, d-amphetamine (placebo, 10 mg, 20 mg) boosted the Reward Positivity event-related potential (ERP) component as well as the spectral delta-band representations of this signal. In mice, d-amphetamine (placebo, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg) boosted both reward and punishment ERP features, yet there was no modulation of spectral activities. In sum, the present results confirm the role of dopamine in the generation of the Reward Positivity in humans, and pave the way toward a pharmacologically valid biomarker of reward sensitivity across species.

Evaluation of the frequency following response as a predictive biomarker of response to cognitive training in schizophrenia.

Neurophysiological biomarkers of auditory processing show promise predicting outcomes following auditory-based targeted cognitive training (TCT) in schizophrenia, but the viability of the frequency following response (FFR) as a biomarker has yet to be examined, despite its ecological and face validity for auditory-based interventions. FFR is an event-related potential (ERP) that reflects early auditory processing. We predicted that schizophrenia patients would show acute- and longer-term FFR malleability in the context of TCT. Patients were randomized to either TCT (n = 30) or treatment as usual (TAU; n = 22), and electroencephalography was recorded during rapid presentation of an auditory speech stimulus before treatment, after one hour of training, and after 30 h of training. Whereas patients in the TCT group did not show changes in FFR after training, amplitude reductions were observed in the TAU. FFR was positively associated with performance on a measure of single word-in-noise perception in the TCT group, and with a measure of sentence-in-noise perception in both groups. Psychometric reliability analyses of FFR scores indicated high internal consistency but low one-hour and 12-week test-rest reliability. These findings support the dissociation between measures of speech discriminability along the hierarchy of cortical and subcortical early auditory information processing in schizophrenia.

Central auditory processing deficits in schizophrenia: Effects of auditory-based cognitive training.

BACKGROUND: Sensory 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. METHODS: SZ (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. RESULTS: Patients 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). CONCLUSION: Findings 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.

Contextualizing the road to recovery: A novel method of assessing outcome trajectories in clinical trials.

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) 2021 APA, all rights reserved).

Anticholinergic Medication Burden-Associated Cognitive Impairment in Schizophrenia.

OBJECTIVE: Many psychotropic medications used to treat schizophrenia have significant anticholinergic properties, which are linked to cognitive impairment and dementia risk in healthy subjects. Clarifying the impact of cognitive impairment attributable to anticholinergic medication burden may help optimize cognitive outcomes in schizophrenia. The aim of this study was to comprehensively characterize how this burden affects functioning across multiple cognitive domains in schizophrenia outpatients. METHODS: Cross-sectional data were analyzed using inferential statistics and exploratory structural equation modeling to determine the relationship between anticholinergic medication burden and cognition. Patients with a diagnosis of schizophrenia or schizoaffective disorder (N=1,120) were recruited from the community at five U.S. universities as part of the Consortium on the Genetics of Schizophrenia-2. For each participant, prescribed medications were rated and summed according to a modified Anticholinergic Cognitive Burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB). RESULTS: ACB score was significantly associated with cognitive performance, with higher ACB groups scoring worse than lower ACB groups on all domains tested on the PCNB. Similar effects were seen on other cognitive tests. Effects remained significant after controlling for demographic characteristics and potential proxies of illness severity, including clinical symptoms and chlorpromazine-equivalent antipsychotic dosage. CONCLUSIONS: Anticholinergic medication burden in schizophrenia is substantial, common, conferred by multiple medication classes, and associated with cognitive impairments across all cognitive domains. Anticholinergic medication burden from all medication classes-including psychotropics used in usual care-should be considered in treatment decisions and accounted for in studies of cognitive functioning in schizophrenia.

Gamma oscillations predict pro-cognitive and clinical response to auditory-based cognitive training in schizophrenia.

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.

Oscillatory biomarkers of early auditory information processing predict cognitive gains following targeted cognitive training in schizophrenia patients.

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.

Verbal learning deficits associated with increased anticholinergic burden are attenuated with targeted cognitive training in treatment refractory schizophrenia patients.

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.

Neurophysiologic measures of target engagement predict response to auditory-based cognitive training in treatment refractory schizophrenia.

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.

Divergence of subjective and performance-based cognitive gains following cognitive training in schizophrenia.

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 30 h 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, p < 0.001), but not global or specific domains of cognition (all rs < 0.1) at baseline. There were no significant relationships between change in subjective cognitive difficulties and change in cognitive or clinical variables (all ps > 0.05). DISCUSSION: Patients with schizophrenia do not detect change in their cognition following cognitive training, even among those 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.

Targeted cognitive training improves auditory and verbal outcomes among treatment refractory schizophrenia patients mandated to residential care.

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.