BACKGROUND: Auditory frequency modulation learning (auditory learning) is a key component of targeted cognitive training (TCT) for schizophrenia. TCT can be effective in enhancing neurocognition and function in schizophrenia, but such gains require significant time and effort and elude many patients. METHODS: As a strategy to increase and/or accelerate TCT-induced clinical gains, we tested the dose- and time-course effects of the pro-attentional drug, amphetamine (AMPH; placebo, 2.5, 5 or 10 mg po; within-subject double-blind, order balanced) on auditory learning in schizophrenia patients [n = 32; M:F = 19:13; age 42.0 years (24-55)]. To understand predictors and/or mechanisms of AMPH-enhanced TCT, we also measured auditory fidelity (words-in-noise (WIN), quick speech-in-noise (QuickSIN)) and neurocognition (MATRICS comprehensive cognitive battery (MCCB)). Some measures were also acquired from age-matched healthy subjects (drug free; n = 10; M:F = 5:5). RESULTS: Patients exhibited expected deficits in neurocognition. WIN and QuickSIN performance at low signal intensities was impaired in patients with low v. high MCCB attention/vigilance (A/V) scores; these deficits were corrected by AMPH, maximally at 2.5-5 mg (ds = 0.79-1.29). AMPH also enhanced auditory learning, with maximal effects at 5 mg (d = 0.93), and comparable effects 60 and 210 min post pill. Pro-learning effects of AMPH and AMPH-induced gains in auditory fidelity were most evident in patients with low MCCB A/V scores. CONCLUSIONS: These findings advance our understanding of the impact of pro-attentional interventions on auditory information processing and suggest dose- and time-course parameters for studies that assess the ability of AMPH to enhance the clinical benefits of TCT in schizophrenia patients.

Background

Schizophrenia patients exhibit cognitive deficits across multiple domains, including verbal memory, working memory, and executive function, which substantially contribute to psychosocial disability. Gamma oscillations are associated with a wide range of cognitive operations, and are important for cortico-cortical transmission and the integration of information across neural networks. While previous reports have shown that schizophrenia patients have selective impairments in the ability to support gamma oscillations in response to 40-Hz auditory stimulation, it is unclear if patients show abnormalities in gamma power at rest, or whether resting-state activity in other frequency bands is associated with cognitive functioning in schizophrenia patients.

Methods

Resting-state electroencephalogram (EEG) was assessed over 3 min in 145 healthy comparison subjects and 157 schizophrenia patients. Single-word reading ability was measured via the reading subtest of the Wide Range Achievement Test-3 (WRAT). Auditory attention and working memory were evaluated using Letter-Number Span and Letter-Number Sequencing. Executive function was assessed via perseverative responses on the Wisconsin Card Sorting Test (WCST). Verbal learning performance was measured using the California Verbal Learning Test second edition (CVLT-II).

Results

Schizophrenia patients showed normal levels of delta-band power but abnormally elevated EEG power in theta, alpha, beta, and gamma bands. An exploratory correlation analysis showed a significant negative correlation of gamma-band power and verbal learning performance in schizophrenia patients.

Conclusions

Patients with schizophrenia have abnormal resting-state EEG power across multiple frequency bands; gamma-band abnormalities were selectively and negatively associated with impairments in verbal learning. Resting-state gamma-band EEG power may be useful for understanding the pathophysiology of cognitive dysfunction and developing novel therapeutics in schizophrenia patients.

Background: Patients with schizophrenia show abnormal spontaneous oscillatory activity in scalp-level electroencephalographic (EEG) responses across multiple frequency bands. While oscillations play an essential role in the transmission of information across neural networks, few studies have assessed the frequency-specific dynamics across cortical source networks at rest. Identification of the neural sources and their dynamic interactions may improve our understanding of core pathophysiologic abnormalities associated with the neuropsychiatric disorders. Methods: A novel multivector autoregressive modeling approach for assessing effective connectivity among cortical sources was developed and applied to resting-state EEG recordings obtained from n = 139 schizophrenia patients and n = 126 healthy comparison subjects. Results: Two primary abnormalities in resting-state networks were detected in schizophrenia patients. The first network involved the middle frontal and fusiform gyri and a region near the calcarine sulcus. The second network involved the cingulate gyrus and the Rolandic operculum (a region that includes the auditory cortex). Conclusions: Schizophrenia patients show widespread patterns of hyper-connectivity across a distributed network of the frontal, temporal, and occipital brain regions. Results highlight a novel approach for characterizing alterations in connectivity in the neuropsychiatric patient populations. Further mechanistic characterization of network functioning is needed to clarify the pathophysiology of neuropsychiatric and neurological diseases.

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.

Synaptic interactions between parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and pyramidal neurons evoke cortical gamma oscillations, which are known to be abnormal in schizophrenia. These cortical gamma oscillations can be indexed by the gamma-band auditory steady-state response (ASSR), a robust electroencephalographic (EEG) biomarker that is increasingly used to advance the development of novel therapeutics for schizophrenia, and other related brain disorders. Despite promise of ASSR, the neural substrates of ASSR have not yet been characterized. This study investigated the sources underlying ASSR in healthy subjects and schizophrenia patients. In this study, a novel method for noninvasively characterizing source locations was developed and applied to EEG recordings obtained from 293 healthy subjects and 427 schizophrenia patients who underwent ASSR testing. Results revealed a distributed network of temporal and frontal sources in both healthy subjects and schizophrenia patients. In both groups, primary contributing ASSR sources were identified in the right superior temporal cortex and the orbitofrontal cortex. In conjunction with normal activity in these areas, schizophrenia patients showed significantly reduced source dipole density of gamma-band ASSR (ITC > 0.25) in the left superior temporal cortex, orbitofrontal cortex, and left superior frontal cortex. In conclusion, a distributed network of temporal and frontal brain regions supports gamma phase synchronization. We demonstrated that failure to mount a coherent physiologic response to simple 40-Hz stimulation reflects disorganized network function in schizophrenia patients. Future translational studies are needed to more fully understand the neural mechanisms underlying gamma-band ASSR network abnormalities in schizophrenia.

Gamma-band (40-Hz) activity is critical for cortico-cortical transmission and the integration of information across neural networks during sensory and cognitive processing. Patients with schizophrenia show selective reductions in the capacity to support synchronized gamma-band oscillations in response to auditory stimulation presented 40-Hz. Despite widespread application of this 40-Hz auditory steady-state response (ASSR) as a translational electroencephalographic biomarker for therapeutic development for neuropsychiatric disorders, the spatiotemporal dynamics underlying the ASSR have not been fully characterized. In this study, a novel Granger causality analysis was applied to assess the propagation of gamma oscillations in response to 40-Hz steady-state stimulation across cortical sources in schizophrenia patients (n = 426) and healthy comparison subjects (n = 293). Both groups showed multiple ASSR source interactions that were broadly distributed across brain regions. Schizophrenia patients showed distinct, hierarchically sequenced connectivity abnormalities. During the response onset interval, patients exhibited abnormal increased connectivity from the inferior frontal gyrus to the superior temporal gyrus, followed by decreased connectivity from the superior temporal to the middle cingulate gyrus. In the later portion of the ASSR response (300-500 ms), patients showed significantly increased connectivity from the superior temporal to the middle frontal gyrus followed by decreased connectivity from the left superior frontal gyrus to the right superior and middle frontal gyri. These findings highlight both the orchestration of distributed multiple sources in response to simple gamma-frequency stimulation in healthy subjects as well as the patterns of deficits in the generation and maintenance of gamma-band oscillations across the temporo-frontal sources in schizophrenia patients.

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.

Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, "bottom-up" effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.