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.

Mismatch negativity predicts initial auditory-based targeted cognitive training performance in a heterogeneous population across psychiatric disorders.

Auditory-based targeted cognitive training (ATCT) programs are emerging pro-cognitive therapeutic interventions which aim to improve auditory processing to attenuate cognitive impairment in a "bottom up" manner. Biomarkers of early auditory information processing (EAIP) like mismatch negativity (MMN) and P3a have been used successfully to predict gains from a full 40 h course of ATCT in schizophrenia (SZ). Here we investigated the ability of EAIP biomarkers to predict ATCT performance in a group of subjects (n = 26) across SZ, MDD, PTSD and GAD diagnoses.

Preliminary Evidence that Memantine Enhances Prepulse Effects on Startle Magnitude and Latency in Patients with Alzheimer's Disease.

Background: The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer's disease (AD); conceivably, its acute impact on PPI might be used to predict a patient's sensitivity to MEM's therapeutic effects.

Objective: To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients.

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.

High-power gamma-related delta phase alteration in schizophrenia patients at rest.

Aim: Information processing is supported by the cortico-cortical transmission of neural oscillations across brain regions. Recent studies have demonstrated that the rhythmic firing of neural populations is not random but is governed by interactions with other frequency bands. Specifically, the amplitude of gamma-band oscillations is associated with the phase of lower frequency oscillations in support of short and long-range communications among networks.

Using Biomarkers to Predict Memantine Effects in Alzheimer's Disease: A Proposal and Proof-Of-Concept Demonstration.

Memantine's benefits in Alzheimer's disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual's clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid).

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.

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.

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.

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.

Abnormal phase discontinuity of alpha- and theta-frequency oscillations in schizophrenia.

Background: Schizophrenia patients have abnormal electroencephalographic (EEG) power over multiple frequency bands, even at rest, though the primary neural generators and spatiotemporal dynamics of these abnormalities are largely unknown. Disturbances in the precise synchronization of oscillations within and across cortical sources may underlie abnormal resting-state EEG activity in schizophrenia patients.

Methods: A novel assessment method was applied to identify the independent contributing sources of resting-state EEG and assess the phase discontinuity in schizophrenia patients (N = 148) and healthy subjects (N = 143).

Unique contributions of sensory discrimination and gamma synchronization deficits to cognitive, clinical, and psychosocial functional impairments in schizophrenia.

Background: Schizophrenia patients show widespread deficits in neurocognitive, clinical, and psychosocial functioning. Mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are robust translational biomarkers associated with schizophrenia and associated with cognitive dysfunction, negative symptom severity, and psychosocial disability. Although these biomarkers are conceptually linked as measures of early auditory information processing, it is unclear whether MMN and gamma-band ASSR account for shared vs.

Sources of the frontocentral mismatch negativity and P3a responses in schizophrenia patients and healthy comparison subjects.

Background: Mismatch negativity (MMN) and P3a are event-related potential measures of early auditory information processing that are increasingly used as translational biomarkers in the development of treatments for neuropsychiatric disorders. These responses are reduced in schizophrenia patients over the frontocentral scalp electrodes and are associated with important domains of cognitive and psychosocial functioning. While MMN and P3a responses are generated by a dynamic network of cortical sources distributed across the temporal and frontal brain regions, it is not clear how these sources independently contribute to MMN and P3a at the primary frontocentral scalp electrode or to abnormalities observed in schizophrenia.

Neural network dynamics underlying gamma synchronization deficits 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.

Neurophysiologic Characterization of Resting State Connectivity Abnormalities in Schizophrenia Patients.

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.

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.

Abnormal Spontaneous Gamma Power Is Associated With Verbal Learning and Memory Dysfunction in Schizophrenia.

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.

Hierarchical Pathways from Sensory Processing to Cognitive, Clinical, and Functional Impairments in 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.

Abnormal Effective Connectivity Underlying Auditory Mismatch Negativity Impairments in Schizophrenia.

Background: Auditory mismatch negativity (MMN) is a translatable event-related potential biomarker, and its reduction in schizophrenia is associated with the severity of clinical symptoms. While MMN recorded at the scalp is generated by a distributed network of temporofrontal neural sources, the primary contributing sources and the dynamic interactions among sources underlying MMN impairments in schizophrenia have not been previously characterized.

Methods: A novel data-driven analytic framework was applied to large cohorts of healthy comparison subjects (n = 449) and patients with schizophrenia (n = 589) to identify the independent contributing sources of MMN, characterize the patterns of effective connectivity underlying reduced MMN in patients, and explore the clinical significance of these abnormal source dynamics in schizophrenia.

A distributed frontotemporal network underlies gamma-band synchronization impairments in schizophrenia patients.

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.

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.