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

Abstract

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.

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

“…Developing effective treatments for the hallmark cognitive symptoms of SZ continues to be one of the more daunting challenges in psychiatric neuroscience. While antipsychotic medications provide modest relief of the more dramatic, but "secondary" symptoms (e.g., hallucinations and delusions) of SZ 56 , the core cognitive symptoms persist and cause profound disability and loss of functioning for many patients 30,57,58 . Auditory-based TCT is a promising approach to cognitive remediation, although considerable interindividual variability in treatment response has limited the translation of TCT from academic laboratories to real-world community settings.…”

“…In the ASSR paradigm, stimulus trains of amplitude-modulated tones or clicks presented at a rate of 40-Hz-drive oscillatory power and synchrony across a distributed thalamocortical network [22][23][24][25] . ASSR deficits in gamma oscillatory power and synchrony are well characterized in SZ 16,17,19 and have been linked to pathophysiologic and phenomenological dimensions of psychotic disorders 12,22,[26][27][28][29][30] and other neuropsychiatric conditions.…”

Gamma-Range Auditory Steady-State Responses and Cognitive Performance: A Systematic Review

“…The main ASSR outcome measures were power and phase synchronization/consistency; two studies provided signal-to-noise ratio evaluations [ 60 , 62 ], and one study provided individual gamma peak frequencies [ 58 ]. Most studies focused on the evaluation of the response during the entire stimulation duration [ 43 , 55 , 59 , 62 , 63 , 64 , 65 , 66 , 67 , 69 , 72 , 75 ]. Rass et al, Sun et al, and Gaskins et al did not include the early response (0–100 ms) part [ 60 , 73 , 74 , 76 ].…”

“…Three of the studies utilized MEG recordings [ 68 , 70 , 75 ]. EEG recordings in the selected reports were either performed with the nose serving as a reference, or electrodes were average referenced [ 44 , 63 , 65 , 66 , 67 , 72 , 76 ]. The EEG results were reported mostly for fronto-central locations, with the exception of van Deursen et al and Hirtum et al, who analyzed temporal and temporoparietal locations [ 55 , 62 ].…”

“…To increase transparency and allow for future meta-analytical studies, it is advisable that the authors fully report on statistics for nonsignificant effects. The power of most studies was only sufficient to detect correlations higher than 0.50, with the exception of Kirihara et al [ 67 ] and Koshiyama et al [ 65 , 66 , 67 ], who performed their analyses on large samples, and thus were able to detect even correlations in the range of 0.10–0.20. Therefore, it is difficult to estimate the real strength of the relationship between ASSR and different cognitive domains.…”