Individuals with schizophrenia (SZ) suffer from basic auditory processing deficits that may be at the root of more severe cognitive deficits. Neural correlates of auditory deficits can be recorded non-invasively using elec- troencephalography (EEG). For example, individuals with SZ show a blunted enhancement of responses for tones presented either after long periods of silence (N1 refractoriness) or after sequences of physically dis- tinct tones (mismatch negativity, MMN). Studies in healthy controls and SZ have linked both of these EEG markers to auditory behaviors that are impaired in SZ. The identification of a presumed homolog of N1 and MMN in macaque monkeys has established them as the most relevant animal model system for auditory defi- cits in SZ. However, since the initial groundbreaking reports in the 1990s, the monkey model has been studied only sporadically, leaving a rich resource untapped. Since the precise neural mechanisms that mediate N1 re- fractoriness and MMN are still poorly understood, this project will provide a detailed understanding of the un- derlying neural networks in order to provide a solid foundation to better understand auditory deficits in SZ. This project will employ a treatment-oriented research approach that views auditory function and neural correlates such as MMN as equally important components in identifying new treatment targets for auditory def- icits in SZ. Experiments will be performed in two stages. Stage one will consist of high-density extra-cranial rhesus EEG recordings over a wide range of passive listening paradigms used to study N1 refractoriness and MMN in humans. These studies will identify tasks and parameter ranges for which the two species show ho- mologous responses. Stage two will measure responses of different auditory regions in the superior temporal plane to assess their contribution to N1 refractoriness and MMN, as well as behaviors believed to be mediated by the underlying neural computations. These questions will be addressed with a new experimental approach that combines three established techniques ? monkey behavioral testing, EEG, and intracranial laminar record- ings/microinjections ? into a new functional unit that we refer to as `invasive EEG'. The invasive EEG experi- ments will measure EEG before and after modulating neural activity in a patch of auditory cortex while the ani- mals perform an auditory task that quantifies the detection of novel events in the auditory environment. The proposed project will establish a single, highly relevant model system that integrates two very promis- ing electrophysiological candidate bio-markers of auditory deficits in SZ (N1 refractoriness and MMN) with the associated behavioral deficit of delayed tone-discrimination. This system will then enable studies that can close the translational gap between electrophysiological correlates of the disease and the causal flow of information in the network that mediates the affected function/behavior and identify novel treatment targets.
Individuals with schizophrenia suffer from basic auditory deficits, which may be at the root of cognitive symptoms that prevent them from functioning effectively in the real world even after acute psychotic symptoms have been controlled. This project will establish a treatment-oriented translational research approach that fo- cuses on the neural mechanisms underlying auditory function in an animal model system. This will provide the foundation from which to explore new treatment approaches/targets for auditory deficits in schizophrenia.
| Holliday, William B; Gurnsey, Kate; Sweet, Robert A et al. (2018) A putative electrophysiological biomarker of auditory sensory memory encoding is sensitive to pharmacological alterations of excitatory/inhibitory balance in male macaque monkeys. J Psychiatry Neurosci 43:182-193 |
| Teichert, Tobias (2017) Loudness- and time-dependence of auditory evoked potentials is blunted by the NMDA channel blocker MK-801. Psychiatry Res 256:202-206 |
