Electrophysiological Markers of Short-term Visual Adaptation: An Examination Across the Schizophrenia Spectrum

The experiments comprising this dissertation sought to contribute to the understanding of basic sensory processing in schizophrenia-spectrum disorders and risk-liability. We leveraged the sensitivity of visual processing deficits along with widely reported sensory-gating deficits (in other modalities) to develop a new paradigm assaying short-term visual adaptation to repetitive stimuli. In the first experiment, adaptation properties of the visual system were characterized in neurotypical adults using a classic paired adaptation paradigm and a more taxing block adaptation paradigm, using high-density EEG. In the second experiment, we deployed our new visual adaptation assay in a clinical population. We replicated classic early VEP amplitude attenuation and uncovered novel visual adaptation deficits in participants diagnosed with a schizophrenia-spectrum disorder. We further tested the specificity of these findings by employing a somatosensory analog to the block adaptation paradigm utilizing vibrotactile stimulation of the median nerve. Differences in basic somatosensory function and adaptation were present in the clinical group although less apparent than in the visual system. In the third experiment, we examined whether altered visual adaptation could serve as a schizophrenia endophenotype. We utilized a shortened version of our visual adaptation paradigm (15mins, 32-channel electrode array) to characterize a larger sample of neurotypical adults who were also assessed using the Schizotypal Personality Questionnaire (SPQ). Multiple regression analysis revealed a significant relationship between high SPQ and less sensitive VEP adaptation. Overall the findings across these studies provide strong support for atypical visual adaptation in schizophrenia and suggest a potential role for altered visual adaptation as an electrophysiological schizophrenia endophenotype. Future studies employing pharmacological manipulations (e.g. administering nicotinic treatment or dopamine/glutamate/GABA agonists) and examining first degree relatives of patients may offer greater mechanistic insight into the processes underlying these observed phenomena

Atypical multisensory integration in Niemann-Pick type C disease – towards potential biomarkers

Background: Niemann-Pick type C (NPC) is an autosomal recessive disease in which cholesterol and glycosphingolipids accumulate in lysosomes due to aberrant cell-transport mechanisms. It is characterized by progressive and ultimately terminal neurological disease, but both pre-clinical studies and direct human trials are underway to test the safety and efficacy of cholesterol clearing compounds, with good success already observed in animal models. Key to assessing the effectiveness of interventions in patients, however, is the development of objective neurobiological outcome measures. Multisensory integration mechanisms present as an excellent candidate since they necessarily rely on the fidelity of long-range neural connections between the respective sensory cortices (e.g. the auditory and visual systems). Methods: A simple way to test integrity of the multisensory system is to ask whether individuals respond faster to the occurrence of a bisensory event than they do to the occurrence of either of the unisensory constituents alone. Here, we presented simple auditory, visual, and audio-visual stimuli in random sequence. Participants responded as fast as possible with a button push. One 11-year-old and two 14-year-old boys with NPC participated in the experiment and their results were compared to those of 35 age-matched neurotypical boys. Results: Reaction times (RTs) to the stimuli when presented simultaneously were significantly faster than when they were presented alone in the neurotypical children, a facilitation that could not be accounted for by probability summation, as evidenced by violation of the so-called ‘race’ model. In stark contrast, the NPC boys showed no such speeding, despite the fact that their unisensory RTs fell within the distribution of RTs observed in the neurotypicals. Conclusions: These results uncover a previously undescribed deficit in multisensory integrative abilities in NPC, with implications for ongoing treatment of the clinical symptoms of these children. They also suggest that multisensory processes may represent a good candidate biomarker against which to test the efficacy of therapeutic interventions