Trial of Stimulus-response Potentiation in Schizophrenia

Schizophrenia is a chronic psychiatric disorder with a lifetime prevalence of 4.0 per 1,000. The introduction of antipsychotic medications in the 1950s resulted in marked clinical improvement in the symptom profile of schizophrenia, nevertheless the disease still contributes to a significant proportion of global disease burden in terms of both morbidity and mortality. In this regard, cognitive deficits and residual negative symptoms are considered major contributing factors to psychosocial disability and poor functional outcome associated with the disorder. Higher-order cognitive functions; e.g. working memory and executive functions; show variable deficits and are considered a core clinical symptom of schizophrenia. On the other hand, the disorder is also characterized by abnormalities at the basic level of primary sensory processing, i.e. auditory, visual and somatosensory processing. Such abnormalities in the primary process of sensory perception could change the sensory experiences of schizophrenia patients and thus contribute to the psychopathology. Event-related potentials (ERPs) are the neurophysiological correlates of sensory processing. ERP abnormalities have been widely described in schizophrenia literature: Pre-pulse inhibition of startle (PPI) in which a weaker pre-stimulus (pre-pulse) inhibits the reaction to a subsequent strong startling stimulus (pulse) is impaired in schizophrenia. P50 suppression, a measure of sensory gating, is also often absent or reduced in the disorder. N100; a measure of basic auditory sensory perception; shows significant amplitude reduction in patients compared to controls. Mismatch negativity (MMN), a measure of automatic deviance detection and shows characteristic attenuation in schizophrenia. P300, which is involved in higher-level stimulus evaluation and categorization, also shows abnormalities along the disease course. In the study by Clapp et al., 2005, auditory high frequency stimulation (tetanizing stimulation) resulted in an increase in auditory-evoked potentials (AEPs) in healthy individuals; i.e. an increase in N1 amplitude that persisted even after stimulation. This augmentation of N1 amplitude was regarded as a result of plastic synaptic potentiation similar to long-term potentiation (LTP) described after electrical tetanic stimulation in cellular studies. Similar findings were later replicated by Lei et al., 2017, where they used pure tones, narrow band noises and white noise to induce stable potentiation and augmentation of N1 amplitude.