Ricardo Gil-Da-Costa

There is growing evidence that impaired sensory-processing significantly contributes to the cognitive deficits found in schizophrenia. For example, the mismatch negativity (MMN) and P3a event-related potentials (ERPs), neurophysiological indices of sensory and cognitive function, are reduced in schizophrenia patients and may be used as biomarkers of the disease. In agreement with glutamatergic theories of schizophrenia, NMDA antagonists, such as ketamine, elicit many symptoms of schizophrenia when administered to normal subjects, including reductions in the MMN and the P3a. We sought to develop a nonhuman primate (NHP) model of schizophrenia based on NMDA-receptor blockade using subanesthetic administration of ketamine. This provided neurophysiological measures of sensory and cognitive function that were directly comparable to those recorded from humans. We first developed methods that allowed recording of ERPs from humans and rhesus macaques and found homologous MMN and P3a ERPs during an auditory oddball paradigm. We then investigated the effect of ketamine on these ERPs in macaques. As found in humans with schizophrenia, as well as in normal subjects given ketamine, we observed a significant decrease in amplitude of both ERPs. Our findings suggest the potential of a pharmacologically induced model of schizophrenia in NHPs that can pave the way for EEG-guided investigations into cellular mechanisms and therapies. Furthermore, given the established link between these ERPs, the glutamatergic system, and deficits in other neuropsychiatric disorders, our model can be used to investigate a wide range of pathologies.

Mental representation of objects and events is a fundamental component of our cognitive processes. The very act of thinking needs implicit content that can be acquired both by ontogeny, and by phylogeny through species evolution. Non-human primates produce a diverse repertoire of species-specific calls and have rich conceptual systems. These calls are designed to convey information about concepts such as predators, food, and social relationships, as well as the affective state of the caller, making vocal communication a powerful ‘tool’ to probe their conceptual representation system. We reported neurophysiological evidence for the evolution of the conceptual representation system. Our results indicate differential activation by categorical association with recall-related activity in higher-order visual areas by auditory meaningful stimuli. These areas included regions in the inferior temporal lobe associated with the visual perception of object form (TE/TEO) and motion (STS, MT) and in storing visual object information into long-term memory (TE). Brain patterns of selective activity were also found in limbic (the amygdala and hippocampus), and paralimbic regions (ventromedial prefrontal cortex) associated with the interpretation and memory encoding of highly salient and affective material and knowledge of conspecifics. This neural circuitry strongly corresponds to the network shown in humans. These findings advance our understanding on the evolution of conceptual representation and long-term memory systems, suggesting that monkeys and humans have a common neural substrate for representing object concepts. Moreover, we have found that such vocalizations, but not control stimuli, evoke distinct patterns of brain activity in ventrolateral frontal cortex (PmV) and Tpt, areas previously reported as the structural homologues of Broca’s and Wernicke’s, the human perisylvian language areas. The activation of these homologue areas may represent a way of coupling meaning encoded in sound to the more general conceptual system. These findings support the hypothesis that the common ancestor of macaques and humans, 25-30 million years ago already possessed the key neural mechanisms later exapted for the evolution of language. Lastly, the knowledge gained by the integration of findings in the macaque with correlated findings in humans should help us move towards the use of these primates as an animal model for human disorders in which the semantic system is affected.