Could Psychosis Arise From the Same Hippocampal Mechanisms That Support Creativity and Learning?

George Dragoi, MD, PhD, proposed that internally generated representations—representations of events or facts not currently present—unify episodic memory, planning, imagining, dreaming, and abstract inference, all of which appeared to depend critically on the hippocampus in humans and rodents. Abnormal internally generated representations were suggested to manifest as hallucinations and delusions, and schizophrenia was conceptualized as a state in which the brain generated representations not driven by external stimuli.

Bilateral hippocampal excision, originally performed for intractable epilepsy, left patients unable to form new memories and launched a large body of research on the role of the hippocampus in episodic memory formation.¹ Dragoi noted that the original report, published in 1957, also described patients with schizophrenia or bipolar disorder, a finding that was often not discussed. Most, if not all, of these patients showed diminished hallucinatory activity afterward, which indicated that the hippocampus participated in internally generated processes.

According to Dragoi, "psychosis like schizophrenia may be supported by the same mechanism that gives us creativity and rapid learning and imagining." The difference was proposed to lie in the balance among excitation, inhibition, connectivity, and neuromodulators.

His laboratory recorded large neuronal ensembles rather than single neurons to examine how neurons interact and form assemblies.² In an unpublished study, Dragoi said: "We injected ketamine in juvenile rats, and ketamine is known to be dissociative. And then we observed that the balance between excitation and inhibition in the hippocampus has been altered." Internally generated activity became more dominant than externally driven activity, which Dragoi described as a potential model of psychosis-like states, although exact interrogation was not possible in rodents. He suggested that the psychiatric research community could adopt similar tasks to study pharmacologically induced psychosis-like states at the network level, or as a basic phenomenon that could inspire new treatment research for psychosis.

Generative network processes had been correlated with learning to date, and blocking high-frequency oscillations, during which network reconfiguration appeared to occur, was an initial step toward establishing causality. Dragoi proposed combining optogenetics with electrophysiological recordings to clarify the role of these generative processes in learning, memory, and imagination.

Dr Dragoi is a professor of psychiatry and neuroscience at Yale University School of Medicine.

References

1. Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957;20(1):11-21.

2. Farooq U, Dragoi G. Emergence of preconfigured and plastic time-compressed sequences in early postnatal development. Science. 2019;363(6423):168-173.