Schizophrenia: from neurochemistry to circuits, symptoms and treatments.

Schizophrenia is a leading cause of global disability. Current pharmacotherapy for the disease predominantly uses one mechanism - dopamine D2 receptor blockade - but often shows limited efficacy and poor tolerability. These limitations highlight the need to better understand the aetiology of the disease to aid the development of alternative therapeutic approaches. Here, we review the latest meta-analyses and other findings on the neurobiology of prodromal, first-episode and chronic schizophrenia, and the link to psychotic symptoms, focusing on imaging evidence from people with the disorder. This evidence demonstrates regionally specific neurotransmitter alterations, including higher glutamate and dopamine measures in the basal ganglia, and lower glutamate, dopamine and γ-aminobutyric acid (GABA) levels in cortical regions, particularly the frontal cortex, relative to healthy individuals. We consider how dysfunction in cortico-thalamo-striatal-midbrain circuits might alter brain information processing to underlie psychotic symptoms. Finally, we discuss the implications of these findings for developing new, mechanistically based treatments and precision medicine for psychotic symptoms, as well as negative and cognitive symptoms.

Hippocampal activity predicts contextual misattribution of false memories.

Failure of contextual retrieval can lead to false recall, wherein people retrieve an item or experience that occurred in a different context or did not occur at all. Whereas the hippocampus is thought to play a crucial role in memory retrieval, we lack understanding of how the hippocampus supports retrieval of items related to a target context while disregarding related but irrelevant information. Using direct electrical recordings from the human hippocampus, we investigate the neural process underlying contextual misattribution of false memories. In two large datasets, we characterize key physiological differences between correct and false recalls that emerge immediately prior to vocalization. By differentiating between false recalls that share high or low contextual similarity with the target context, we show that low-frequency activity (6 to 18 Hz) in the hippocampus tracks similarity between the current and retrieved context. Applying multivariate decoding methods, we were able to reliably predict the contextual source of the to-be-recalled item. Our findings elucidate one of the hallmark features of episodic memory: our ability to distinguish between memories that were formed on different occasions.

Overnight transdermal scopolamine patch administration has no clear effect on cognition and emotional processing in healthy volunteers.

There has been increasing interest in the antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine. Here we assess, for the first time, whether a transdermal scopolamine patch is sufficient to induce changes in cognition that are consistent with the reported cognitive and antidepressant effects of scopolamine. A scopolamine or placebo patch was administered to healthy volunteers ( n=33) for 17 h in a double-blind, between-subject procedure. There was no clear effect of scopolamine patch on emotional cognition, verbal or working memory, suggesting that the effective dose of scopolamine available through the patch is too low to represent a viable antidepressant mechanism.