Scientists from Cambridge have identified specific brain circuitry in primates that, when disrupted, reduces motivation and increases anxiety — symptoms closely linked to depression. The findings, published today in Science, offer new insights into how therapies like transcranial magnetic brain stimulation (TMS) and ketamine may work.
Joint first authors, senior scientist, Dr Christian Wood and PhD student, Rana Banai-Tizkar, in the laboratory of Professor Angela Roberts, used advanced chemogenetic techniques to temporarily inactivate Area 46 of the dorsolateral prefrontal cortex (dlPFC) and associated pathways in marmoset monkeys.
dlPFC is a target for TMS therapy for depression in patients that have proven treatment resistant to other more conventional treatments such as SSRIs or psychological therapies. But we currently have very little understanding of the brain mechanisms by which TMS in this region works.
Christian Wood
To address this, the researchers acutely reduced activity in this region which resulted in a drop in the marmosets’ willingness to work for a treat and at the same time heightened their sensitivity to perceived threats — two hallmark features of depression and anxiety.
Monkeys are a good model for studying Area 46 because this region is present in both humans and non-human primates but has not been identified in other species such as rodents, which are the most commonly used species for experimental brain research.
By studying the projections from Area 46 the researchers then revealed that these behaviours were regulated by distinct brain pathways: motivation through projections to Area 32, and anxiety through projections to ventral Area 32.
“Neuroimaging in humans has suggested that TMS in dlPFC is most successful in those patients in which there is anti-correlated activity in another nearby brain region, the subcallosal anterior cingulate cortex (scACC), itself, also a therapeutic target for treatment resistant depression. This led us to ask the question whether the motivational deficits of inactivating Area 46 could be ameliorated by targeting scACC” said Professor Roberts, a researcher in the University of Cambridge’s Dept of Physiology, Development and Neuroscience, in whose laboratory the research was performed.
The researchers targeted Area 25 within scACC as they had shown in a previous study that increasing activity in Area 25 not only reduced motivation for reward, similar to that seen when reducing activity in Area 46, but also caused reciprocal activity changes in Area 46, as well as being reciprocally connected with Area 32.
Remarkably, administering ketamine, a fast-acting antidepressant and anxiolytic, directly into Area 25 restored normal motivational behaviour.
The researchers have also uncovered that the effects on motivation and anxiety are lateralised, dependent on the left hemisphere only, mirroring the selective targeting of this hemisphere in therapies such as TMS.
Roberts said “We hope that by careful mapping of the specific brain circuits involved in motivation and anxiety, and identifying the circuits responsive to antidepressants, this work can help refine and personalise future treatments for depression — particularly in cases where symptoms like anhedonia, the loss of pleasure, and anxiety, show resistance to standard therapies”.
The research was funded by the Wellcome Trust and the Medical Research Council of Great Britain.
Reference
Wood CM, Banai Tizkar R, Fort M, Zhang X, Mulvihill KG, Liao N, Cockcroft GJ, McIver LB, Sawiak SJ, Roberts AC Dysfunction in primate dorsolateral prefrontal area 46 affects motivation and anxiety. Science, August 2025. DOI https://doi.org/10.1126/science.adx4142
Typogram of a marmoset face in profile constructed with words describing the behavioural effects of reduced activity in dorsolateral prefrontal area 46 and the insights the study provides into how depression therapies such as TMS and Ketamine work.
Image credit: Original designed by Nicole Horst, adapted by Adrian Newman
Posted on 21/08/2025
