Introduction: The hormone and neuropeptide oxytocin (OT) is suggested to be a crucial chemical modulator of social behavior, and exogenous intranasal oxytocin administration has been proposed as a potential treatment for affective and social deficits. Animal studies have found that repeated administration of OT induced cellular changes in the brain, particularly in the hippocampus complex (Sanchez-Vidana et al., 2016). To test this modulatory role of OT on brain structure in humans, we pooled data from three independent double-blind placebo-controlled OT studies that included structural magnetic resonance imaging (MRI), one study with repeated doses over time (repeated) and two studies with single dose (acute) oxytocin administration.

Methods: The first analytic step included data from 25 older individuals (61-84y) who were exposed to four weeks of intranasal (24 IUs twice a day) administration of OT or placebo (P) and who underwent 3T-MRI before and after this intervention. The second analytic step included data from a total of 191 younger (18-31y) and older (63-81y) individuals from two similar studies administering a single-dose of OT (24 and 40 IUs respectively) and a single 3T-MRI session (scanning was performed about 40 minutes after the OT or P administration). Grey matter (GM) volume was assessed on T1-weighted anatomical images using automated tools (i.e., CAT12/SPM12). We applied total intracranial volume, sex, and education as covariates of no interest and hippocampus voxel-wise analyses were small volume corrected with a family-wise error (FWE) to determine statistical significance. A portion of the analyses were performed blindly, i.e., the researchers were not aware of the assigned group labels (OT vs. P).

Results: First, a group x time interaction (xyz[–16,–10,–22], Z=4.40, pFWE=.005) suggested that repeated administration of OT in older adults showed no significant change in left hippocampal GM volume (trend toward increase), whereas the P group showed significant reduction in left hippocampal GM volume over time. Second, the acute effect of a single dose of OT showed reduction in left hippocampal GM volume after OT relative to P administration (xyz[–22,–12,–22], Z=2.96, pFWE=.023), i.e. the acute findings were reversed within the same hippocampal region compared to the findings after repeated administration.

Conclusions: These results provide first evidence of an opposite effect in hippocampus GM volume after acute and repeated administration of OT. This points towards a potential mechanism wherein hippocampal GM volume shows rapid reduction after a single dose, but stable (and potentially greater) GM volume after repeated exposure to OT. Thus, hippocampus may be a key target of OT's modulatory potential on the human brain. Future studies should assess both acute and long-lasting effects of OT administration on brain structures and links to behavior, affect, and quality of life. This approach could advance our understanding of the neurobiological mechanisms of OT as a potential treatment for affective and social deficits.