Depressive symptoms reduce when dorsolateral prefrontal cortex-precuneus connectivity normalizes after functional connectivity neurofeedback.

Depressive disorders contribute heavily to global disease burden; This is possibly because patients are often treated homogeneously, despite having heterogeneous symptoms with differing underlying neural mechanisms. A novel treatment that can directly influence the neural circuit relevant to an individual patient's subset of symptoms might more precisely and thus effectively aid in the alleviation of their specific symptoms. We tested this hypothesis in a proof-of-concept study using fMRI functional connectivity neurofeedback. We targeted connectivity between the left dorsolateral prefrontal cortex/middle frontal gyrus and the left precuneus/posterior cingulate cortex, because this connection has been well-established as relating to a specific subset of depressive symptoms. Specifically, this connectivity has been shown in a data-driven manner to be less anticorrelated in patients with melancholic depression than in healthy controls. Furthermore, a posterior cingulate dominant state-which results in a loss of this anticorrelation-is expected to specifically relate to an increase in rumination symptoms such as brooding. In line with predictions, we found that, with neurofeedback training, the more a participant normalized this connectivity (restored the anticorrelation), the more related (depressive and brooding symptoms), but not unrelated (trait anxiety), symptoms were reduced. Because these results look promising, this paradigm next needs to be examined with a greater sample size and with better controls. Nonetheless, here we provide preliminary evidence for a correlation between the normalization of a neural network and a reduction in related symptoms. Showing their reproducibility, these results were found in two experiments that took place several years apart by different experimenters. Indicative of its potential clinical utility, effects of this treatment remained one-two months later.Clinical trial registration: Both experiments reported here were registered clinical trials (UMIN000015249, jRCTs052180169).

How do we generalize?

Humans and animals are able to generalize or transfer information from previous experience so that they can behave appropriately in novel situations. What mechanisms-computations, representations, and neural systems-give rise to this remarkable ability? The members of this Generative Adversarial Collaboration (GAC) come from a range of academic backgrounds but are all interested in uncovering the mechanisms of generalization. We started out this GAC with the aim of arbitrating between two alternative conceptual accounts: (1) generalization stems from integration of multiple experiences into summary representations that reflect generalized knowledge, and (2) generalization is computed on-the-fly using separately stored individual memories. Across the course of this collaboration, we found that-despite using different terminology and techniques, and although some of our specific papers may provide evidence one way or the other-we in fact largely agree that both of these broad accounts (as well as several others) are likely valid. We believe that future research and theoretical synthesis across multiple lines of research is necessary to help determine the degree to which different candidate generalization mechanisms may operate simultaneously, operate on different scales, or be employed under distinct conditions. Here, as the first step, we introduce some of these candidate mechanisms and we discuss the issues currently hindering better synthesis of generalization research. Finally, we introduce some of our own research questions that have arisen over the course of this GAC, that we believe would benefit from future collaborative efforts.