a b s t r a c tWe propose an explanatory and computational theory of transformative discoveries in science. The theory is derived from a recurring theme found in a diverse range of scientific change, scientific discovery, and knowledge diffusion theories in philosophy of science, sociology of science, social network analysis, and information science. The theory extends the concept of structural holes from social networks to a broader range of associative networks found in science studies, especially including networks that reflect underlying intellectual structures such as co-citation networks and collaboration networks. The central premise is that connecting otherwise disparate patches of knowledge is a valuable mechanism of creative thinking in general and transformative scientific discovery in particular. In addition, the premise consistently explains the value of connecting people from different disciplinary specialties. The theory not only explains the nature of transformative discoveries in terms of the brokerage mechanism but also characterizes the subsequent diffusion process as optimal information foraging in a problem space. Complementary to epidemiological models of diffusion, foraging-based conceptualizations offer a unified framework for arriving at insightful discoveries and optimizing subsequent pathways of search in a problem space. Structural and temporal properties of potentially high-impact scientific discoveries are derived from the theory to characterize the emergence and evolution of intellectual networks of a field. Two Nobel Prize winning discoveries, the discovery of Helicobacter pylori and gene targeting techniques, and a discovery in string theory demonstrated such properties. Connections to and differences from existing approaches are discussed. The primary value of the theory is that it provides not only a computational model of intellectual growth, but also concrete and constructive explanations of where one may find insightful inspirations for transformative scientific discoveries.

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum-and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.antidepressants | hypothalamus-pituitary-adrenal axis | stem cells | neuroplasticity

All antidepressant classes are associated with a withdrawal syndrome. SSRI withdrawal syndrome occurs often and can be severe, and may compel patients to re-commence their medication. Although the withdrawal syndrome can be differentiated from recurrence of the underlying disorder, it may also be mistaken for recurrence, leading to long-term unnecessary medication. Authorities currently recommend short tapers, of between two to four weeks, down to therapeutic minimum, or half minimum doses before complete cessation. Studies have demonstrated that these tapers show minimal benefit over abrupt discontinuation, and are often not tolerated by patients. Tapers over months and down to doses significantly lower than minimum therapeutic doses have shown greater success rates. Other medications associated with withdrawal symptoms are tapered to reduce their biological effect at receptors by fixed amounts in order to minimise withdrawal effects. These are exponential tapering programmes which reduce to very small doses. We examined the PET imaging data of serotonin transporter occupancy by SSRIs to demonstrate that hyperbolically reducing doses of SSRI will reduce their effect on serotonin transporter inhibition in a linear manner. We therefore suggest that SSRIs are tapered hyperbolically and slowly to doses much lower than therapeutic minimums, in line with tapering regimes for other medications associated with withdrawal symptoms. Withdrawal symptoms will then be minimised.

The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.