Connectivity‐Based Real‐Time Functional Magnetic Resonance Imaging Neurofeedback in Nicotine Users: Mechanistic and Clinical Effects of Regulating a Meta‐Analytically Defined Target Network in a Double‐Blind Controlled Trial

One of the fundamental questions in real-time functional magnetic resonance imaging neurofeedback (rt-fMRI NF) investigations is the definition of a suitable neural target for training. Previously, we applied a meta-analytical approach to define a network-level target for connectivity-based rt-fMRI NF in substance use disorders. The analysis yielded consistent connectivity alterations between the insula and anterior cingulate cortex (ACC) as well as the dorsal striatum and the ACC. In the current investigation, we addressed the feasibility of regulating this network and its functional relevance using connectivity-based neurofeedback. In a double-blind, sham-controlled design, 60 nicotine users were randomly assigned to the experimental or sham control group for one NF training session. The preregistered primary outcome was defined as improved inhibitory control performance after regulation of the target network compared to sham control. Secondary outcomes were (1) neurofeedback-specific changes in functional connectivity of the target network; (2) changes in smoking behavior and impulsivity measures; and (3) changes in resting-state connectivity profiles. Our results indicated no differences in behavioral measures after receiving feedback from the target network compared to the sham feedback. Target network connectivity was increased during regulation blocks compared to rest blocks, however, the experimental and sham groups could regulate to a similar degree. Accordingly, the observed activation patterns may be related to the mental strategies used during regulation attempts irrespective of the group assignment. We discuss several crucial factors regarding the efficacy of a single-session connectivity-based neurofeedback for the target network. This includes high fluctuation in the connectivity values of the target network that may impact controllability of the signal. To our knowledge, this investigation is the first randomized, double-blind controlled real-time fMRI study in nicotine users. This raises the question of whether previously observed effects in nicotine users are specific to the neurofeedback signal or reflect more general self-regulation attempts.