Human fear conditioning and extinction in neuroimaging: a systematic review

Abstract

Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm. A Pubmed search, as of December 2008, was performed and supplemented by manual searches of bibliographies of key articles. Two independent reviewers made the final study selection and data extraction. A total of 46 studies on cued fear conditioning and/or extinction on healthy volunteers using positron emission tomography or functional magnetic resonance imaging were reviewed. The influence of specific experimental factors, such as contingency and timing parameters, assessment of conditioned responses, and characteristics of conditioned and unconditioned stimuli, on cerebral activation patterns was examined. Results were summarized descriptively. A network consisting of fear-related brain areas, such as amygdala, insula, and anterior cingulate cortex, is activated independently of design parameters. However, some neuroimaging studies do not report these findings in the presence of methodological heterogeneities. Furthermore, other brain areas are differentially activated, depending on specific design parameters. These include stronger hippocampal activation in trace conditioning and tactile stimulation. Furthermore, tactile unconditioned stimuli enhance activation of pain related, motor, and somatosensory areas. Differences concerning experimental factors may partly explain the variance between neuroimaging investigations on human fear conditioning and extinction and should, therefore, be taken into serious consideration in the planning and the interpretation of research projects.

Figure 1. QUOROM flow chart used to identify studies for review.

Figure 2. Brain areas involved in aversive conditioning and/or extinction.

Different brain areas (with at least unilateral activation during aversive conditioning and/or extinction) are plotted against the x-axis. The number of studies out of 46 studies per brain region is plotted against the y-axis, taking into account the conditioning design which is delay conditioning in 40, trace conditioning in two, delay and trace conditioning in four, and extinction in seven studies.

Figure 3. Brain areas involved in aversive conditioning according to the modality of the US.

Different brain areas (with at least unilateral activation during aversive conditioning) are plotted against the x-axis. The number of studies out of 46 studies per brain region is plotted against the y-axis, taking into account US modality, which is tactile in 33 studies (such as electrical shocks), auditory in nine studies (such as noise), olfactory in one study (such as odors), or visual in three studies (such as aversive pictures).

Figure 4. Number of studies employing an independent assessment of the conditioning process.

Different independent assessments of the conditioning process which may be autonomous (such as skin-conductance responses), or behavioral (such as verbal ratings), are plotted against the x-axis. The number of studies out of 46 studies per technique is plotted against the y-axis taking into account if the technique is applied online during scanning, offline after scanning or offline before and after scanning (pre/post).