Return Of Conditioned Responses Research Articles

‘Nip it in the bud’: Low-frequency rTMS of the prefrontal cortex disrupts threat memory consolidation in humans

It is still unclear how the human brain consolidates aversive (e.g., traumatic) memories and whether this process can be disrupted. We hypothesized that the dorsolateral prefrontal cortex (dlPFC) is crucially involved in threat memory consolidation. To test this, we used low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) within the memory stabilization time window to disrupt the expression of threat memory. We combined a differential threat-conditioning paradigm with LF-rTMS targeting the dlPFC in the critical condition, and occipital cortex stimulation, delayed dlPFC stimulation, and sham stimulation as control conditions. In the critical condition, defensive reactions to threat were reduced immediately after brain stimulation, and 1 h and 24 h later. In stark contrast, no decrease was observed in the control conditions, thus showing both the anatomical and temporal specificity of our intervention. We provide causal evidence that selectively targeting the dlPFC within the early consolidation period prevents the persistence and return of conditioned responses. Furthermore, memory disruption lasted longer than the inhibitory window created by our TMS protocol, which suggests that we influenced dlPFC neural activity and hampered the underlying, time-dependent consolidation process. These results provide important insights for future clinical applications aimed at interfering with the consolidation of aversive, threat-related memories.

Extinction and spontaneous recovery of ataxic tolerance to ethanol in rats.

Two experiments with rats using an ethanol ataxia method investigated extinction and spontaneous recovery of tolerance. Tolerance extinction has been shown with a variety of drugs and methods, but until now it has not been shown with ethanol ataxia. Extinction was investigated here because of its connection with cue exposure treatments, and also to allow an assessment of spontaneous recovery. Spontaneous recovery is the return of conditioned responses, such as those potentially contributing to tolerance, when time passes after extinction. In terms of response topography it resembles instances of relapse in humans. Its demonstration constitutes one technique for illustrating that the effects of extinction are often temporary. There are no published reports showing a recovery of tolerance to any drug due to the passage of time after extinction. A demonstration of spontaneous recovery contributes to an understanding of the effects and time course of tolerance extinction. It also raises the possibility that spontaneous recovery involving drug tolerance has mechanisms similar those involved in instances of spontaneous recovery studied more extensively with non-drug methods. In one experiment, ataxic tolerance was conditioned to a strobelight conditioned stimulus (CS) by exposing rats to the strobelight while experiencing the effects of an ethanol injection. Tolerance was extinguished in 17 or 24 once-daily trials by presenting the strobelight without ethanol (with saline). The effect of those numbers of trials was assessed on the day after extinction in the presence of the strobelight when ethanol was again injected. The effect was compared to the effect of the strobelight and ethanol in naive rats and in rats that had received only tolerance conditioning. In a second experiment, ataxic tolerance was conditioned and then extinguished over 17 trials, just as in the other experiment. Different groups were then tested 1, 12, 18, and 24 days after extinction in the presence of the strobelight when ethanol was again injected. Ataxic tolerance was fully extinguished after either 17 or 24 trials, as shown by comparisons with the naive and conditioning-only controls. Tolerance was greater (it recovered) when the strobelight CS was reintroduced 24, 18, and even 12 days after extinction, compared with testing 1 day after extinction. Conditioned ataxic tolerance can be extinguished, just as other conditioned tolerances can. More important, the return of tolerance over time after extinction represents spontaneous recovery of ethanol tolerance, and indicates that as in other conditioning preparations, extinction does not result in unlearning of the original conditioning association. The identification of spontaneous recovery of tolerance isolates a robust source of the potential for drug use relapse: the mere passage of time after extinction.