Deep Brain Stimulation of the Ventromedial Prefrontal Cortex Disrupts Consolidation of Fear Memories

Abstract

Anxiety disorders pose one of the biggest threats to mental health worldwide, yet current therapeutics have been mostly ineffective due to issues with relapse, efficacy, and toxicit. Deep brain stimulation (DBS) is a promising therapy for treatment-resistant psychiatric disorders including anxiety, but very little is known about the effects of DBS on fear memories. In this study, we used a modified plus-maze discriminative and showed that DBS of the ventromedial prefrontal cortex (vmPFC) was able to disrupt consolidation, but not acquisition or retrieval of fear memories. We validated these results using a standard tone-footshock fear conditioning paradigm. We further demonstrated short-term changes in dopaminergic receptor and c-Fos expression in the ventral hippocampus (vHPC) and established a partial casual role of dopamine 2 receptors in this effect. Lastly, we showed changes in neurotransmitter levels in the vHPC. This study highlights the potential therapeutic effect of vmPFC DBS to treat anxiety disorders.

Dropout in Neural Networks Simulates the Paradoxical Effects of Deep Brain Stimulation on Memory

“…On the contrary, we found that dropout applied post training dramatically decreases the accuracy of prediction, which is similar to the disruption of memory seen when DBS was applied during consolidation of memory in our previous animal studies [6] (Fig 1D).…”

“…To the best of our knowledge, this paper is the first to suggest a cohesive mechanism in which disruption of neural activity through DBS can lead to both disruption and enhancement of memory. Although no behavioural experiments were performed in conjunction with our modelling, we based the models on our previous animal behavioural experiments that showed memory enhancement with DBS prior to the behavioural task [8] and memory disruption with DBS dur-ing consolidation of memory [6], which demonstrated similar results to the present paper.…”

“…This model showed similar results to our previous study of chronic mPFC DBS on memory enhancement [8] and suggests a potential mechanism for this process. An early hypothesis of the mechanism of DBS was that it creates a temporary neural activity lesion, and we further showed that prelimbic cortex DBS was associated with the disruption of memory and a drop in the neural activity marker c-fos in the ventral hippocampus [6]. Dropout of neural nodes, while congruent with the disruption of memory, has not played a major role in the mechanistic understanding of memory enhancement seen in DBS (though it should be noted that other mechanism such as neurogenesis and wave syncing have been suggested [3]).…”

“…We used CNNs (as opposed to a standard fully connected networks) in this study as they are commonly applied in image recognition tasks. Although CNNs are modelled on the visual cortex, dropout was only applied on fully connected latter layers in the network to represents dropouts applied in the hippocampus rather than the visual cortex, which mimic our previous experiments on the effects of prefrontal cortex stimulation on the hippocampus [6,8].…”

“…Neuromodulation techniques such as Deep Brain Stimulation (DBS) have shown promising results as treatments for such memory-related disorders [3,4], yet the mechanisms behind these effects are still largely unknown. Furthermore, the effects of treatments such as DBS appear to be paradoxical, in that they can both disrupt [5,6] and enhance memories [7,8], even when applied to the same brain target [3]. We have previously suggested that DBS is able to disrupt memory by "removing" nodes in an engram [4].…”