Sleep and REM sleep disturbance in the pathophysiology of PTSD: the role of extinction memory

Edward F Pace-Schott, Anne Germain, Mohammed R Milad, Edward F Pace-Schott, Anne Germain, Mohammed R Milad

Abstract

Post-traumatic stress disorder (PTSD) is accompanied by disturbed sleep and an impaired ability to learn and remember extinction of conditioned fear. Following a traumatic event, the full spectrum of PTSD symptoms typically requires several months to develop. During this time, sleep disturbances such as insomnia, nightmares, and fragmented rapid eye movement sleep predict later development of PTSD symptoms. Only a minority of individuals exposed to trauma go on to develop PTSD. We hypothesize that sleep disturbance resulting from an acute trauma, or predating the traumatic experience, may contribute to the etiology of PTSD. Because symptoms can worsen over time, we suggest that continued sleep disturbances can also maintain and exacerbate PTSD. Sleep disturbance may result in failure of extinction memory to persist and generalize, and we suggest that this constitutes one, non-exclusive mechanism by which poor sleep contributes to the development and perpetuation of PTSD. Also reviewed are neuroendocrine systems that show abnormalities in PTSD, and in which stress responses and sleep disturbance potentially produce synergistic effects that interfere with extinction learning and memory. Preliminary evidence that insomnia alone can disrupt sleep-dependent emotional processes including consolidation of extinction memory is also discussed. We suggest that optimizing sleep quality following trauma, and even strategically timing sleep to strengthen extinction memories therapeutically instantiated during exposure therapy, may allow sleep itself to be recruited in the treatment of PTSD and other trauma and stress-related disorders.

Keywords: Anxiety; Extinction; Insomnia; PTSD; REM sleep; Sleep; Stress.

Figures

Fig. 1
Fig. 1
The “anterior paralimbic REM activation area” overlaps with fear and extinction circuits. 18Fluoro-deoxyglucose PET image of areas that reactivate during REM sleep following relative quiescence during NREM sleep. Dashed lines surround approximate cortical regions commonly activated in experimental protocols during fear conditioning (yellow lines) and during recall of extinguished conditioned fear (white) based upon Milad and Rauch [61], Fig. 3. Solid lines encircle approximate anatomic loci of subcortical structures similarly activated during fear conditioning (yellow) and extinction recall (white). The anterior paralimbic REM activation area includes the amygdala (A), and regions of dorsal anterior cingulate (dACC) and insular (not shown) cortices linked to a putative fear expression network. Additionally, this region includes the ventromedial prefrontal (vmPFC) and hippocampal (H) areas [–129] linked to a putative extinction memory network
Fig. 2
Fig. 2
Possible pathway whereby sleep disruption accompanying acute response to trauma can lead to PTSD. In vulnerable individuals, acute post-traumatic insomnia can become chronic and disrupt processes of sleep-dependent emotional memory consolidation, thereby contributing to the etiology of PTSD. Chronic sleep disruption can subsequently perpetuate PTSD symptoms by continued interference with normal processing of emotional memories as well as impaired consolidation of therapeutic extinction memories if exposure therapy has been initiated. Stars indicate possible strategic points for sleep interventions to prevent PTSD onset or enhance exposure-based treatment
Fig. 3
Fig. 3
Hypothetical interactions among activated stress systems and disrupted sleep in PTSD. Note that multiple positive feedback loops result in depicted effects at any one node further driving effects at other nodes. Experimental evidence for many specific interactions depicted is provided in text. For clarity, the following mechanisms mentioned in the text are not depicted: 1) interaction between sympathetic activation and the HPA axis, 2) possible negative feedback mechanisms involving hypothalamic corticotropin releasing factor (CRF) that may explain hypocortisolemia in PTSD, and 3) direct effects of stress systems on extinction memory and habituation. The dashed line depicts an additional positive feedback mechanism whereby poor extinction memory promotes continued activation of neuroendocrine stress systems by failing to inhibit expression of conditioned fears. HPA hypothalamic-pituitary-adrenal, CRF corticotropin releasing factor, NE norepinephrine
Fig. 4
Fig. 4
Comparison of REM activations in individuals with insomnia versus without insomnia. When comparing REM to wake, there is a greater increase in regional cerebral glucose metabolism (18fluoro-deoxyglucose PET) in an anterior midline region in close proximity to the region of the dACC that has been associated with fear expression (a). However, in a comparison of two different groups, the insomnia group showed lesser increase in the vmPFC, an area associated with the memory and expression of fear extinction (b)

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