Effects of sleep on memory for conditioned fear and fear extinction.

“This time-of-day effect could be due to either or both elements of the Two-Process model of sleep propensity (Borbely, 1982)—circadian rhythms (Process C: controlled by the endogenous 24-h clock) or sleep homeostasis (Process S: controlled by duration of prior waking).”

“…are transferred to more permanent storage in the cortex during slow wave sleep (SWS), is a key tenet of explanatory theories on sleep dependent consolidation of declarative memory (Diekelmann & Born, 2010; Diekelmann et al., 2009; Hobson & Pace-Schott, 2002; Rasch & Born, 2013; Stickgold, 2005).”

“…which the most generalized function has been suggested to be predicting the value of exerting effort and control (Shenhav, Botvinick, & Cohen, 2013) but, In the emotional domain, has been increasingly implicated in negative emotional responses (Etkin, Egner, & Kalisch, 2011; Etkin & Wager, 2007).”

“Such vmPFC regions include the subgenual anterior cingulate cortex, an area homologous to the rat IL (Ongur, Ferry, & Price, 2003; Phelps & LeDoux, 2005; Vertes, 2004, 2006).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript slow wave sleep (Skaggs & McNaughton, 1996; Wilson & McNaughton, 1994) in a compressed time frame (Nadasdy, Hirase, Czurko, Csicsvari, & Buzsaki, 1999).”

“Hippocampus-dependent tasks have, in turn, been those most clearly linked with the NREM-sleep oscillatory activity such as percent SWS, sleep spindles, sharp-wave ripple events and the < 1Hz slow oscillation (Diekelmann & Born, 2010; Rasch & Born, 2013).”

“Importantly, there is high comorbidity of insomnia with mood and anxiety disorders (Alvaro, Roberts, & Harris, 2013; Baglioni et al., 2011; Riemann, 2007; Stepanski & Rybarczyk, 2006) and evidence that, in some cases, insomnia itself can be preexisting risk factor for incident anxiety disorders (Breslau, Roth, Rosenth…”

“As in other mammals, the human amygdala is involved in the affective labeling of stimuli particularly fear (Janak & Tye, 2015) and interacts continuously with the hippocampus in processing emotional aspects of episodic memories (Fanselow & Dong, 2010; McGaugh, 2004).”

“Recently, these findings have been augmented by a rapidly expanding literature on functional neuroimaging of extinction in healthy individuals and those with psychiatric disorders (reviewed in Milad & Quirk, 2012; Milad & Rauch, 2012; Shin & Liberzon, 2010).”

“As in other mammals, the human amygdala is involved in the affective labeling of stimuli particularly fear (Janak & Tye, 2015) and interacts continuously with the hippocampus in processing emotional aspects of episodic memories (Fanselow & Dong, 2010; McGaugh, 2004).”

“…are transferred to more permanent storage in the cortex during slow wave sleep (SWS), is a key tenet of explanatory theories on sleep dependent consolidation of declarative memory (Diekelmann & Born, 2010; Diekelmann et al., 2009; Hobson & Pace-Schott, 2002; Rasch & Born, 2013; Stickgold, 2005).”

“…cortex (IL) is necessary for the consolidation and retrieval of extinction memory in the rat (Herry et al., 2010; Lebron, Milad, & Quirk, 2004; Milad & Quirk, 2002, 2012; Milad, Rauch, Pitman, & Quirk, 2006; Milad, Vidal-Gonzalez, & Quirk, 2004; Quirk, Garcia, & Gonzalez-Lima, 2006; Quirk &…”

“(2) Renewal: The CR returns when the extinguished CS is presented in a context differing from the context within which extinction occurred (Bouton, 2002, 2004; Bouton et al., 2006; Milad, Orr, Pitman, & Rauch, 2005; Vervliet, Baeyens, Van den Bergh, & Hermans, 2013).”

“For example, Phelps et al. (2004) showed that, whereas amygdala activity correlated with SCR during fear conditioning and initial extinction, delayed recall of extinction memory (tested 24 hours after fear conditioning and initial extinction) was correlated with activity in the subgenual anterior…”

“(2) Renewal: The CR returns when the extinguished CS is presented in a context differing from the context within which extinction occurred (Bouton, 2002, 2004; Bouton et al., 2006; Milad, Orr, Pitman, & Rauch, 2005; Vervliet, Baeyens, Van den Bergh, & Hermans, 2013).”

“…sections (for more extensive reviews, see: Graham & Milad, 2011; Herry et al., 2010; Maren, 2011; Maren, Phan, & Liberzon, 2013; Maren & Quirk, 2004; Milad & Quirk, 2012; Milad & Rauch, 2012; Myers & Davis, 2007; Pape & Pare, 2010; Quirk & Mueller, 2008; Sotres-Bayon, Cain, & LeDoux, 2006).”

“The ability to remember fear extinction is key to the treatment of PTSD and other anxiety disorders treated using exposure therapy (Craske et al., 2008; Hermans et al., 2006; McNally, 2007).”

“…to the view that sleep disturbances, rather than being secondary to the development of PTSD, may play a key role in the etiology of this disorder (Alvaro et al., 2013; Babson, Badour, Feldner, & Bunaciu, 2012; Babson, Blonigen, Boden, Drescher, & Bonn-Miller, 2012; Babson & Feldner, 2010;…”

“Such vmPFC regions include the subgenual anterior cingulate cortex, an area homologous to the rat IL (Ongur, Ferry, & Price, 2003; Phelps & LeDoux, 2005; Vertes, 2004, 2006).”

“Human studies of fear conditioning and extinction have generally used skin conductance response (SCR), a reliable measure of sympathetic activation (Milad & Quirk, 2012), or fear potentiation of the blink startle response (Grillon & Baas, 2003; Jovanovic & Ressler, 2010) as psychophysiological CR…”

“When extinction is recalled, the IL activates gamma-aminobutyric acid (GABA)-ergic circuits within the amygdala that inhibit output from its central nucleus (CeA) to autonomic and brainstem circuits controlling fearful behavior (Maren & Quirk, 2004; Pape & Pare, 2010; Quirk & Mueller, 2008).”

“…and functional abnormalities in limbic regions associated with extinction recall including the perigenual anterior cingulate, amygdala and hippocampus (Milad et al., 2013; Milad et al., 2008; Milad, Pitman, et al., 2009; Milad, Rauch, et al., 2006; Rauch et al., 2006; Shin, Rauch, & Pitman, 2006).”

“…case is the fact that, in this same group, individuals with later timing of sleep (later midpoint) and greater subjective “eveningness” (reviewed in Adan et al., 2012) showed an exaggerated time-ofday effect in the evening (i.e., yet poorer generalization of extinction memory), whereas those…”

“…sections (for more extensive reviews, see: Graham & Milad, 2011; Herry et al., 2010; Maren, 2011; Maren, Phan, & Liberzon, 2013; Maren & Quirk, 2004; Milad & Quirk, 2012; Milad & Rauch, 2012; Myers & Davis, 2007; Pape & Pare, 2010; Quirk & Mueller, 2008; Sotres-Bayon, Cain, & LeDoux, 2006).”

“, 1996), basal ganglia (Braun et al., 1997), amygdala (Maquet et al.”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Maren, 2011; Monfils, Cowansage, Klann, & LeDoux, 2009; Quirk et al., 2010; Schiller & Delgado, 2010; Schiller et al., 2010).”

“…synaptic level, evidence exists that NREM slow-wave sleep can lead to either the potentiation via LTP-like processes (Abel et al., 2013) or de-potentiation (Tononi, 2009; Tononi & Cirelli, 2003) of excitatory cortical synapses (the latter being a key tenet of the “synaptic homeostasis hypothesis”).”

“Milad et al. (2007) suggested that contextual information, resulting from differentiation of the conditioning and extinction contexts, was represented by such hippocampal activity.”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript slow wave sleep (Skaggs & McNaughton, 1996; Wilson & McNaughton, 1994) in a compressed time frame (Nadasdy, Hirase, Czurko, Csicsvari, & Buzsaki, 1999).”

“, 1997), as well as limbic cortices including rostral and subcallosal anterior cingulate (Braun et al., 1997; Maquet et al., 1996), anterior insula, caudal orbitofrontal, paracingulate [Brodmann Area (BA) 32], medial prefrontal cortex (BA10) (Braun et al.”

“Introduction Two research domains of intense and growing interest in biological psychology are the study of fear extinction (Graham & Milad, 2011; Milad & Quirk, 2012) and that of sleep dependent memory consolidation (Rasch & Born, 2013; Walker & Stickgold, 2006).”

“, 2007) whereas it was reduced in the vmPFC (Thomas et al., 2000; Yoo, Gujar, et al., 2007), a region known to inhibit expression of negative emotion (Diekhof, Geier, Falkai, & Gruber, 2011) as well as express extinction memory (Milad & Quirk, 2012).”

“…wave co-occurring with a rapid approximately 200 Hz oscillation) that arise in the CA3 field of the hippocampus (Siapas, Lubenov, & Wilson, 2005; Siapas & Wilson, 1998) is widely believed to represent a mechanism whereby sleep promotes such hippocampal-neocortical memory transfer (Abel,…”

“…components that could be classified, respectively, as declarative versus (potentially) implicit, hippocampusdependent versus amygdala-dependent, or, as in the case of the SRSF model, the declarative memory itself versus its affective “charge” (Goldstein & Walker, 2014; Walker & van der Helm, 2009).”

“…experimental paradigms that test effects of sleep on emotional memory by eliciting both recognition memory and subjective ratings of stimulus valence (e.g., Baran et al., 2012; Nishida, Pearsall, Buckner, & Walker, 2009; van der Helm et al., 2011) are, of necessity, testing a compound stimulus.”

“Although the plasticity associated with learning and storage of fear extinction also occurs within the BLA (Pape & Pare, 2010), the infralimbic prefrontal cortex (IL) is necessary for the consolidation and retrieval of extinction memory in the rat (Herry et al., 2010; Lebron, Milad, & Quirk, 2004;…”

“For example, the widely accepted model of hippocampal-neocortical dialog (Buzsaki, 1996), proposing that memories initially encoded in the hippocampus are transferred to more permanent storage in the cortex during slow wave sleep (SWS), is a key tenet of explanatory theories on sleep dependent…”

“…activation is modulated primarily by acetylcholine (ACh) rather than the complex aminergic, cholinergic and peptidergic activation of wakefulness (Pace-Schott & Hobson, 2002), is believed to impact the way in which memories are processed during this sleep stage (Stickgold et al., 2001; Stickgold…”

“…formation of a new memory that competitively inhibits the memory of the CS−US contingency when the CS is subsequently encountered (Bouton et al., 2006; Herry et al., 2010; Ji & Maren, 2007; Konorski, 1967; Maren, 2011; Milad & Quirk, 2012; Myers & Davis, 2002; Pavlov, 1927; Quirk & Mueller, 2008).”

“…are transferred to more permanent storage in the cortex during slow wave sleep (SWS), is a key tenet of explanatory theories on sleep dependent consolidation of declarative memory (Diekelmann & Born, 2010; Diekelmann et al., 2009; Hobson & Pace-Schott, 2002; Rasch & Born, 2013; Stickgold, 2005).”

“Such vmPFC regions include the subgenual anterior cingulate cortex, an area homologous to the rat IL (Ongur, Ferry, & Price, 2003; Phelps & LeDoux, 2005; Vertes, 2004, 2006).”

“(3) Reinstatement: An isolated US, presented in the absence of the CS, causes return of the CR when the CS is subsequently presented (Bouton & Bolles, 1979; Dirikx, Hermans, Vansteenwegen, Baeyens, & Eelen, 2007; Rescorla & Heth, 1975).”

“…modulated primarily by acetylcholine (ACh) rather than the complex aminergic, cholinergic and peptidergic activation of wakefulness (Pace-Schott & Hobson, 2002), is believed to impact the way in which memories are processed during this sleep stage (Stickgold et al., 2001; Stickgold & Walker, 2013).”

“While beyond the scope of this article, these findings are summarized in several outstanding recent reviews (Abel et al., 2013; Rasch & Born, 2013; Stickgold & Walker, 2013).”

“Delgado et al. (2008) suggested that DLPFC areas subserving higher cognition recruit more phylogenetically primitive neuronal networks in the vmPFC that, in turn, regulate fear-associated activity in the amygdala during this uniquely human form of emotional regulation.”

“…represents formation of a new memory that competitively inhibits the memory of the CS−US contingency when the CS is subsequently encountered (Bouton et al., 2006; Herry et al., 2010; Ji & Maren, 2007; Konorski, 1967; Maren, 2011; Milad & Quirk, 2012; Myers & Davis, 2002; Pavlov, 1927;…”

“Patients with PTSD, compared to traumaexposed controls (TENC), extinguish fear conditioning more poorly (Blechert, Michael, Vriends, Margraf, & Wilhelm, 2007; Orr et al., 2000) and, after 24 hours, recall less extinction (Milad et al.”

“…newly acquired declarative information learned before sleep (e.g., word associates, visual memory) and the quantity of Stage 2 NREM sleep spindles (Fogel & Smith, 2011) as well as delta frequency (0.5–4.0 Hz) and slow (<1 Hz) oscillations during the sleep following learning (Ackermann & Rasch,…”

“…involved in multiple emotion-related processes such as consolidation of emotional memories (Nieuwenhuis & Takashima, 2011) including extinction (Corcoran & Quirk, 2007b), top-down regulation of amygdala activity (Myers-Schulz & Koenigs, 2012) and value-based decision making (O’Doherty, 2011).”

“…fear conditioning and extinction have generally used skin conductance response (SCR), a reliable measure of sympathetic activation (Milad & Quirk, 2012), or fear potentiation of the blink startle response (Grillon & Baas, 2003; Jovanovic & Ressler, 2010) as psychophysiological CR indices of fear.”

“Interestingly, the repetitive, highly veridical nightmares of PTSD could play a significant role in the relative balance of fear and extinction memory in such patients, for example, by reinforcing conditioned fear via re-traumatization (see Levin & Nielsen, 2007).”

“The slow (<1Hz) oscillation, believed to reflect synchronized alternation in cortical circuits of prolonged hyperpolarization (“down state”) and depolarization with rapid firing (“up state”), is assigned particular significance as a potential driver of both sleep spindles and sharp-wave ripple complexes (Abel et al.,…”

“…in the etiology of this disorder (Alvaro et al., 2013; Babson, Badour, Feldner, & Bunaciu, 2012; Babson, Blonigen, Boden, Drescher, & Bonn-Miller, 2012; Babson & Feldner, 2010; Germain, 2013; Germain, Buysse, & Nofzinger, 2008; Mellman, 2008b; Spoormaker & Montgomery, 2008; Wright et al., 2011).”

“The transition from wake to NREM sleep is accompanied by global reductions in wake-promoting aminergic and cholinergic neuromodulation (reviewed in Pace-Schott & Hobson, 2002) and widespread forebrain deactivation (Braun et al., 1997; Maquet et al., 1997; Nofzinger et al., 2002) that decreases further with the deepeni…”

“Compared to TENC, individuals with PTSD showed poorer retention of extinction as measured by SCR (Milad et al., 2008) and, during extinction learning, there was greater activation of the amygdala, while, during extinction recall, there was lesser activation of the vmPFC and hippocampus but greater activation of the dA…”

“This area includes the septum, hypothalamus, ventral striatum and pallidum, hippocampus and uncus, as well as insular, anterior cingulate, orbitofrontal, and supplementary motor cortices (Nofzinger et al., 2004; Nofzinger et al., 1997) (Figure 1C).”

“Contextual factors determine whether or not extinction recall recruits the hippocampus in addition to the vmPFC (Kalisch et al., 2006; Milad, Wright, et al., 2007).”

“Milad et al. (2007) suggested that contextual information, resulting from differentiation of the conditioning and extinction contexts, was represented by such hippocampal activity.”

“…fear extinction is a form of memory for which neural circuits of encoding, consolidation and retrieval have been well described in animal models (Herry et al., 2010; Maren, 2011; Quirk & Mueller, 2008) and which is of increasing interest to clinical investigators as the neurobehavioral basis of…”

“(3) Reinstatement: An isolated US, presented in the absence of the CS, causes return of the CR when the CS is subsequently presented (Bouton & Bolles, 1979; Dirikx, Hermans, Vansteenwegen, Baeyens, & Eelen, 2007; Rescorla & Heth, 1975).”

“Sleep and fear conditioning—As in the rat (Graves et al., 2003; Kumar & Jha, 2012), sleep’s role in promoting the consolidation of fear is implied by studies showing that TSD can attenuate consolidation of fear conditioning in humans.”

“…fear conditioning and extinction have generally used skin conductance response (SCR), a reliable measure of sympathetic activation (Milad & Quirk, 2012), or fear potentiation of the blink startle response (Grillon & Baas, 2003; Jovanovic & Ressler, 2010) as psychophysiological CR indices of fear.”

“One mechanism by which sleep disturbance might precipitate or perpetuate such disorders is by preventing the consolidation and generalization of naturally occurring or therapeutically induced extinction memories during sleep (Germain et al., 2008).”

“…that subjective insomnia, nightmare severity and abnormalities of REM, especially its fragmentation, in the early aftermath of a traumatic injury predicted later development of PTSD (Mellman et al., 2002; Mellman & Hipolito, 2006; Mellman, Knorr, Pigeon, Leiter, & Akay, 2004; Mellman et al., 2007).”

“At the synapse, sleep may facilitate NMDA receptor-dependent memory processes as evidenced by impairment of hippocampal long-term potentiation (LTP) by sleep deprivation (McDermott et al., 2003) and sleep restriction (Kopp, Longordo, Nicholson, & Luthi, 2006) as well as by selective REM deprivation (Ishikawa et al.”

“Moreover, in PTSD, the same traumatic event can produce conditioned fear to multiple stimuli in multiple perceptual modalities (Ehlers et al., 2002).”

“These animal and human findings are briefly discussed in the following sections (for more extensive reviews, see: Graham & Milad, 2011; Herry et al., 2010; Maren, 2011; Maren, Phan, & Liberzon, 2013; Maren & Quirk, 2004; Milad & Quirk, 2012; Milad & Rauch, 2012; Myers & Davis, 2007; Pape & Pare,…”

“For example, motor vehicle accident survivors who later developed PTSD, unlike survivors who did not, had more severe immediately post-trauma sleep disturbances that failed to normalize over time (Koren et al., 2002).”

“It is likely, therefore, that immediate REMD overlapped a “REM window” (Smith, 2001) crucial to consolidating hippocampus-independent extinction memory.”

“Moreover, conditions of high endogenous or exogenous estrogen enhance extinction memory in both women and female rats (Graham & Milad, 2013; Milad et al., 2010; Zeidan et al., 2011).”

“C. Application of sleep interventions for anxiety disorders The ability to remember fear extinction is key to the treatment of PTSD and other anxiety disorders treated using exposure therapy (Craske et al., 2008; Hermans et al., 2006; McNally, 2007).”

“C. Application of sleep interventions for anxiety disorders The ability to remember fear extinction is key to the treatment of PTSD and other anxiety disorders treated using exposure therapy (Craske et al., 2008; Hermans et al., 2006; McNally, 2007).”

“Generalization and multiplication of fear responses in PTSD may occur via processes such as second-order fear conditioning to primary trauma-reminder cues (Wessa & Flor, 2007).”

“Moreover, conditions of high endogenous or exogenous estrogen enhance extinction memory in both women and female rats (Graham & Milad, 2013; Milad et al., 2010; Zeidan et al., 2011).”

“…and functional abnormalities in limbic regions associated with extinction recall including the perigenual anterior cingulate, amygdala and hippocampus (Milad et al., 2013; Milad et al., 2008; Milad, Pitman, et al., 2009; Milad, Rauch, et al., 2006; Rauch et al., 2006; Shin, Rauch, & Pitman, 2006).”

“…this is the case includes the following phenomena that were first discovered in animals and have since been demonstrated in humans: (1) Spontaneous recovery: An extinguished CR re-emerges in response to the CS with the simple passage of time (Pavlov, 1927; Quirk & Gehlert, 2003; Rescorla, 2004).”

“…uthor M anuscript A uthor M anuscript An important limitation of sleep research in PTSD has been the focus on male subjects, a limitation that extends to the animal literature where studies of fear conditioning and extinction are primarily carried out on male animals (Lebron-Milad & Milad, 2012).”

“…formation of a new memory that competitively inhibits the memory of the CS−US contingency when the CS is subsequently encountered (Bouton et al., 2006; Herry et al., 2010; Ji & Maren, 2007; Konorski, 1967; Maren, 2011; Milad & Quirk, 2012; Myers & Davis, 2002; Pavlov, 1927; Quirk & Mueller, 2008).”

“The transition from wake to NREM sleep is accompanied by global reductions in wake-promoting aminergic and cholinergic neuromodulation (reviewed in Pace-Schott & Hobson, 2002) and widespread forebrain deactivation (Braun et al., 1997; Maquet et al., 1997; Nofzinger et al., 2002) that decreases further with the deepeni…”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Maren, 2011; Monfils, Cowansage, Klann, & LeDoux, 2009; Quirk et al., 2010; Schiller & Delgado, 2010; Schiller et al., 2010).”

“, 2002) that decreases further with the deepening of NREM sleep (Dang-Vu et al., 2010; Kaufmann et al., 2006).”

“Moreover, conditions of high endogenous or exogenous estrogen enhance extinction memory in both women and female rats (Graham & Milad, 2013; Milad et al., 2010; Zeidan et al., 2011).”

“…Roth, Rosenthal, & Andreski, 1996; Ford & Kamerow, 1989; Johnson, Roth, & Breslau, 2006; Neckelmann, Mykletun, & Dahl, 2007) especially PTSD (Babson & Feldner, 2010; Koren, Arnon, Lavie, & Klein, 2002; Mellman, Bustamante, Fins, Pigeon, & Nolan, 2002; Mellman, Pigeon, Nowell, & Nolan, 2007).”

“The forebrain targets of the rat p-wave include the amygdala and hippocampus (Datta, Siwek, Patterson, & Cipolloni, 1998), p-waves increase during REM following learning trials on an active avoidance task (Datta, 2000) and this increase is accompanied by increased expression of plasticity related genes in these same l…”

“Similarly, among procedural memory systems, the hippocampus provides contextual modulation of motor-sequence learning (Albouy et al., 2013).”

“, 2002) that decreases further with the deepening of NREM sleep (Dang-Vu et al., 2010; Kaufmann et al., 2006).”

“…example, successful recall of emotional stimuli was accompanied by greater activation of the amygdala, hippocampus and vmPFC in a group that slept versus one that was sleep deprived following learning, a difference still seen a full 6 months later (Sterpenich et al., 2007; Sterpenich et al., 2009).”

“…in the etiology of this disorder (Alvaro et al., 2013; Babson, Badour, Feldner, & Bunaciu, 2012; Babson, Blonigen, Boden, Drescher, & Bonn-Miller, 2012; Babson & Feldner, 2010; Germain, 2013; Germain, Buysse, & Nofzinger, 2008; Mellman, 2008b; Spoormaker & Montgomery, 2008; Wright et al., 2011).”

“Furthermore, similar bivalent memory enhancement has been reported for the stress hormone cortisol that, at high levels, can enhance both fear conditioning and the extinction of this conditioning (de Quervain, Aerni, Schelling, & Roozendaal, 2009; de Quervain et al., 2011).”

“[It is also noteworthy that the TSD-mediated reduction in fear termed “extinction” by Kuriyama et al. (2010) does not actually involve extinction learning but rather is reduced consolidation and generalization of fear conditioning—a process more akin to fear “erasure” (Maren, 2011).]”

“Of clinical importance, such findings have led to the suggestion that depriving traumatized patients of sleep during the first night post-trauma may serve to attenuate consolidation of traumatic memories (Baran et al., 2012; Kuriyama et al., 2010; Menz et al., 2013; Wagner, Hallschmid, Rasch, & Born, 2006).”

“Extinction learning—Extinction learning has been associated with amygdala (Knight et al., 2004; Milad, Wright, et al., 2007; Phelps et al., 2004) and vmPFC activity (Milad, Wright, et al.”

“, 2009; Silvestri & Root, 2008) and extinction of fear conditioning (Davis, 2011; Ledgerwood et al., 2005; Norberg, Krystal, & Tolin, 2008) depending on timing of its administration relative to encoding.”

“Moreover, a procedural task shown to consolidate across either wake or sleep when learned in isolation, requires sleep to consolidate when learned simultaneously with a declarative memory task (Robertson, 2009).”

“A recent fMRI study has further shown that the sleep debt accrued by prolonged sleep restriction can produce a similar hyper-responsivity of the amygdala to emotional faces as well as reduce its functional connectivity with the vmPFC (ventral anterior cingulate) (Motomura et al., 2013).”

“…that subjective insomnia, nightmare severity and abnormalities of REM, especially its fragmentation, in the early aftermath of a traumatic injury predicted later development of PTSD (Mellman et al., 2002; Mellman & Hipolito, 2006; Mellman, Knorr, Pigeon, Leiter, & Akay, 2004; Mellman et al., 2007).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Maren, 2011; Monfils, Cowansage, Klann, & LeDoux, 2009; Quirk et al., 2010; Schiller & Delgado, 2010; Schiller et al., 2010).”

“…example, successful recall of emotional stimuli was accompanied by greater activation of the amygdala, hippocampus and vmPFC in a group that slept versus one that was sleep deprived following learning, a difference still seen a full 6 months later (Sterpenich et al., 2007; Sterpenich et al., 2009).”

“The degree to which extinction learning can generalize will also strongly impact the efficacy of such therapy (Craske et al., 2008; Pace-Schott, Verga, et al., 2012a; Rowe & Craske, 1998; Vansteenwegen et al., 2005; Vansteenwegen et al., 2007; Vervliet, Craske, & Hermans, 2013).”

“Importantly, there is high comorbidity of insomnia with mood and anxiety disorders (Alvaro, Roberts, & Harris, 2013; Baglioni et al., 2011; Riemann, 2007; Stepanski & Rybarczyk, 2006) and evidence that, in some cases, insomnia itself can be preexisting risk factor for incident anxiety disorders (Breslau, Roth, Rosenth…”

“Similarly, whereas sleep enhanced extinction generalization from an extinguished to an un-extinguished CS+, it did not enhance extinction memory for an extinguished CS+ (Pace-Schott et al., 2009).”

“The degree to which extinction learning can generalize will also strongly impact the efficacy of such therapy (Craske et al., 2008; Pace-Schott, Verga, et al., 2012a; Rowe & Craske, 1998; Vansteenwegen et al., 2005; Vansteenwegen et al., 2007; Vervliet, Craske, & Hermans, 2013).”

“…of fear conditioning and extinction engage limbic circuits that utilize hippocampal input to disambiguate contextual factors, but that can also operate in a hippocampus-independent manner if the context is ambiguous or uninformative (Fu et al., 2007; Kalisch et al., 2006; LaBar & Phelps, 2005).”

“…there is high comorbidity of insomnia with mood and anxiety disorders (Alvaro, Roberts, & Harris, 2013; Baglioni et al., 2011; Riemann, 2007; Stepanski & Rybarczyk, 2006) and evidence that, in some cases, insomnia itself can be preexisting risk factor for incident anxiety disorders…”

“The Spoormaker group has also examined whether the rodent findings of REM disruption following fear conditioning (Pawlyk et al., 2008) and the subsequent amelioration of this disruption by extinction training (Wellman et al., 2008) could be duplicated in humans (Sturm, Czisch, & Spoormaker, 2013).”

“Another fMRI study suggested that retrieval of an emotional memory following a night of sleep engaged a more discrete and integrated set of limbic structures than retrieval following a day awake (Payne & Kensinger, 2011).”

“REM has also been suggested to be key to the integration of recently acquired information into existing networks in a flexible manner that allows novel associations to be expressed in the form of creativity (Cai, Mednick, Harrison, Kanady, & Mednick, 2009; Genzel et al., 2015; Stickgold, Hobson, Fosse, & Fosse, 2001).”

“How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. American Journal of Psychiatry.”

“such as occurs in active avoidance learning paradigms, can instead lead to enhanced total and REM sleep with robust rebound of any loss resulting from the stress manipulation (Sanford et al., 2014; Sanford et al., 2010; Suchecki, Tiba, & Machado, 2012).”

“Therefore, in a subsequent fMRI study (Spoormaker et al., 2012), these investigators directly manipulated one of these variables (REM amount) following extinction learning by comparing REMD to NREM-deprived (NREMD) controls.”

“…& Born, 2009; Rasch & Born, 2013; Stickgold, 2005) including processes related to prioritization and integration of newly acquired memories with existing stores (Landmann et al., 2014; Pace-Schott, Nave, Morgan, & Spencer, 2012; Payne, Chambers, & Kensinger, 2012; Stickgold & Walker, 2013).”

“The degree to which extinction learning can generalize will also strongly impact the efficacy of such therapy (Craske et al., 2008; Pace-Schott, Verga, et al., 2012a; Rowe & Craske, 1998; Vansteenwegen et al., 2005; Vansteenwegen et al., 2007; Vervliet, Craske, & Hermans, 2013).”

“Further support for the SRSF model were findings that, compared to a baseline night, a night with selective REMD showed an increase in behavioral and neural reactivity to emotional images that was not observed following selective NREM deprivation (Rosales-Lagarde et al., 2012).”

“In the first fMRI study of sleep and extinction memory, Spoormaker et al. (2010) showed that greater extinction recall (lower SCR to an extinguished stimulus), as well as vmPFC activation, to the extinguished stimulus were greater in individuals who achieved REM during a 90-min afternoon nap that…”

“Although REM has been specifically shown to be important to the consolidation of extinction of cued conditioned fear (Fu et al., 2007), evidence for a role of REM in consolidation of the fear memory itself remains equivocal with indirect evidence suggesting that REM may, in some cases, oppose fear…”

“In these studies, REMD that followed cued fear conditioning but preceded subsequent extinction training by 48 hours, impaired acquisition of that later extinction (Silvestri, 2005; Silvestri & Root, 2008).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript emotional declarative memory have been mixed (For a review see Deliens et al., 2014).”

“This intriguing difference is believed to reflect the fact that, during escapable shock, new instrumental learning is taking place whereas, for inescapable shock, only the unavoidable contingency is learned (Sanford et al., 2014; Sanford et al., 2010; Suchecki et al., 2012).”

“, 2009; Silvestri & Root, 2008) and extinction of fear conditioning (Davis, 2011; Ledgerwood et al., 2005; Norberg, Krystal, & Tolin, 2008) depending on timing of its administration relative to encoding.”

“Sleep abnormalities that either precede or follow traumatic experiences, predict later development of PTSD (reviewed in Babson & Feldner, 2010; Mellman & Hipolito, 2006; Wright et al., 2011) leading to the view that sleep disturbances, rather than being secondary to the development of PTSD, may…”

“Very similar midline regions showing greater activation in REM compared to wakefulness were observed using 18Flurordeoxyglucose PET and have been characterized as an “anterior paralimbic REM activation area” (Nofzinger et al., 2004; Nofzinger, Mintun, Wiseman, Kupfer, & Moore, 1997) (Figure 1C).”

“…involved in multiple emotion-related processes such as consolidation of emotional memories (Nieuwenhuis & Takashima, 2011) including extinction (Corcoran & Quirk, 2007b), top-down regulation of amygdala activity (Myers-Schulz & Koenigs, 2012) and value-based decision making (O’Doherty, 2011).”

“Therefore, the memory enhancing function of sleep might be exploited to strengthen therapeutic extinction learned in exposure-based therapy by using strategically timed sleep bouts (Kleim et al., 2013; PaceSchott, Verga, et al., 2012a).”

“Sleep is important for basic 16 emotional responses such as fear conditioning and f ear extinction [48] and also impacts on 17 more complex forms of emotional processing such as the discrimination of threatening and 18 friendly faces [49] and response to reward [50].”

“Which of these competing memory representations is selectively strengthened depends on contextual factors such a recency of learning and replay [109].”

“Recent experimental findings, which are reviewed in reference [8], suggest that sleep may play key roles in the consolidation, integration, and balance of fear and extinction memory.”

“Laboratory studies suggest that sleep plays an impo rtant role in maintaining optimal homeostasis of affective functioning, and sleep dis turbance alters our emotional state (6,7).”

“…consolidation of emotional memory albeit with mixed findings as to whether sleep preferentially augments emotional over neutral memories (reviewed in Goldstein and Walker, 2014; Hutchison and Rathore, 2015; Kahn et al., 2013; Pace-Schott, 2015; Palmer and Alfano, 2016; Tempesta et al., 2017).”

“Neuroimaging research indicates that fear extinction is mediated in large part by the mPFC, in particular the ventromedial PFC and rACC, which are structures implicated in anxiety-related disorders [13, 219].”

“More interestingly, the extent of the fear extinction was found to be correlated with the amount of REM-sleep [51,52].”

“While the ventral parts of the ACC and mPFC (sgACC, pgACC, rACC, vmPFC) exert an inhibitory control over subcortical structures and promote the consolidation of emotional memories, including FE memories (Milad et al., 2007b; Pace-Schott et al., 2015).”

“…plays a specific role in emotional memory consolidation (Goldstein and Walker, 2014), especially in fear memory consolidation (for recent reviews, see Genzel et al., 2015; Pace-Schott et al., 2015), although few studies focus on night sleep and even fewer on specific sleep stages within the night.”

“, 2015) and REM sleep stages (Menz et al., 2016; Pace-Schott et al., 2015) have been found to promote the retention and generalization of extinction learning.”

“An intriguing question is also whether synaptic renormalization contributes to the role of REM sleep in emotional regulation [93].”

“In healthy aged individuals, sleep-dependent memory consolidation and certain procedural tasks, such as motor sequence learning, are impaired [8].”

“, 2020) and also plays a role in the extinction of long-term memories (Pace-Schott et al., 2015; Sun et al., 2019; Zhang Y. et al., 2021).”

“Along these lines, sleep disturbances have been found to impair memory consolidation processes and yield reduced fear extinction, including among PTSD patients [148, 151].”

“Accordingly, animal and human studies demonstrated that sleep can serve to consolidate memory for fear and fear extinction (Menz et al., 2013; Pace-Schott et al., 2015).”

“Thus, the facilitative effects of sleep on memory consolidation may extend also to extinction [8].”

“Furthermore, based on the recent finding of Pace-Schott et al.,[5] we hypothesized that hours-since-waking would be a significant moderator between fear extinction learning and PTSD symptoms, with increased periods of wakefulness predicting significantly poorer extinction learning in participants with greater PTSD sym…”

“, 2018), sleep loss following a traumatic event could prevent consolidation of fear extinction memory in other conditions (Pace-Schott et al., 2015).”

“Pace-Schott, Germain, and Milad (2015) suggest that improving sleep quality before PTSD treatment may strengthen the extinction process, leading to better treatment outcomes.”

“These and other findings suggest that sleep disturbances play an important role in the development and maintenance of PTSD [11].”

“Some studies have explored the relationship between trait anxiety, sleep quality and the ability to remember the extinction of conditioned fear, reporting associations between poor quality sleep and poor extinction and between poor quality sleep and trait anxiety [12].”

“habituation as well as of extinction memory (48, 90, 93).”

“In addition to behavioral findings, rodent in vivo recordings and functional neuroimaging in humans have pointed to three key brain regions associated with the conditioning process: the amygdala, the ventromedial prefrontal cortex (vmPFC), and the hippocampus (Pace-Schott et al., 2015).”

“Sleep was maintained or disturbed might predict an individual’s ability to recover from a preexisting psychiatric condition (Pace-Schott et al., 2015; Kuhn et al., 2016; Schmitt et al., 2016).”

“Sleep promotes consolidation in multiple memory systems (Diekelmann and Born, 2010) and thus could also promote consolidation of fear-extinction recall (Pace-Schott et al., 2015).”

“40 Because PTSD is characterized by impairments of both sleep and extinction memory, improving sleep quality may improve these symptoms by strengthening naturally acquired extinction.”

“Poor sleep quality may worsen fatigue, anxiety, depression, and lower pain tolerance by impairing emotional regulation [41].”

“Recent humans and animals research suggest that REM sleep may be of particular importance for the emotional processing [24].”

“In addition, the tendency to generalize fear extinction responses across contexts is stronger in the morning [15, 21].”

“Compared with the placebo, yohimbine administration was associated with significantly elevated predominantly during sleep (Pace-Schott et al., 2015); therefore, yohimbine effects would be expected especially on day 2.”

“However, these mechanisms are not specific to REM sleep [17].”

“In a recent review, Pace-Schott et al. (2015) Correspondence concerning this article should be addressed to Thomas A. Mellman, Howard University College of Medicine, 520 W Street, NW, Washington, DC 20059. tmellman@howard.edu.”