Depotentiation  of  the  suffering  aspect  of  aversive  memories (dACC memories) as key  to​ ​mental​ ​and​ ​physical​ ​health  by​ ​Rudger​ ​Alexander​ ​Kanding July​ ​24,​ ​2017 Text​ ​version:​ ​0.3,​ ​early​ ​and​ ​conceptual Contact:​ ​emd.as.etiology​ ​at​ ​the​ ​google​ ​mail​ ​service Abstract: The main text of the EMD hypothesis (Kanding, 2017a) proposes that the continuous reduction of emotional memory strength observed during memory consolidation (Goldstein and Walker, 2014) is not only achieved by memory depotentiation, but also by memory inhibition. It was furthermore proposed that the resulting collection of emotional memories and counterbalancing extinction-like inhibitory memories (termed ‘e/x balance’) is at the root of a large array of currently unexplained medical phenomena​. ​The predictions part of the EMD hypothesis states that not re-extinction or erasure/forgetting/decay of emotional memories, but rather their true depotentiation eliminates the detrimental effects of the e/x balance and that this depotentiation process is therefore a key to physical and mental health. The present text further explores this hypothesis by arguing that, surprisingly, evolution already conferred humans, and possibly a few other species, with a process to depotentiate some specific traumatic aversive memories, and that the underlying general aversive memory depotentiation (AMD) process should be applicable to depotentiate a wide range of types of aversive memories. The article analyses the functional and mechanistic structure of the putative AMD process and the involved brain regions. Finally a reasoning is developed, why the AMD process can only take place during the waking state, and why two major, and very difficult to overcome, obstacles exist​ ​that​ ​under​ ​normal​ ​conditions​ ​impede​ ​the​ ​application​ ​of​ ​the​ ​AMD​ ​process. Terminology: BLA = basolateral amygdala; dACC = dorsal anterior cingulate cortex; EMD = extinction memory damage; MO = memory overexpression; offline = during sleep; online = during the waking state; vmPFC = ventromedial​ ​prefrontal​ ​cortex

Introduction  The main text of the EMD hypothesis (Kanding, 2017a) developed two fundamental concepts that explain in what way aversive memories may exert detrimental health effects by means of scientifically well established mechanisms of Brain-Body Medicine (Lane and Wager, 2009). The first concept, ‘memory overexpression’ (MO) argued that intrinsic network activity as well as extinction memory damage (EMD) related memory disinhibition may permanently activate aversive memories. The second concept, ‘functionally identical neuronal engagement’ (FINE) explained in what way MO translates into permanent end organ symptoms and health effects by means of well established brain-body mechanisms. Depotentiation of aversive memories was proposed in the predictions part of the EMD hypothesis to revert these detrimental consequences of MO and therefore to represent a key to mental and physical health. But how can aversive memory depotentiation be achieved? It is here hypothesized that not erasure/forgetting/decay of an aversive memory but rather depotentiation of ​only ​the suffering part of an aversive

1

memory eliminates its intrinsic as well as EMD-based overexpression and the accompanying detrimental effects. It is further hypothesized, that, surprisingly, evolution already conferred humans (and possibly some few other species) with the ability to depotentiate certain kinds of aversive memories, and that the underlying general process possibly can be applied to a wide range, if not all, aversive memory types for the purpose of their depotentiation. The following sections will first give an account for the evolutionary need and origin of memory depotentiation, and thereafter will try to explain the action of this depotentiation mechanism on a functional, and to a certain extent on a mechanistic level. For​ ​a​ ​summary​ ​of​ ​the​ ​data​ ​supporting​ ​the​ ​existence​ ​of​ ​the​ ​e/x​ ​balance,​ ​see​ ​chapter​ ​5.5​ ​of​ ​the​ ​main​ ​text.

The​ ​evolutionary​ ​origin​ ​of​ ​aversive​ ​memory​ ​depotentiation  If a species is over evolutionary time spans too frequently exposed to a fitness reducing stressor, then evolution is forced to develop protective measures (e.g. immunity to bacterial infection, fur against cold, etc.). Mental traumatization (closer specified below) is such a fitness reducing stressor due to the resulting increased disease vulnerability (Rohleder, 2014; Miller et al., 2009) and due to impairment of fecundity by e.g. entailed social disability, reduced parentization abilities, etc. (-). Thus, when occurring too frequently over evolutionary time spans, it creates a selection pressure for traits that would reduce the problem of mental traumatization (for the sake of keeping things brief,​ ​hereafter​ ​just​ ​termed​ ​‘traumatization’). The fact that the problem of traumatization still exists after 500 million years of nervous system evolution suggests that this problem was not under sufficient evolutionary pressure or is extremely difficult to solve. It is here hypothesized that the problem of traumatization is indeed extremely difficult to solve for evolution, but that nevertheless in animals with certain mental capacities and certain life-history characteristics, traumatization occurs so frequently, that the resulting negative effects on fecundity created over an evolutionary long period of time a sufficient high evolutionary pressure that successfully selected for traits that reduce ​some specific traumatization problems​. In order to substantiate this idea, a better definition of the here utilized concept of traumatization is necessary. The basic mental capacities an animal must possess in order to be vulnerable to traumatization are hypothesized to be i) long-term memory (implicit or explicit), and ii) the ability to create, on basis of memory and experience, not necessarily the concept of logic deduction, but the basic concept of ‘long-term consequence’. These two abilities will allow an animal to create the concept of ‘(apparently) unchangeable consequence of an event’. In case an animal creates on basis of this ability a concept of an unchangeable event with strong negative outcome, i.e. with an associated strong aversive emotion, a memory in the e/x balance is created that exhibits a special property: It is very difficult to handle by common emotion regulation (ER) strategies (see e.g. the introduction of Brans et al., 2013 for an overview of ER strategies). First, it cannot be handled by cognitive reappraisal, because the relevant causing event and its negative outcome are unchangeable. For the same reason it cannot be handled by coping ER strategies. Second, as the event is associated with strong negativity, it is difficult to extinguish and prone to renewal and spontaneous recovery, and therefore difficult to handle by inhibitory ER strategies such as expressive suppression, diversion, etc. As a result, the intrinsic or EMD-related overexpression of the aversive memory may exert strong long-term or recurring detrimental physical and mental consequences, or, expressed in common terminology, may lead​ ​to​ ​traumatization. In summary, the preconditions for the evolvability (Goldsmith, 2008) of a process that solves the traumatization problem are i) the delineated mental capacities, ii) frequent traumatization on basis of these mental capacities, and iii) occurrence of this type of traumatization over an evolutionary long time span. It is here hypothesized that these preconditions are given (not necessarily exclusively) in some social animals with strong long-term emotional bonds, including humans. In humans, the prototypical (but not unique) traumatizing event is thought to be bereavement, the prototypical (but not unique) life-history trait is thought to be the frequent occurrence of bereavement due to general high mortality (life expectancy ~ 20y over evolutionary long periods of time (Kim, 2007, p. 1609)). It is further hypothesized that evolution solved the problem of intractability of the unchangeable strong negativity of bereavement (and several other unchangeable events, see discussion below) with common ER strategies by creating a completely new type of ER strategy, that is not based on reappraisal, coping, or inhibition of the emotional memory to regulate,

2

but rather by its depotentiation, and that the prototypical (but not unique) process representing this ER strategy is the process​ ​of​ ​crying​ ​(Miceli​ ​and​ ​Castelfranchi,​ ​2003). Crying happens after positive unchangeable events (e.g. a victory; the necessity of its depotentiation is briefly discussed below), and after negative unchangeable events (e.g. bereavement, helplessness in e.g. states of anger or fear). Crying seems therefore not only to be able to depotentiate memories of bereavement but also memories of anger and fear. This suggests that crying possibly underlies a more general process that could be applicable to depotentiate​ ​a​ ​wide​ ​range​ ​of​ ​types​ ​of​ ​aversive​ ​memories.

Basic  functional  structure  depotentiation​ ​process

of 

the 

aversive 

memory 

The above deliberations created an account for the evolutionary necessity of aversive memory depotentiation, and for the idea that this process is already realized for certain types of aversive memories by means of the process of crying. But how does the putative aversive memory depotentiation (AMD) work on a functional and on a mechanistic level, and what is the specific difficulty that led to a late invention of this trait in evolution despite its strong fitness improving effect? Research data indicates that the dACC brain region plays a pivotal role in determining whether an aversive memory is expressed or inhibited (Do Monte et al., 2015; Milad and Quirk, 2012). The fact that this part of the brain is strongly associated with the suffering aspect of aversive memories (Etkin et al., 2011; Eisenberger and Lieberman, 2004) motivates the speculation that the suffering associated with an aversive memory is crucially involved in the decision for memory expression vs. memory inhibition. In this case it will be plausible to further speculate that the intensity of intrinsic or EMD-related overexpression of an aversive memory mainly depends on the intensity of the associated suffering part and that therefore depotentiation of only the suffering part of an aversive memory could reduce the overexpression of the whole memory and thereby reduce the related detrimental health effects. This would make sense, because in contrast to the erasure of the whole aversive memory, the original memory would remain as neutral memory for the purpose of future adaptive utilization. However in contrast to i.e. declarative memories, where the significance for survival is encoded to a comparable extent in the many details of the declarative memory, the significance for survival of an aversive autobiographical memory is to a large extent encoded in its suffering part, and the many details of the associated autobiographical event are not significant per se, but only rendered significant by the associated suffering. Simply depotentiating the suffering part, which is small in terms of involved neurons and synapses, but large in terms of significance, would be functionally equivalent with erasing the crucial part of the memory. A simple depotentiation of a dACC memory would therefore be in opposition to the already mentioned, indispensable function of the e/x balance to keep potentially significant memories potentially accessible. AMD is therefore only possible if, somehow, the relevance of the depotentiated memory is preserved. This implies that during the depotentiation process, the relevance encoded in the suffering part is transferred into a further memory system, where it is potentially accessible as it was before, during its storage in the e/x balance. Moreover, to meet the evolutionary necessity for the reduction of the traumatization problem, the new memory​ ​system​ ​should​ ​exhibit​ ​significant​ ​less​ ​detrimental​ ​MO​ ​effects​ ​than​ ​dACC​ ​memories. Transfer of memories from one to another memory system is a common procedure during memory consolidation. For instance, newly encoded, hippocampus dependent memories are thought to be gradually transferred to neocortical representations during memory consolidation (Talamini and Gorree, 2012; Nieuwenhuis and Takashima, 2011). And recent research on fear conditioning demonstrated the gradual transfer of fear memory aspects from several initially encoding neuron populations in the dACC and BLA into new, distinct neuron populations (Do Monte et al., 2016), possibly accompanied by depotentiation of the original memory trace (mentioned as “detaching BLA neurons from . . . long-term memories’’ in Do Monte et al., 2016, p. 1032). As memory transfer is thought to heavily rely on memory consolidation during sleep, and this trait evolved already ~ 180 million years ago in early mammalian evolution (see

3

Hobson, 2009, fig. 2b), copying a memory trace into a new neuron population and thereby depotentiating the original memory trace, was most probably a problem already solved when the evolutionary need for AMD appeared, and these mechanisms had no need to be newly developed. Copying and depotentiating a memory was therefore not the difficult​ ​task​ ​that​ ​led​ ​to​ ​the​ ​late​ ​development​ ​of​ ​AMD.

Why​ ​AMD​ ​can​ ​only​ ​take​ ​place​ ​in​ ​the​ ​waking​ ​state    Copying a memory trace during memory consolidation depends on a kind of replay of the memory trace (reviewed in Rasch and Born, 2013, pp. 695-699). A putative AMD process should therefore show memory replay characteristics. Crying seems to possess the property of a (more or less) uninterrupted replay of an aversive memory, because it seems to involve a reexperience/reprocessing of the aversive event that provoked crying. Crying seems therefore to possess the memory replay property demanded from an AMD process. But why does the putative AMD process underlying crying take place during the waking state, even though the properties of the processes taking place during sleep (memory replay, depotentiation, copy) seem to be predestined to support an offline AMD process? Several arguments suggest that it was not possible for evolution to develop an AMD process that takes place during sleep. Concerning replay of aversive memories during dreaming, one peculiar observation has to be considered: replay of aversive memories seems in principle not to constitute a problem, since aversive memories are regularly replayed during dreaming (Levin and Nielsen, 2007, 2009). However, it seems that some aversive memories exhibit properties that stop sleep-related replay and lead to waking up. To my best knowledge, overly aversive, traumatic memories can exert this effect (Levin and Nielsen, 2007), and after my own experience and after reports in internet forums, crying during sleep also can lead to waking up. Two major reasons for this ‘waking up problem’ are conceivable. First, salient sensory input (pain, baby crying, etc.) during sleep can provoke waking up (-). It is conceivable that the underlying alarm mechanisms are triggered during replay of too aversive memories, and that evolution could not inhibit these mechanisms by simultaneously preserving the evolutionary important ability to react to salient sensory input during sleep. A further explanation would be that certain types of aversive memories are so deeply entangled with the self, that replay of such memories activates the self, thus leads to waking up (see discussion in the Notes chapter). It seems therefore that AMD during sleep is not possible for strong aversive memories that either lead to waking​ ​up​ ​by​ ​alarm​ ​mechanisms​ ​or​ ​by​ ​too​ ​strong​ ​involvement​ ​of​ ​the​ ​self. Thus, if the life history traits of a species created during the reproduction period too frequently this type of fitness reducing memory, then a strong selection pressure evolved for an online process that reduces the traumatization problem. Developing a powerful online extinction process for such memories would perhaps have been possible. However, on the one hand, memories can probably never perfectly be extinguished and remain to a certain extent vulnerable to phenomena like spontaneous recovery and renewal. Moreover, vulnerability to EMD-related MO is still present in even perfectly extinguished memories (see in the main text the threshold mechanisms and the reasoning for permanent EMDs). And on the other hand, it is here hypothesized that overly strong or too many extinction memories lead to severe side effects (not further explored here, see the alexithymia problem briefly mentioned in the main text), so that evolution selected against an online extinction process for strong aversive memories. Thus, when assuming that the selection pressure that evolved from the ‘wake up problem’ for a traumatization reducing process is strong enough, the only remaining alternative for the reduction of the traumatization problem seems to have been the development​ ​of​ ​an​ ​online​ ​AMD​ ​process.

Functional​ ​and​ ​mechanistic​ ​structure​ ​of​ ​the​ ​online​ ​AMD​ ​process  Evolution tends to reuse already present mechanisms in order to adapt them for a new purpose (-). An online memory replay mechanism that occurs spontaneously during quiet wakefulness can be observed in rodents and humans (reviewed in Rasch and Born, 2013, pp. 700-702) and it seems to exhibit the same properties as offline

4

replay mechanisms, such as gist extraction and memory transfer (Miall and Robertson, 2006). Furthermore, the brain state associated with this replay mechanism “may in part be devoted to the processing of past experiences to support memory consolidation” (Miall and Robertson, 2006). As rodents do not seem to possess an online AMD process to the purpose of which the online replay process could have evolved, it seems that this replay process serves normal memory consolidation purposes and therefore evolved early in mammalian evolution. It is therefore here hypothesized that evolution adapted this preexisting replay mechanism in order to create an online AMD process. The location of the memory system that serves as a target for the gist extracted during memory replay, and whether an existing system is used or a new, specialized system was developed by evolution, is currently not clear (but see the related discussion below). It is further hypothesized that the gist extracted during AMD is, in a functional manner, an accurate copy of the original aversiveness of the replayed memory, and that it can be utilized for adaptive purposes in the same, or even in a better way, than the original aversiveness that was depotentiated during gist extraction. Viewed on a functional level, it is evident that aversive memory depotentiation, when actually realized in the described way, solves the traumatization problem without impairing the survival-decisive properties of the e/x balance. In order to further buttress the hypothesis of an online AMD process, the following section tries to create a more​ ​mechanistic​ ​account​ ​for​ ​the​ ​above​ ​functional​ ​description​ ​of​ ​dACC​ ​memory​ ​depotentiation. The original location of the aversiveness, the dACC, is also termed the motor cortex of the limbic system (Shackman et al., 2011), i.e. the motor cortex of the emotional brain. It is also considered to be among higher brain regions the one with the fastest reactivity to aversive stimuli (Critchley, 2009). For this purpose it is intensely and directly connected with autonomic and somatomotor brain regions in order to elicit fast physical reactions for the expression of emotional states and activation of goal-directed behaviour (Shackman et al., 2011; Roy et al., 2012). (Whereby for the sake of briefness, in the present text autonomic effects are meant to include immune, neuroendocrine and somatomotor effects). This direct and intense connection is here thought to be the basis for the autonomic effects of EMD-related and intrinsic MO, by engaging well known brain-body mechanisms (Lane et al., 2009; Gianaros and Wager, 2015; see also the related FINE concept in the main text). Conscious intervention into these brain-body mechanisms is difficult, if not impossible, because these mechanisms actually constitute ‘memory-body mechanisms’. A successful intervention can therefore only be achieved by a change of the memory (or, in principle by memory inhibition, but this would again create an e/x balance and the related problems). As AMD depotentiates and takes the MO causing aversive memory out of this system and transfers it to another memory system, an aversive memory thereby loses its overexpression and consequently does no longer engage the brain-body mechanisms that caused its detrimental physical and mental effects. This is at least to be expected if the target memory system lays outside the dACC, because no other neocortical region exhibits such a strong activating effect on autonomic effector regions (-). In case the target memory system is situated within the dACC, mechanistic predictions about MO effects of the transferred memory are difficult to create (see also the related discussion on ‘overlapping systems’ in Kanding, 2017b).

Difficulties  occurring  in  the  application  of  the  general  AMD  process  It was hypothesized in this text, that the theoretical AMD process delineated above is realized by evolution in the form of crying. As crying seems not only to process sadness, but also feelings of anger and fear, it was further hypothesized that crying possibly underlies a more general depotentiation process that can be used to depotentiate a wide range of aversive memories in order to improve physical and mental health. This idea is further supported by the observation that the suffering aspect of distinct emotional and physical modalities is processed in a common brain region, the dACC (Etkin et al., 2011; Eisenberger and Lieberman, 2004). This suggests that an AMD process is modality independent and can depotentiate all kind of aversive memories. (However, it has to be noted that on basis of the current state of research, it cannot be excluded that modality-specific subregions exist in the dACC, which would​ ​entail​ ​the​ ​possibility​ ​of​ ​modality-specific​ ​AMD​ ​processes).

5

But an utilization of such a general AMD process cannot at all be observed in the general population. Assuming that a general AMD process indeed exists, this implies that very strong obstacles exist that impede its application. Two of these obstacles will be briefly discussed here. First, as can be observed in crying, AMD seems to demand a conscious perception of the aversive memory to depotentiate. But an entrance of an aversive memory into consciousness will, under normal conditions, very quickly and possibly unnoticed, engage ER strategies in order to avoid the perception of the aversive memory. This activation of ER strategies will divert attention away from the aversive memory and thereby impede the initiation of aversive memory replay, on which AMD crucially depends. Thus, AMD can not take place, when ER strategies interfere. Besides this very evident and well known obstacle, in my opinion a second, quite surprising major obstacle exists. When the human brain works in its default mode, thus conscious perception is focused on the current somatovisceral and autobiographical state, the brain region vmPFC exhibits a strong baseline activity (Raichle et al., 2001). As this brain region exerts a strong inhibitory action on autonomic and limbic brain regions (Roy et al., 2012; Etkin et al., 2011), it is here hypothesized that the inhibitory activity of the vmPFC that results from its baseline activity (probably driven by ‘volitionality’ originating from baseline attentional processes in the PFC [-]) is too strong to allow for the initiation of the aversive memory replay on which AMD depends. Extremely aggravating this problem, it is additionally hypothesized that, paradoxically, focusing attention toward an aversive memory increases this problem, instead of decreasing it, as it would be needed for the initiation​ ​of​ ​memory​ ​replay. These hypotheses can be substantiated when appreciating that the AMD process properties (introspective and autobiographical memory based) suggest a strong dependence on brain regions active in the default mode of the brain (Raichle et al., 2001). However, this state maintains a continuous “broad information gathering activity” (Raichle et al., 2001, p. 681) and should be curtailed “when successful task performance demands focused attention” (Raichle et al., 2001, p. 681). Such a state, even though subjectively perceived as quiet wakefulness, is actually continuously busy by self-maintenance and the entailed baseline attentional activity is contradictory to the AMD process. Supporting the hypothesized problem of volition, it can be expected that a trial of an individual to view AMD as a task, would activate the core components of the task-positive network (Fox et al., 2005). However, this network has a suppressive effect on the introspection-related parts of the default mode network. Thus by loading consciousness with the concept of “there is a task to fulfil”, the very part of default mode network which is necessary for this task (AMD) is deactivated instead of activated and attentional activity is increased, instead of decreased. This is the opposite of what should happen and therefore the aim to perform AMD will impede the initiation of memory replay. (It is noteworthy here that remembering a snapshot-like part of an aversive memory is not memory replay, see below.) This problem is intuitively understandable because memory replay cannot be ‘done’, it can only happen. This is exemplified by the fact that crying cannot be ‘done’, it also only can happen. Not the individual drives the crying process​ ​by​ ​his​ ​volition,​ ​rather​ ​the​ ​memory​ ​replay​ ​process​ ​is​ ​the​ ​driving​ ​force​ ​and​ ​volitional​ ​activity​ ​is​ ​low. [Unfortunately the previous paragraph is not really conclusive. Please read the comment on the Brewer (2013) study below​ ​for​ ​a​ ​better​ ​understanding.] Under the precondition of these hypotheses, AMD is only possible if i) memory replay takes place, ii) the replayed memory is consciously perceived, and iii) attentional activity has to be kept low, even below levels as occurring during meditation. These described obstacles are both considered as severe, but in particular the second one is considered to be extremely difficult to overcome. Both problems are also considered as the major obstacles for evolution in the development of a general AMD process. The state of consciousness of the AMD process is too contradictory to the normal default mode state of information gathering and proneness for goal oriented task activation. Therefore, the more the memory to depotentiate lacks aspects that could lead to an adaptive task activation, the more probable is a switch from the default mode state to the AMD state. A complete lack of possibilities for adaptive task activation is given in bereavement due to its finality and unchangeability. Possibly this is the reason why the putative AMD process, crying, is mainly seen (in adults) after this type of event. Propositions how to deal with the described obstacles in order to initiate the AMD process also for aversive memories without ‘finality’ component will be presented​ ​in​ ​a​ ​dedicated​ ​text​ ​(see​ ​the​ ​reference​ ​at​ ​the​ ​end​ ​of​ ​the​ ​short​ ​version​ ​of​ ​the​ ​EMD​ ​hypothesis).

6

The memory replay process underlying AMD activates the whole memory ‘film’, and thereby puts the entire memory trace, not only snapshot-like parts of it as in normal autobiographical memory retrieval, into a labile state ready for memory reconsolidation. In the dedicated text, AMD will therefore be proposed as to constitute a realization of recently proposed hypothetical therapeutic interventions that use memory as therapeutic target by means of memory reactivation and reconsolidation (Nader et al., 2013; Chiamulera et al., 2014). With two main differences that i) AMD is not extinction based, and ii) not only depotentiation, but also reconsolidation takes place entirely online, at the moment​ ​of​ ​replay​ ​of​ ​a​ ​memory​ ​component.

Notes  Origin of this hypothesis. ​The basic idea was that crying depotentiates aversive memories. The hypothesis presented in this text is actually a trial to reverse engineer the factors that governed the evolutionary development of AMD, and the mechanisms possibly involved in the AMD process. The reason to develop a somewhat abstract concept of traumatization (long-term memory + concept of consequence = concept of unchangeability) was to provide a​ ​framework​ ​that​ ​allows​ ​for​ ​the​ ​search​ ​of​ ​precursor​ ​or​ ​full​ ​AMD​ ​processes​ ​in​ ​animal​ ​species. Self involvement, not aversiveness, is the reason for online AMD. ​Even highly negative emotional states seem not necessarily to involve the conscious core self. E.g. during hypnosis, strong negative emotions and related complex behaviour can be observed (-). And during REM sleep, partly very strong emotions are processed that seem not to involve the core self and do not lead to wake up. This is for instance demonstrated in REM sleep behaviour disorder, where somatomotor inhibition is defective, and severe injuries can result from physical reactions to highly emotional dream content (Coeytaux et al., 2013). Such dream content and the accompanying physical reactions do not necessarily lead to waking up. This suggests that strong aversive emotions can be experienced during sleep, without leading to waking up. Therefore from the two possibilities for waking up during memory replay, aversiveness or self involvement of the replayed memory, I favor self involvement. It seems to me that the amount of ‘affectedness ‘ is relevant for waking up and that aversiveness depends on affectedness. Please note here the very interesting real-time feedback fMRI study of Brewer et al. (2013). The comments of one study participant demonstrate intriguingly the two main problems that occur when one tries to volitionally generate self-involvement, i) paradoxical deactivation of the self, by stating “... I’m focusing but I can’t get, I can’t get the self to kick in when I’m told to” (p. 4) and, ii) putative interference of ER strategies by stating “... and then I started conjuring up images of [my boyfriend] with her and it super spiked [red; i.e. the self got active] and ​then it just took a lot of effort so then I had to drop it… it was just so much energy, I couldn’t sustain it…” (p. 4, emphasis added). The ‘effort’ and ‘energy’ is here thought to be needed by the study participant in order to sustain the attentional focus on the emerging aversive memory against the focus shifting drive emanating from ER strategies that are automatically triggered by the emerging aversive memory (automatically triggered and difficult to withstand, because the aversive memory emerges from an ‘overlapping system’, where for the purpose of the generation of fast and automatic homeostatic reactions, the memory system and the pertaining homeostatic regulatory system are realized in the same neuronal network, see Kanding,​ ​2017b). Limitations. ​i) the focus is here on dACC memory depotentiation. But in reality, other parts of the memory have also to undergo depotentiation, e.g. the extinction part (probably located in the vmPFC), and aspects of aversive memories in deeper brain regions such as the periaqueductal gray (PAG), ii) the here covered spectrum of traumata that cause the wake up problem is probably too restricted. The concept of ‘affectedness’ would allow to broaden this spectrum to e.g. the mental aspects of physical traumatization and to traumata arising during childhood from the exquisite sensitivity of human children to social stress and unmet, emotionally laden expectations (in particular the latter problem leads to apparently unchangeable events). Also additive effects of traumata could increase the waking up problem. This problem is therefore probably underestimated in the current version of the AMD hypothesis. iii) the concept of ‘memory copy’ is too restricted. Actually, a memory is also changed during copy, e.g. by gist extradition,

7

loss of details etc. iv) of outstanding importance with respect to memory depotentiation, but not yet further developed in​ ​this​ ​text,​ ​is​ ​the​ ​probably​ ​fundamental​ ​difference​ ​between​ ​autobiographical​ ​memory​ ​retrieval​ ​and​ ​replay. Conflict​ ​of​ ​interest​ ​statement. The​ ​author​ ​declares​ ​no​ ​conflict​ ​of​ ​interest. Acknowledgements. Many​ ​thanks​ ​to​ ​Sulayman​ ​J.​ ​for​ ​his​ ​extensive​ ​work​ ​in​ ​typing​ ​and​ ​correcting​ ​this​ ​manuscript. Author information: RA Kanding is the pen name of a german computer scientist with lifelong interest in neurosciences.

References   1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

11. 12. 13. 14. 15. 16. 17. 18. 19.

Brans,​ ​K.,​ ​Koval,​ ​P.,​ ​Verduyn,​ ​P.,​ ​Lim,​ ​Y.​ ​L.,​ ​&​ ​Kuppens,​ ​P.​ ​(2013).​ ​The​ ​regulation​ ​of​ ​negative​ ​and​ ​positive​ ​affect​ ​in​ ​daily​ ​life. Emotion​,​ ​13​(5),​ ​926. Brewer,​ ​J.​ ​A.,​ ​Garrison,​ ​K.​ ​A.,​ ​&​ ​Whitfield-Gabrieli,​ ​S.​ ​(2013).​ ​What​ ​about​ ​the​ ​“self”​ ​is​ ​processed​ ​in​ ​the​ ​posterior​ ​cingulate cortex?. Chiamulera,​ ​C.,​ ​Hinnenthal,​ ​I.,​ ​Auber,​ ​A.,​ ​&​ ​Cibin,​ ​M.​ ​(2014).​ ​Reconsolidation​ ​of​ ​Maladaptive​ ​Memories​ ​as​ ​a​ ​Therapeutic​ ​Target: Pre-Clinical​ ​Data​ ​and​ ​Clinical​ ​Approaches.​ ​Front.​ ​Psychiatry​ ​Frontiers​ ​In​ ​Psychiatry​,​ ​5.​ Coeytaux, A., Wong, K., Grunstein, R., & Lewis, S. J. (2013). REM sleep behaviour disorder-more than just a parasomnia. Australian​ ​family​ ​physician​,​ ​42​(11),​ ​785. Critchley, H. D. (2009). Psychophysiology of neural, cognitive and affective integration: fMRI and autonomic indicants. International​ ​Journal​ ​of​ ​Psychophysiology​,​ ​73(​ 2),​ ​88-94. Do-Monte,​ ​F.​ ​H.,​ ​Quinones-Laracuente,​ ​K.,​ ​&​ ​Quirk,​ ​G.​ ​J.​ ​(2015).​ ​A​ ​temporal​ ​shift​ ​in​ ​the​ ​circuits​ ​mediating​ ​retrieval​ ​of​ ​fear memory.​ ​Nature​,​ ​519​(7544),​ ​460-463. Do​ ​Monte,​ ​F.​ ​H.,​ ​Quirk,​ ​G.​ ​J.,​ ​Li,​ ​B.,​ ​&​ ​Penzo,​ ​M.​ ​A.​ ​(2016).​ ​Retrieving​ ​fear​ ​memories,​ ​as​ ​time​ ​goes​ ​by….​ M ​ olecular​ ​psychiatry​, 21​(8),​ ​1027-1036. Eisenberger,​ ​N.​ ​I.,​ ​&​ ​Lieberman,​ ​M.​ ​D.​ ​(2004).​ ​Why​ ​rejection​ ​hurts:​ ​a​ ​common​ ​neural​ ​alarm​ ​system​ ​for​ ​physical​ ​and​ ​social​ ​pain. Trends​ ​in​ ​cognitive​ ​sciences​,​ ​8​(7),​ ​294-300. Etkin,​ ​A.,​ ​Egner,​ ​T.,​ ​&​ ​Kalisch,​ ​R.​ ​(2011).​ ​Emotional​ ​processing​ ​in​ ​anterior​ ​cingulate​ ​and​ ​medial​ ​prefrontal​ ​cortex.​ T ​ rends​ ​In Cognitive​ ​Sciences​,​ ​15​(2),​ ​85–93.​ ​http://doi.org/10.1016/j.tics.2010.11.004 Fox, M. D., Snyder, A. Z., Vincent, J. L., Corbetta, M., Van Essen, D. C., & Raichle, M. E. (2005). The human brain is intrinsically organized into dynamic, anticorrelated functional networks. ​Proceedings of the National Academy of Sciences of the United States​ ​of​ ​America​,​ ​102​(27),​ ​9673-9678. Gianaros, P. J., & Wager, T. D. (2015). Brain-body pathways linking psychological stress and physical health. ​Current directions in​ ​psychological​ ​science​,​ ​24​(4),​ ​313-321. Goldsmith, T. C. (2008). Aging, evolvability, and the individual benefit requirement; medical implications of aging theory controversies.​ ​Journal​ ​of​ ​theoretical​ ​biology​,​ ​252​(4),​ ​764-768. Goldstein, A. N., & Walker, M. P. (2014). The Role of Sleep in Emotional Brain Function. ​Annu. Rev. Clin. Psychol. Annual Review​ ​Of​ ​Clinical​ ​Psychology​,​ ​10​(1),​ ​679–708.​ ​http://doi.org/10.1146/annurev-clinpsy-032813-153716 Hobson, J. A. (2009). REM sleep and dreaming: towards a theory of protoconsciousness. ​Nature Reviews Neuroscience​, 10​(11),​ ​803-813. Kanding R. A. (2017a). Extinction memory damage - a common etiological mechanism for functional somatic syndromes like fibromyalgia,​ ​for​ ​the​ ​somatic​ ​symptom​ ​disorder,​ ​aging​ ​related​ ​health​ ​changes,​ ​and,​ ​surprisingly,​ ​the​ ​alcohol​ ​hangover. Kanding​ ​R.​ ​A.​ ​ ​(2017b).​ ​Memory​ ​formation​ ​in​ ​regulatory​ ​systems​ ​as​ ​a​ ​fundamental​ ​source​ ​of​ ​aging​ ​and​ ​disease. Kim, S. K. (2007). Common aging pathways in worms, flies, mice and humans. ​Journal of Experimental Biology​, ​210​(9), 1607-1612. Lane, R. D., & Wager, T. D. (2009). The new field of Brain–Body Medicine: What have we learned and where are we headed? NeuroImage​,​ ​47​(3),​ ​1135–1140.​ ​http://doi.org/10.1016/j.neuroimage.2009.06.013 Lane, R. D., Waldstein, S. R., Chesney, M. A., Jennings, J. R., Lovallo, W. R., Kozel, P. J., ... & Cameron, O. G. (2009). The rebirth of neuroscience in psychosomatic medicine, Part I: historical context, methods, and relevant basic science. Psychosomatic​ ​medicine​,​ ​71​(2),​ ​117-134.

8

20. Levin, R., & Nielsen, T. (2009). Nightmares, bad dreams, and emotion dysregulation a review and new neurocognitive model of dreaming.​ ​Current​ ​Directions​ ​in​ ​Psychological​ ​Science​,​ ​18​(2),​ ​84-88. 21. Levin,​ ​R.,​ ​&​ ​Nielsen,​ ​T.​ ​A.​ ​(2007).​ ​Disturbed​ ​dreaming,​ ​posttraumatic​ ​stress​ ​disorder,​ ​and​ ​affect​ ​distress:​ ​A​ ​review​ ​and neurocognitive​ ​model.​ ​Psychological​ ​Bulletin​,​ ​133​(3),​ ​482–528.​ ​http://doi.org/10.1037/0033-2909.133.3.482 22. Miall,​ ​R.​ ​C.,​ ​&​ ​Robertson,​ ​E.​ ​M.​ ​(2006).​ ​Functional​ ​imaging:​ ​is​ ​the​ ​resting​ ​brain​ ​resting?.​ ​Current​ ​Biology​,​ ​16​(23),​ ​R998-R1000. 23. Miceli,​ ​M.,​ ​&​ ​Castelfranchi,​ ​C.​ ​(2003).​ ​Crying:​ ​Discussing​ ​its​ ​basic​ ​reasons​ ​and​ ​uses.​ N ​ ew​ ​ideas​ ​in​ ​Psychology​,​ ​21​(3),​ ​247-273. 24. Milad,​ ​M.​ ​R.,​ ​&​ ​Quirk,​ ​G.​ ​J.​ ​(2012).​ ​Fear​ ​Extinction​ ​as​ ​a​ ​Model​ ​for​ ​Translational​ ​Neuroscience:​ ​Ten​ ​Years​ ​of​ ​Progress.​ A ​ nnual Review​ ​Of​ ​Psychology​,​ ​63​(1),​ ​129–151.​​ ​http://doi.org/10.1146/annurev.psych.121208.131631 25. Miller, G., Chen, E., & Cole, S. W. (2009). Health psychology: Developing biologically plausible models linking the social world and​ ​physical​ ​health.​ ​Annual​ ​review​ ​of​ ​psychology​,​ ​60​,​ ​501-524. 26. Nader,​ ​K.,​ ​Hardt,​ ​O.,​ ​&​ ​Lanius,​ ​R.​ ​(2013).​ ​Memory​ ​as​ ​a​ ​new​ ​therapeutic​ ​target.​ D ​ ialogues​ ​Clin​ ​Neurosci​,​ ​15(​ 4),​ ​475-86. 27. Nieuwenhuis,​ ​I.​ ​L.,​ ​&​ ​Takashima,​ ​A.​ ​(2011).​ ​The​ ​role​ ​of​ ​the​ ​ventromedial​ ​prefrontal​ ​cortex​ ​in​ ​memory​ ​consolidation.​ B ​ ehavioural brain​ ​research​,​ ​218​(2),​ ​325-334. 28. Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Powers, W. J., Gusnard, D. A., & Shulman, G. L. (2001). A default mode of brain function.​ ​Proceedings​ ​of​ ​the​ ​National​ ​Academy​ ​of​ ​Sciences​,​ ​98​(2),​ ​676-682.

29. Rasch,​ ​B.,​ ​&​ ​Born,​ ​J.​ ​(2013).​ ​About​ ​sleep's​ ​role​ ​in​ ​memory.​ ​Physiological​ ​reviews​,​ ​93​(2),​ ​681-766.

30. Rohleder,​ ​N.​ ​(2014).​ ​Stimulation​ ​of​ ​systemic​ ​low-grade​ ​inflammation​ ​by​ ​psychosocial​ ​stress.​ P ​ sychosomatic​ ​medicine​,​ ​76​(3), 181-189. 31. Roy,​ ​M.,​ ​Shohamy,​ ​D.,​ ​&​ ​Wager,​ ​T.​ ​D.​ ​(2012).​ ​Ventromedial​ ​prefrontal-subcortical​ ​systems​ ​and​ ​the​ ​generation​ ​of​ ​affective meaning.​ ​Trends​ ​In​ ​Cognitive​ ​Sciences​,​ 1 ​ 6​(3),​ ​147–156.​ ​http://doi.org/10.1016/j.tics.2012.01.005 32. Shackman,​ ​A.​ ​J.,​ ​Salomons,​ ​T.​ ​V.,​ ​Slagter,​ ​H.​ ​A.,​ ​Fox,​ ​A.​ ​S.,​ ​Winter,​ ​J.​ ​J.,​ ​&​ ​Davidson,​ ​R.​ ​J.​ ​(2011).​ ​The​ ​integration​ ​of​ ​negative affect,​ ​pain​ ​and​ ​cognitive​ ​control​ ​in​ ​the​ ​cingulate​ ​cortex.​ ​Nature​ ​Reviews​ ​Neuroscience​,​ ​12​(3),​ ​154-167. 33. Talamini, L. M., & Gorree, E. (2012). Aging memories: Differential decay of episodic memory components. ​Learning & Memory​, 19​(6),​ ​239-246.

9