Stress- and trauma-related blockade of episodic-autobiographical memory processing

Journal Pre-proof Stress- and trauma-related blockade of episodic-autobiographical memory processing Angelica Staniloiu, Andreas Kordon, Hans J. Markowitsch PII:

S0028-3932(20)30034-8

DOI:

https://doi.org/10.1016/j.neuropsychologia.2020.107364

Reference:

NSY 107364

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Neuropsychologia

Received Date: 30 June 2019 Revised Date:

14 January 2020

Accepted Date: 24 January 2020

Please cite this article as: Staniloiu, A., Kordon, A., Markowitsch, H.J., Stress- and trauma-related blockade of episodic-autobiographical memory processing, Neuropsychologia (2020), doi: https:// doi.org/10.1016/j.neuropsychologia.2020.107364. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.

1 Stress- and trauma-related blockade of episodic-autobiographical memory processing Angelica Staniloiu1, 2 3 Andreas Kordon3 4 and Hans J. Markowitsch1 1

University of Bielefeld, Germany, 2University of Bucharest, Romania, 3Oberberg Clinic Hornberg, Germany, University of Freiburg, Germany

Address for all correspondence: Hans Markowitsch University of Bielefeld Physiological Psychology POB 100131 33501 Bielefeld Germany [email protected]

2 Abstract Memory disorders without a direct neural substrate still belong to the riddles in neuroscience. Although they were for a while dissociated from research and clinical arenas, risking becoming forgotten diseases, they sparked novel interests, paralleling the refinements in functional neuroimaging and neuropsychology. Although Endel Tulving has not fully embarked himself on exploring this field, he had published at least one article on functional amnesia (Schacter et al., 1982) and ignited a seminal article on amnesia with mixed etiology (Craver et al., 2013). Most importantly, the research of Endel Tulving has provided the researchers and clinicians in the field of dissociative or functional amnesia with the best framework for superiorly understanding these disorders through the lens of his evolving concept of episodic memory and five long term memory systems classification, which he developed and advanced. Herein we use the classification of long-term memory systems of Endel Tulving as well as his concepts and views on autonoetic consciousness, relationships between memory systems and relationship between episodic memory and emotion to describe six cases of dissociative amnesia that put a challenge for researchers and clinicians due to their atypicality. We then discuss their possible triggering and maintaining mechanisms, pointing to their clinical heterogeneity and multifaceted causally explanatory frameworks.

Keywords: Functional amnesia Autonoetic consciousness Effort Malingering Conversion syndrome

belle indifference

3 1. Introduction Starting with the so-called cognitive revolution (Neisser, 1967; Gardner, 1985; Miller, 2003), cognition and emotion have frequently been considered to be opposing concepts: Cognition being associated with “high”, “cold”, and “complex” and related to the cerebral cortex, and emotion as “low”, “hot” and “simple” and as processed subcortically (see, e.g., Table 1 of Cromwell and Panksepp, 2011, and their conceptual criticisms; see also Northoff, 2012; Oatley and Johnson-Laird, 1987; Pinker, 2005). Though the cognitive revolution began prior to the boom of the neurosciences, it had a major influence on memory research (Tulving, 1972, 1983). Here it led to a transition from research in verbal learning (Tulving et al., 1965; Tulving, 1969) to general mechanisms of information recall, including research on familiarity and recollection. Neisser (1967) emphasized that internal mental processes could be measured and that we do not remember actual events, but memories of them which are fragments of the events and may be distorted (see his later research, e.g., Neisser and Harsh, 1992). Hardt et al. (2010) wrote on page 152: “The very act of reconstruction gives room for distortions of many kinds.” And here comes an important link between emotion and cognition (and introspection): Emotions influence memory and the ability to memorize to a major extend. They can enable and enhance or delay memory recall (Markowitsch and Staniloiu, 2011a). On the other hand, cognitive processing may be needed to elicit emotional responding (Brosch et al., 2013). Thompson and Tulving’s (1970) encoding-specificity principle implies that memory recall is most effective when the conditions at the time of encoding correspond to the conditions at the time of retrieval. This means that, for example, an euphoric or a depressive state at the time of encoding should match an euphoric or a depressive state during retrieval (see Makowski et al., 2017; Mizrak and Öztekin, 2016). The importance of emotion in supporting remembering had been suggested by Sigmund Freud at the end of the 19th century. Although the intimate relationship between emotion and episodic memory is not captured by the last definition of episodic memory by Endel Tulving (Tulving, 2007), already in 1983 Tulving underlined that affect is more important for episodic memory than for semantic memory (p. 9, p. 42f). Probably the most extreme case where memory is affected by emotions concern the psychiatric disease condition of dissociative amnesia (Markowitsch and Staniloiu, 2016; Staniloiu and Markowitsch, 2014). In dissociative amnesia the main symptom is usually an inability to retrieve the personal past (or portions of it), accompanied by a loss of personal identity (when the total past is inaccessible). More recently, there has been an increase in the number of cases studies describing patients with preponderantly anterograde, instead of retrograde dissociative amnesia (although in comparison to the cases of retrograde dissociative amnesia, the cases of isolated or preponderantly anterograde dissociative amnesia seem rare) (Staniloiu and Markowitsch, 2014; Markowitsch and Staniloiu, 2013). In both conditions, usually no concomitant brain damage can be detected on the structural level. In line with the principal preservation of brain tissue, it is assumed that the autobiographical memories are not totally lost, but temporarily inaccessible. Evidence for this assumption comes from several sources: First, there are patients who recover and then are able to retrieve all their memories (Lucchelli et al., 1995); secondly, under specific treatment conditions such as sodium amytal abreaction (Stuss and Guzman, 1988), hypnosis (Fine, 2012), or more conventional forms of psychotherapy, memories may be reinstated (Staniloiu and Markowitsch, 2018). The mechanisms, leading to dissociative amnesia can be divided into those which trigger the immediate outbreak of the amnesia and those which over longer time periods provide the ground for a later outbreak of the amnesia. The immediate outbreak is sometimes in the dark, sometimes it can

4 only indirectly be inferred, and sometimes it appears to be minor to the outsider. Examples are the message that one must do something which one dislikes doing, or the message that one has a disease, or a minor car accident. The long-term acting mechanisms, making a person prone to dissociative amnesia are different and were discussed in detail in Staniloiu and Markowitsch (2012). Staniloiu and Markowitsch (2012) listed nine possible – though not mutually exclusive – longterm acting mechanisms inducing (and maintaining) dissociative amnesic states: • The psychological stress model: stress and episodic-autobiographical memory retrieval blockade • The psychological stress model: stress and episodic-autobiographical memory consolidating defect • The executive deficit model in functional amnesia • Motivated forgetting • The impairment in emotional colorization and first person autonoetic connection • The binding deficiency model • The fantasy proneness model or the cognitive failures model (errors by commission) • The loss of information model • Socio-cognitive models of functional amnesia The two stress models assume that past individual stress and trauma situations – together with further factors such as personality features and prior experiences – lead to a stress hormonesrelated changes in the brain of the patients, inducing and maintaining the psychogenic amnesic state. These models relate to Sigmund Freud’s (1893) idea that hysteria is caused by incompletely abreacted traumata. Usually dissociative amnesia occurs in patients with a labile personality; frequently the occurrence of stressful or traumatic events starts already in childhood or youth (Staniloiu and Markowitsch, 2014, 2015; Markowitsch and Staniloiu, 2016). The first stress model is assumed to hold for the frequently found retrogradely amnesic cases, the second one for the rare anterograde version (cf., e.g., Table 2 of Staniloiu and Markowitsch, 2014, in which features of cases with anterograde dissociative amnesia are depicted. Research with functional brain imaging (glucose positron-emission-tomography) carried out in patients with dissociative amnesia of preponderantly retrograde nature revealed a dysfunction of fronto-temporal regions, especially of the right hemisphere (LaBar and Cabeza, 2006; Brand et al., 2009; Tramoni et al., 2009; Thomas-Antérion et al., 2010, 2014); here are also the hippocampal formation and the amygdala situated- regions containing a high density of receptors for stress hormones in the brain (Lupien et al., 2005, 2009, 2011; Lupien and Maheu, 2000; Vaisvaser et al., 2013). The prefrontal cortex inhibits the retrieval of unwanted, stressful memories via its supervisory attention system. Like the anterior temporal structures, the prefrontal cortex contains many receptors for glucocorticoids (stress hormones) (Shansky and Lipps, 2013). This constellation provides the scaffolding of the executive deficit model, in which it is assumed that an overload of the executive system may reduce frontal capacities necessary for successful retrieval of other nontraumatic or non-stressful personal memories. The fourth hypothesis – ‘motivated forgetting’ – assumes that there may have been a motif to forget which even may have been conscious, but that then with time, there came a transition phase which at the end led to unconscious forgetting or functional amnesia. Ideas towards such a constellation are old (Lennox, 1943) and were revived from time to time (Barbarotto et al., 1996; Jenkins et al., 2009). Already Sigmund Freud repeatedly pointed out, that patients with neuroses, traumata, psychic conflicts, and hysterical amnesia “flee into illness” (Freud, 1915, 1916-17/1999, 1919/1999; Langnickel and Markowitsch, 2006).

5 With the (fifth) hypothesis on impaired emotional colorization and its relation to a first person autonoetic perspective, it is described that patients with dissociative amnesia lack the normal embeddedness of newly acquired episodes in an emotional flavor and also the perspective of “meness” (Claparede, 1911; Vandekerckhove, 2009; Markowitsch and Staniloiu, 2011c), that is that the new episode is part of myself. The binding deficiency model (sixth hypothesis) assumes deficits in binding and reassembling details of the personal past in patients with dissociative amnesia. The seventh hypothesis – fantasy proneness as long-lasting trigger in patients with dissociative amnesia – has been debated in relation to the stress hypothesis (Giesbrecht et al., 2008; Dalenberg et al., 2012, 2014; Lynn et al., 2014). Proponents to the fantasy model assume that the reports of traumatic memories in dissociative disorders are largely errors of commission, due to fantasy proneness, suggestibility, or cognitive failures. Dalenberg and co-workers (2012, 2014), however, provide good arguments against the fantasy proneness model and in favor of the stress models. The loss of information model (eighth hypothesis) holds for memories which do not recover when other memories reappeared in patients with a history of dissociative amnesia. It is assumed that these memories were never properly encoded or consolidated at the time of the incident or that the person suffers from global intellectual deterioration over time. (It is assumed that continued and severe stress conditions may lead to dementia, or at least contribute to intellectual decline; Porter and Landfield, 1998; Ladowsky-Brooks and Fischer, 2003). Lastly, the socio-cognitive models of functional amnesia refer to the socio-cultural milieu in a broad sense. Social learning and expectancies, culturally molded sensation schemas, and explanatory models of illness may shape the existence (Xiao et al., 2006) and symptomatology in functional amnesia (Hinton et al., 2008; Linden et al., 2012). These mechanisms show that dissociative amnesias are triggered and maintained on the bases of manifold interacting internal and external variables. Herein we present six cases of dissociative amnesia that are less typical, in order to emphasize the diverse and heterogenous nature of this diagnostic entity with respect to clinical, neuropsychological, comorbidity aspects as well as putative mechanisms causally involved and subsequently draw the attention of clinicians and researchers to its chameleonic presentation. We underline the importance of the concept episodic memory for understanding the phenomenology of dissociative amnesia, a disorder in which the episodic memory tends to be preponderantly or solely affected. In addition, we emphasize the usefulness of the classification of the long-term memory systems and the SPI (Serial, Parallel, Independent) model promoted by Endel Tulving in understanding this condition. We also elaborate on his concept of autonoetic consciousness and how this concept applies to patients with dissociative amnesia. We briefly touch on less known aspects of the work of Tulving in the realm of episodic memory, such as the relationship of the episodic memory with emotion or affectivity. We aim to examine which of the theories/hypotheses described above best fit the cases described below and how they might relate to each other, and to show how diverse and multifaceted amnesia without a clear brain basis can be. 2. Cases with dissociative amnesia and related amnesic conditions All patients were investigated in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and for all of them written informed consent was obtained for publishing them in anonymous form. Features of the cases are summarized in Table 1. _______________________

6 Insert Table 1 about here _______________________ Case Ninja. Ninja was a second-generation female migrant with a multicultural family background. A migration background may at times constitute a facilitating factor for developing dissociative amnesia, as suggested by surveys on possible relations between dissociative amnesic conditions and migration (Staniloiu et al., 2010, 2017; Markowitsch and Staniloiu, 2011b; Tsoi, 1973). Ninja was 16-year-old when she was assessed by our team. Prior to the onset of her amnesic condition she had performed excellently in school, being among the best students. Her performance decreased dramatically after age 12 years, when she sustained a sport-related accident. During gymnastics she fell from the top of a pyramid of girls on the floor. A traumatic brain injury of mild severity (concussion) was highly suspected. While there was no evidence of brain damage on standard neuroimaging, she showed a mental state suggestive of a moderate post-traumatic confusional state and subsequently she was admitted to a rehabilitation clinic; in the rehabilitation center Ninja sustained a second fall on stony stairs. Shortly after the second fall she lost conscious access to her personal past events or episodes. In addition, she showed an inability to retrieve large portions of her acquired school knowledge. After the fall on the staircase Ninja also developed a paralysis of her right arm. She underwent neurological investigations that yielded negative results and was subsequently diagnosed with a functional (conversion) paralysis (Table 1). In addition to retrograde amnesia for personal events and school general knowledge, Ninja showed changes in other cognitive, somatic and behavioral areas, which followed a chronic course. She became unable to attend a public school, and subsequently received private schooling. New somatic symptoms emerged just a few weeks before the neuropsychological and neuropsychiatric testing with our group. Several weeks (more than four weeks) prior to the testing session, Ninja was a passenger seated in the back seat of a car that was involved in a car accident. Her mother drove the car at the time of the accident. No injuries (including mild traumatic brain injury) were noted or documented at the time of the accident (It is however worth mentioning that a substantial number of concussions situated at the very mild spectrum of severity are often missed or undiagnosed); in the aftermath of the accident Ninja became unable to micturate and subsequently had to be catheterized. A surgical attempt to alleviate the voiding dysfunction was unsuccessful and subsequently strengthened the suspicion that the voiding condition had strong psychogenic components. Similar cases of psychogenic or functional voiding dysfunctions accompanying or not dissociative amnesic conditions have been described in the literature by our group (Staniloiu et al., 2011) and others (Berlin et al., 1980). Ninja was tested by our team neuropsychologically, psychiatrically and with questionnaires circa four years after her two falls. Her paralyzed right arm already showed signs of muscular atrophy due to long-term nonuse and more frequent use of the left upper extremity. Ninja did not meet full diagnostic criteria for a Post-traumatic stress disorder or major depressive disorder at the time of the assessment. At the time her parents reported that her intellectual condition appeared to be worse than in the years before. She and her parents reported that Ninja at present could count and calculate only up to the number ten. Her performance in neuropsychological tests was overall poor or very poor. Interestingly, Ninja performed quite poorly in tests of memory malingering, including the simplest Rey-15-item test (8 out of 15 correct). With scores of 15 (Trial 1), 13 (Trial 2), and 13 (Retention trial) in the Test of Memory Malingering (TOMM; Tombaugh, 1996) she scored widely

7 below chance level, which would be interpreted as definite feigning or malingering (as 25 out of 50 would be chance level). We could not detect any specific pattern in her correct or incorrect responses aside from a somewhat slower reaction in the case of incorrect responses (e.g., Spence and Kaylor-Hughes, 2008). While several studies found that effort (and therefore also the scores in the TOMM) is or are correlated with psychometric test performance (e.g., Locke et al., 2008), scores so deviant even from chance level cannot be fully explained by a more general neurocognitive deterioration, because then she should have performed at chance level, but not nearly 50% below chance. Ninja stated that she can only count to 10, an information that was corroborated by her parents. This assertion was puzzling given that Ninja performed very successfully in school until the age of 12 years. The case of Ninja is an example of challenges that might arise in clinical and research arena with respect to timely and accurately securing a diagnosis of dissociative amnesia. Her amnesia had its onset after two falling incidents; at least one of the falling incidents was accompanied by a mild traumatic brain injury. The onset of dissociative amnesia or other dissociative disorders or conversion disorders after a mild traumatic brain injury or falling incidents has been largely documented in the literature (Mooney and Speed, 2001). We relatively recently underlined through a case series that a substantial number of neurological and cognitive symptoms that develop after a mild traumatic brain injury may be dissociative or functional in nature. The extent to which these symptoms are the direct result of the mild traumatic brain injury or the primary result of the psychological consequences of the event triggering the mild TBI (such as in the case of mild TBI after motor vehicle accidents) remains still debated. Most of the cases with functional or dissociative amnesia after mild traumatic brain injury on a background of immigration, which were described in past publications by our group, were men. This is congruent with the fact that traumatic brain injuries are more frequent in men than in women. However, higher rates of sport concussions may occur in women than in men when similar sports are compared (Laker, 2011). The emergence of the full symptomatology of Ninja after the second fall suggests an element of learned behavior (Harrison et al., 2017). The co-existence of functional (conversion) neurological symptoms with dissociative amnesia has been extensively documented by our research group and others and found to potentially worsen the memory impairment, self-referential processing and prognosis (Arzy et al., 2011). Although the criterion of psychological stress is not a prerequisite anymore for a diagnosis of functional neurological disorder (FND) in DSM-5, research continues to unearth evidence for past sensitizing psychological and or physical events in the case of the FND. Ninja case also reflects one of the biggest challenges in the clinical and research realm of dissociative amnesia: the task of accurately differentiating between the true amnesia and simulation. Several authors pointed over the years to the possibility of the existence of an overlap in dissociative amnesia between “true” amnesia and simulation (Lennox, 1943; Barbarotto et al., 1996; Jenkins et al., 2009; Spiegel et al., 2009). The performance of Ninja on the TOMM test is suggestive of a deceptive component in addition to (or superimposed on) the dissociative mechanism. While we could not find clear evidence for malingering, there were suggestions of concurrent symptoms of factitious disorder. Factitious (derived from the Latin verb facere [to do]) disorder was in 2013 reclassified in DSM-5 (APA, 2013) under the heading of Somatic Symptom and Related Disorders (like functional neurological symptom [conversion] disorders). Selfimposed factitious disorders have been described in children (especially at the time of puberty) and adolescents, especially in girls, with various socio-economic backgrounds, with several reports mentioning that the affected children or adolescents performed or had performed well in school (Ehrlich et al., 2008). A retrospective study (Ehrlich et al., 2008) found that falsified illness through

8 simulation or by describing a fictitious history or symptomatology (Pseudologia fantastica) was more common in the pediatric or adolescent population than fabrication of verifiable abnormalities. In another vein, negative correlations were found between age and dissociation scale scores (Putnam, 1997). This may partly explain why most cases of functional amnesia are diagnosed in the young age (Coons and Milstein, 1992; Maldonado and Spiegel, 2008; Reinhold and Markowitsch, 2007), including childhood. The case Ninja merits in our opinion clinical and research attention due to several distinct features: the age of onset, the chronic course, the mixed antecedents or past sensitizing incidents (mild TBI, falling incidents, car accident with its possible psychological and physical consequences), the overlap between true amnesia and simulation, the apparent cognitive and behavioral deficits extending beyond the amnesia, the second generation migration background. the high premorbid performance level, the co-occurrence of Somatic Symptom and Related Disorders. The likely presence of more than a psychological mechanism maintaining Ninja s condition is not uncommon. In fact, McKay and Kopelman (2009) have criticized the use of the term dissociative amnesia interchangeably with the term psychogenic amnesia. The term dissociative amnesia is a priori theoretically loaded, while the term psychogenic amnesia allows flexibility in terms of the psychological mechanisms causally involved. The patient on the one hand reflects in principal the condition leading to dissociative amnesia, namely at least two incidents which were seen by her as severely stressful or traumatic (cf. also the case of Piolino et al., 2005). We have termed this the ‘two-hit hypothesis’ (Staniloiu and Markowitsch, 2014; Markowitsch and Staniloiu, 2016) and depicted in Figure 6 in Staniloiu and Markowitsch (2019a) and in Table 36.2 in Markowitsch and Staniloiu (2016). She also shows that a dissociative amnesic condition may lead to further psychosomatic disease conditions (paralyzed arm, urinary dysfunction) which may help to maintain the role of a disabled person. We previously described a patient with a similar expansion of diseases in this field in Staniloiu et al. (2018) (Patient P) and originally in Fujiwara et al. (2008) (Patient G.H.). Ninja’s case in a way is paralleled by the case of TA, described in Markowitsch et al. (1999). TA at the start of her anterograde dissociative amnesia had had a car accident. Subsequently, she remained amnesic up to the present. In addition to her amnesia she also manifested changes on the somatic level (e.g., hormonal changes). Likewise, in a way like Ninja (though later in her study career), TA prior to her amnesia seemed to have had all prerequisites to become a successful lawyer, judge or related professional. Case Peter. Peter was a 29-year-old married student with two young children. He became amnesic after a car accident, when he suffered a fracture in the thorax area that resulted in a short hospitalization. Magnetic resonance imaging (MRI) of the brain was unremarkable. However, after the accident, Peter became severely retrogradely amnesic, a state that persisted over months. He failed to recognize his wife, children and parents. He reportedly could not recognize his face in a mirror (similar as in 2 other cases we published on: Markowitsch et al., 1997; Pommerenke et al., 2012). He lost all past personal memories; he also lost access to prior knowledge, which he had acquired, in order to study for his desired future professions. Third party information revealed that Peter had grown up with a dominant father, who considered Peter a “failure” and who had divorced from Peter’s mother for another romantic relationship. The father stated that Peter was negatively impacted by the divorce of his parents. Peter wished to study medicine, but could not enter medical school due to insufficient grades. He then trained as a nurse, in order to acquire medical practical knowledge and experience for fulfilling his still active dream of becoming a medical doctor. When he

9 realized that his chances to study medicine were slim, he enrolled in studying biology. After concluding that the biology field was not a good fit for him, he decided to train to become a teacher and subsequently began studying Latin and history. Peter stated that after his accident he attempted to attend university seminars in history and Latin, but, especially in the case of Latin, he was unable to grasp anything. When our team tested Peter neuropsychologically, we also asked him to translate some basic Latin expressions such as “Plenus venter non studet libenter”, “Dona nobis pacem”, or apply grammatical rules (declination of ‘unus, solus, totus, ullus, alius’). He was unable to consciously understand any Latin word or describe or apply any grammatical rule. Similar problems with being unable to consciously recall a welllearned second language or even the mother tongue were reported previously in cases of dissociative or functional amnesia (e.g., Kritchevky et al., 1997; Glisky et al., 2004). After reviewing the pros and cons with one of the authors, Peter and his wife decided to participate in an interview conducted by a major magazine that produced a special issue on memory. In this interview Peter provided additional information about his symptoms and life. For example, he revealed that he met an old friend at his sibling’s party. He reported that, although he knew that his face was familiar to him, he did not recall anything about the relation he had had with him, or the degree of emotional closeness. He stated that his feeling in such situations is like the feeling during a tip-of-the-tongue phenomenon: “The mind says, the information must be there, and the other persons tell you that you know this person. And you always give the order to the brain – now work on it. But in my head is nothing. It is a huge hole, and one does not understand why nothing comes up. It is not even like a needle in the haystack. There is no needle.” Apparently, Peter’s amnesia did not start immediately after the car accident, but more likely in the hospital (Minnich and Sweetwood, 2008). His wife said that he wanted to call her in the ambulance car, but (probably because of the very stressful situation) he did not recall the pin of his mobile phone and her telephone number – although he apparently recalled that he had a wife. Upon arrival in the hospital, he was able to freely recall that he was a nurse by profession; however, he apparently already forgot that he had quit the nurse job and had become again a student (first of biology, then of Latin and history). He did not recall passwords but was partly lucky as a friend told him that they both had the same sequence of numbers, namely that that was written on the back of the shirt of a football star. Peter’s wife revealed that prior to the accident, Peter had a vast knowledge; he always seemed to know everything and explained it to her at length, while after the accident he could not even laugh about common jokes from their past life. Peter also reflected in the interview about what he termed his incomplete personality: He reported being unable to remember his past. He said that he did not know what to do in the future. He commented on the concern of his wife and relatives about his future, saying that they all have their thoughts about him, while he himself is, as he stated, much less concerned. He said: “I am the only one for whom my amnesia more or less does not matter much.” He seemed, however, to be concerned about what would come up in his therapy, whether it would turn out that he was victim of a crime or whether he himself had done something unlawful. He doubted that he had done a criminal act, because he did not think that this was his type. He however stated: “But I cannot guarantee. Because so much is unsure, so much is gone, one must give such things a residual probability. … That brings a huge uncertainty. If someone would persuade me, I would have to accept, though it would be totally strange. My memory are the others.” During the neuropsychological assessment, Peter showed difficulties in retrieving more difficult words during the naming task; therefore, his IQ of 97 might have been an underestimation

10 (Table 1). For instance, he did not know what a piranha or a drake is, or what the difference between a dromedary and a camel is (despite having started to study biology). He also did not know what an APP is, or what ecstasy is, nor could he explain what halogen headlights are, what the ozone hole is, or what bungee jumping is. He also had no associations with the word ‘Dracula’ or with ‘Lady Diana’. In general, his retrograde memory abilities – also with respect to famous persons – were poor, while in anterograde memory tests he performed generally average (e.g., Doors test of the Doors and People Test of Baddeley et al., 1994; Verbal Learning and Memory Test of Helmstädter et al., 2001). Only in the Logical Memory Test of the Wechsler-Memory-Scale-revised (Härting et al., 2000) his performance was poor. He had problems with word generation and abstraction (finding commonalities) as revealed by his results from testing with the Boston Naming Test (Kaplan et al., 2001), MoCa, DemTect, the Abstract Reasoning Test, and the Sorting Task of Delis et al. (1992). His emotional theory-of-mind capabilities appeared significantly impaired as measured by Baron-Cohen’s Reading the Mind in the Eyes Test (Baron-Cohen et al., 2001; German translation). He responded to less than half of the stimuli correctly. The diagnosis of dissociative amnesia, given to Peter, may also be supported by his lack of concern about his mental condition and professional future. This has been described as la belle indifference in the old literature (Breuer and Freud, 1895; Janet, 1894, 1907) and found repeatedly also in present-day work on patients with dissociative amnesia (e.g., Reinhold and Markowitsch, 2009). (The term la belle indifference has nevertheless been criticized for its vagueness and not enabling a clear differentiation between patients with functional and organic amnesia; Stone et al., 2006). Despite that Peter behaved inconspicuously in symptom validity tests such as the Test of Memory Malingering (Tombaugh, 1996) and the Rey-15-Item Test (Arnett et al., 1995; Back et al., 1996; Goldberg and Miller, 1986), his poor performance in many of the applied tests (whether measuring attentive, affective, or other cognitive functions) resembles the behavior of patients demonstrating a lack of effort. We already in 1997 had described a young man with very similar characteristics to Peter (including the lack of effort in continuing his professional studies) (Kessler et al., 1997). Below we describe another patient who shared many similarities to both the case of Kessler et al. and to Peter. Case Karl. Karl was a young man of 26 years of age, who lived with his parents. He stated that since several years his memory had deteriorated considerably. He reported beyond unable to recall information beyond a very few seconds. He stated that at present, he was unable to work. However, in the evening prior to being tested neuropsychologically (the testing took place the next morning), he had dictated to his mother all his problems, covering circa six pages. In this “manifesto” he stated that was unable to watch TV (he had a very large TV screen in his room), because “the pictures move too fast”. He would try from time to time to view soccer games or the news but would not succeed. In the last five years he would make notes; his logical thinking no longer would function, and he would be unable to formulate long sentences. When watering the flowers, he after a few pots would have forgotten which ones already were watered and which not. Sometimes he would forget to switch off the stove or his pizza would burn in the microwave. When showering he sometimes would forget whether he already had used shampoo. He even would forget routine sequences, for example, for preparing and serving coffee. However, some of his above descriptions were not objectively confirmed when observing his behavior. He reported to have had three girlfriends during the last years who all left him very soon, partly by mocking him. A mobbing behavior allegedly occurred to him at this workplace where he –

11 prior to being granted sick leave and one year later dismissed – increasingly wrote notes to recall what he had to do. Structural brain imaging remained inconspicuous (Table 1). Testing results did not reflect the severity of his description about his attentive and cognitive capacities. His performance yielded within normal limits results in the Trail Making Test (TMT) A and B. In the revised Wechsler-Memory-Scale (WMS-r), his Attention Quotient was 110 and therefore even above average. In other parts of the WMS-r, his performance yielded mixed results (General Memory Index: 72, Visual Memory Index: 99, Verbal Memory Index: 62, Delayed Memory Index: 74). He made no errors in Part A of the Doors Test of Baddeley et al. (1994), and 5 errors in the more difficult part B. Retrograde memories seemed to be partly preserved, especially with respect to events pertaining to diseases he had had as a child, namely neurodermitis until about age seven, allergy against molds, a bike accident with a broken leg at age eight. He also recalled several famous faces. Performance on verbal fluency and abstract reasoning tasks yielded results that were within normal limits. However, very similar to patient Peter, he was impaired in his theory-of-mind capacity, responding correctly in only half of the items of the Reading the Mind in the Eyes Test. In the Beck Depression Inventory (BDI-II; Beck et al., 1996) he was with a score of 12 just at the border to a minor depressive symptomatology. Karl showed no indices of malingering or feigning in any of several symptom validity tests. In the Rey-15-Item Test (Lezak et al., 2012) he repeated all 15 items, in the Test of Memory Malingering (Tombaugh, 1996) he first scored 46 (which is 1 point below what can be expected), but then was errorless in the next two repetitions. In the Amsterdam Short-Term Memory Test (Schagen et al., 1997) he also performed at a normal level (2 errors in the first half of the test). In addition to these international symptom validity tests we administered him tests from a German language test battery on forensic neuropsychology (Heubrock and Petermann, 2000). His only error was that he mixed roses with cloves. In Personality Questionnaires (Saarbrücken Personality Questionnaire; Freiburg Personality Inventory; Beven et al., 2004; Paulus, 2012; Fahrenberg et al., 2001) Karl in general had no gross deviations from normality. In the Freiburg Personality Inventory responses gave indications that he was sociable, extraverted and enterprising. However, this interpretation has to be made with caution as he only had a stanine-score of 2 in the scale ‘openness’, and the advice of the authors of the questionnaire emphasizes that all other results cannot be interpreted rigorously, when the stanine falls in the range between 1 and 3. Karl, Peter and A.A. – the patient described in Kessler et al. (1997) – were men in their late twenties who had broken careers and seemed to have not had too much impetus to engage in working for their future life. They had suffered from several probably stressful situations in their childhood and youth. This lack of effort and energy also resulted in cognitive, particularly memory problems which had the character of dissociative amnesia: They did not care much about their conditions; the investigation took place preponderantly at the request of their close relatives, such as parents. The patients agreed with the testing but showed an emotional bluntness (la belle indifference; see above). Case Charles. Charles, on the other hand, presented by himself, asking to be assessed by our team. He was already 41 years old, had high-school education and stated that he had very severe memory problems. In addition, he described having certain similar symptoms as Karl; he also said that TV watching became impossible for him, as the sequence of pictures was too fast for him to follow it meaningfully. He also stated that he grinded his teeth so much that they all had to be

12 sanded. He had been a very successful estate agent with several employees. He stated that he sometimes already phoned with employees at 5 o’clock in the morning and flew within a day back and forth (for circa 5-6 hours a day) to another country to for negotiations. He was divorced and had a child but could only see his child for one day every second weekend. After an accident on the highway with his sportscar, during which he only suffered from minor traumatic brain injury without any visible brain damage (MRI), he suddenly developed significant cognitive problems, especially in the memory domains. Measures of his intellect and global cognition varied between tests: IQ estimation was 104, in the MoCa he scored within normal limits (27), but in the DemTect, a test screening for dementia, his performance was below normal with a score of 10, which – according to test authors – should be interpreted as “mild cognitive impairment”. He also was somewhat below average in attention and concentration (TMT: A=37 s; B = 119 s) and in his problem-solving abilities. In all memory tests he was considerably impaired. An example is Rey-Osterrieth Figure (Lezak et al., 2012), a test of visual memory. After asking him after 30 min to repeat the figure by heart, he just produced the lines shown in Figure 1. The details shown are very unusual: “Normal” patients with amnesia much more likely would draw the basic surroundings of the figure, but not the line details and the circle with the three dots (cf. Fig. 48.6 in Markowitsch, 1995, and Figure 2). _____________________ Insert Figure 1 about here _____________________ Charles also had problems in retrograde episodic-autobiographical memory. When remembering events these were usually produced in a very neutral “semanticized” way, similarly to what is observed in patients with Alzheimer’s disease (cf. U. Seidl et al., 2006; Spreng et al., 2018). He repeatedly stated “difficult, difficult” when asked about specific events of his past. In the Test of Memory Malingering, he in the first trial scored only with 40 out of 50 possible correct points, which is considered to be an invalid result which has to be interpreted as showing poor effort or malingering, at least according to the test author’s interpretation (Tombaugh, 1996). However, in the second trial he scored 49 trials correct. Other authors than Tombaugh suggested (especially for patients with minor traumatic brain injury) alternative interpretations such as “intentionally or unintentionally performing below their optimal ability due to a complex psychological process (e.g. distorted expectations)” (Locke et al., 2008, p. 277). Another interpretation of poor test result was the “cry for help hypothesis” (Locke et al., 2008, p. 278), meaning that the patients exaggerate their symptoms in order to receive attention and treatment. Such behavior could – according to Locke et al. – occur “at various levels of awareness” (p. 278). Though Charles had asked himself to be tested, his behavior indicated reduced effort (similar as in the patient of Kessler et al., 1997, and as in Karl and Peter) and a kind of resignation with his condition was reinforced by his sayings that “everything does not matter to me” and that his “forebrain” would be “empty” and “a black hole”. Case Heidi. Heidi was a 31-year-old married nurse with two small children. She had worked full-time in the department of trauma surgery of a clinic. She was in psychotherapy because of feeling that she would get or already have Alzheimer’s disease, a condition which two of her older family members had. However, all brain imaging results were negative, revealing a normal brain (Table 1). Her therapist told us that Heidi had reported to her that she sometimes would be forgetful. For example, that she went with her dog to the supermarket and drove back without him. One

13 morning she reportedly forgot to get dressed in underclothes. Furthermore, she left the oven in the kitchen on for three hours until a burning smell appeared. Her husband and her mother also noted that she became forgetful and sometimes had word finding difficulties. She had already been assessed neuropsychologically in a Neurological hospital before undergoing a neuropsychological evaluation with our team – initiated by her therapist. In the Neurological hospital the neuropsychologist found several deficits, especially in anterograde memory and with respect to word finding faults. She herself noted “psychic pressure” at her workplace. A thorough neuropsychological investigation by our team principally confirmed the reported and observed deficits. In the DemTect she only obtained a score of 8 which indicates “suspicion of dementia”. For instance, in the DemTect subtest on Transferring Numbers she wrote for the number 4054 “viertauendfünfundvierig” which is not only wrong German (correct transfer would read “viertausendvierundfünfzig”), but also contained two writing errors. In the MoCa she only reached 21 points which is deficient (suggestive of minimal cognitive impairment). In the Boston Naming Test, she was unable to name ten words and paraphrased several others (e.g., scissors – to cut; compasses – to make circles; escalator – to go up and down; beaver – gnawing trees). She showed severe anterograde memory deficits as measured by a number of verbal and nonverbal memory tests (Rey-Osterrieth Figure, Doors Test, Wechsler Memory Scale-revised [WMSR], Verbal Learning and Memory Test; Baddeley et al., 1994; Härting et al., 2000; Helmstädter et al., 2001) (Fig. 2). In retrograde episodic and semantic memory tests (Autobiographical Memory Interview; Famous Faces Test; U. Seidl et al., 2006) her performance was below normal, but not significantly deficient (when taking cued recall into account). _____________________ Insert Figure 2 about here _____________________ Low scores were obtained in all symptom-validity tests, except the simplest one, which she, however, had already performed before in the first neurological testing in the Neurological Clinic. In the other tests, the TOMM, the Amsterdam Short-Term Memory (ASTM) Test, and the subtest ‘Everyday Memory Abilities’ of the Test Battery for Neuropsychology (TBFN; Heubrock and Petermann, 2000), her performance yielded results that were below the normal range. In the subtest of the TBFN she made five errors, in the ASTM test 15 errors, and in the TOMM she made 19, 21, and 25 errors in Trials I, II, and the Retention Trial. Her score in the ASTM test is considered to reflect a score ‘probably below the actual performance level – limited test motivation’. Her scores in the TOMM became worse over trials, though, of course, it would be expected that they would become better. Furthermore, these scores are all in the range of definite malingering (25 being exactly chance level). In interpreting these results in the symptom validity tests, particularly in the TOMM, one can again refer to the interpretations given by Locke et al. (2008): They might reflect a plea for help and support. (However, as one reviewer suggested, the claim of amnesia itself can be a plea for help.) Furthermore, there is some resemblance to the behavior of (usually still young) adults who do not show any effort for achievement and appear very phlegmatic (Kessler et al., 1997). When Heidi was told that some of her test results indicated malingering, she just commented that then, after all, she might not have Alzheimer’s dementia. Case Rebecca. Rebecca was a 35 years old divorced woman with two children. Nine years prior to the neuropsychological examination she had suffered from what was initially considered to

14 be a gastrointestinal infection and then a limbic encephalitis, however without clear proof of a viral etiology. Immediately the next morning after having been taken into a hospital, she became retrogradely amnesic with respect to her total past life (including events pertaining to her children and relatives; the only exception was a godchild, whom she recognized). The amnesia was largely limited to the episodic-autobiographical domain and remained unchanged over the past nine years. In the last 12 months she deteriorated in her anterograde memory abilities and subsequently she lost her job; at the time of the assessment she was unable to work in her own profession. Refined 3 Tesla MRI of her brain, done nine years after the diagnosis of possible encephalitis revealed structural changes in both hippocampi with partly blurred internal structure and flattening. Analyses of blood serum and cerebrospinal fluid, including immunological assessments failed to detect any indices of encephalitis-related changes in the brain. Neuropsychological test results indicated an IQ of 101, still normal results in the MoCa (27 points due to failure to freely recall 3 of the 5 words), normal attention and concentration abilities, some deficits in recognizing and differentiating facial emotional expressions and inferring the emotions of others (as assessed by the Florida Affect Battery and the Reading the Mind in the Eyes Test; Bowers et al., 1991; Baron-Cohen et al., 2001), and severe retrograde and anterograde memory problems. She did not have any conscious access to her personal past until the time of her diagnosis of possible encephalitis and only scattered personal memories of the time thereafter. Her retrograde semantic memories were largely unimpaired. On the anterograde side, she showed significant verbal and nonverbal memory deficits as measured with the WMS-R (delayed memory index of 60, while all other indices were between 86 and 90), the Verbal Learning and Memory Test, the Doors test, and the Rey-Osterrieth Figure. She showed no indication of malingering or feigning (repeating all 15 items in the Rey-15-Item Test and 43 and 50 items in Trials 1 and 2 of the TOMM). Interestingly, in the TOMM, she stated that she just did not recall certain items during the first recall (Trial 1), while she then – after the second presentation – apparently had learned those missing in Trial 1. In the Dissociative Experiences Scale (Bernstein and Putnam, 1986; Frischholz et al., 1990) she obtained a score of 42% which indicates suspicion of severe dissociative disturbances. In the Freiburg Personality Inventory, she showed principally average results (stanines 3-7). Treatment status of the six patients. Ninja’s parents, at our recommendation, decided to arrange for specialized inpatient treatment for Ninja in a psychosomatic clinic for the youth, but encountered difficulties with convincing Ninja to participate in the program, because she did not want to leave the mother and stay alone in a clinic. Peter immediately after our assessment started to receive a combination of cognitive behavioral and Eye Movement Desensitization and Reprocessing (EMDR) therapies. He stated that his therapist is optimistic to regain parts of his biography, but not the knowledge for Latin. She considers a near-death experience at the time point of the accident as likely. Karl and Charles were recommended to start psychotherapy and provided with information about treatment resources; it is however unknown whether they pursued therapy. Heidi continued her psychotherapy, telling the therapist that she is happy that the reason for her intellectual deterioration might not be an early dementia. Heidi’s condition did not change after the last months, though she obtained some additional diagnostic information that she either might suffer from autoimmune-mediated Hashimoto disease or that there is a psychic basis of her deficits. We recommended to Rebecca that she should undergo specialized therapy for her condition and provided her and her sister with information about local treatment resources.

15

3. Conclusions from these cases The described six cases show several commonalities and several differences among each other and in comparison, to other patients with dissociative amnesia, described in the literature. None of them represents a typical case of dissociative/psychogenic amnesia (cf. e.g. the cases described in Staniloiu et al., 2018, or in Harrison et al., 2017). For instance, in our sample three out of six patients had head injury (mild TBI-traumatic brain injury) and one had suspicion of brain damage due to encephalitis, while for the 53 patients in the study of Harrison et al. (2017) a past or precipitating (minor) head injury was mentioned for 41.5% of the psychogenic group, compared to 10% in the “neurological” controls. Although the brain MRIs, carried out after amnesia onset, were inconspicuous in all patients, with the exception of Rebecca, we cannot completely rule out that there were brain abnormalities, which escaped detection by conventional structural imaging methods, which might have had an impact on the patients’ present behavior and cognition. It is known, for instance, that even a mild traumatic brain injury or concussion, may lead to cognitive deficits, (neuro-)psychiatric disorders, diffuse axonal injuries, synaptic dysfunction, reduction of hippocampal volumes later in life, and molecular dysfunctions (Kim et al., 2007; Koponen et al., 2002; Monti et al., 2013; Rapp et al., 2013; Taber and Hurley, 2013; Walker and Tesco, 2013). It seems logical that there is a brain basis for all behavior, and indeed, already more than 100 years ago scientists such as Maudsley (1870), Meynert (1884) and Flechsig (1896) postulated that all psychological events should be explainable by anatomy and physiology (see also Markowitsch, 1996). The degree to which the mild traumatic brain injury or brain injury (encephalitis) might have contributed to providing a fertile biological ground or psychological ground for the initiation and maintenance of dissociative amnesia remains debated. As mentioned, Peter’s amnesia did not start immediately after the car accident and the subsequent mild traumatic brain injury, but more likely in the hospital, suggesting from the onset an element of learned behavior (Spiegel, Minnick). The development of the full symptomatology of Ninja after the second fall is also suggestive of an element of learned behavior The expansion of the conversion symptoms of Ninja occurred after a car accident, suggesting a causation related to the psychological impact of the accident (rather than to a possible mild TBI). Four of our patients were anterogradely amnesic with respect to their biography, a condition that was described for patients with dissociative amnesia, but has up to now been reported for less than a dozen patients with so-called anterograde dissociative amnesia (see Staniloiu and Markowitsch, 2014; Markowitsch and Staniloiu, 2013; Markowitsch et al., 1999); a fifth patient (Rebecca) had anterograde memory impairments of less severity. All patients had retrograde amnesia in the episodic-autobiographical domain – the standard criteria for dissociative amnesia (Staniloiu and Markowitsch, 2014; Markowitsch and Staniloiu, 2016). Ninja, Peter and Rebecca had a complete loss of access to their former personality; Charles had severe retrograde memory problems in the episodic-autobiographical domain. Karl subjectively felt that he had lost portions of his past, but test results did not reflect this; and Heidi had among her multiple cognitive problems also a deficient retrograde memory. Evidence for feigning or malingering. An interesting and unexpected outcome was that three out of the six patients (Ninja, Heidi, Charles) showed evidence for feigning in respective tests, assessing anterograde memory functions. Charles showed evidence of feigning only in the first trial of the TOMM. Heidi showed evidence of feigning or simulation in all three trials of the TOMM, where

16 she even became worse from the first to third trial and performed below the expected level in the ASTM test. Ninja was clearly below any expected level in both the TOMM and the simple Rey-15Item Test. In the TOMM she became worse from trial to trial (35, 37, 37 errors). In the Rey-15-Item Test she, for example, repeated the circle, though it seems logical to see the three clearly different symbols (circle, square, triangle). These results of the three patients have, of course, to be related to their general cognitive performance. This was poor in all three: Charles had an IQ estimation in the normal range but scored clearly subnormal in a dementia screening test and in the Rey-Osterrieth Figure after delay (cf. Fig. 1). His autobiographical retrograde memory was poor as well. Heidi was very deficient in all diagnosis cognitive tests which, however, was in line with her beliefs that she might get Alzheimer’s dementia. The self-perceived threat that she may show an incipient Alzheimer’s dementia may have influenced neuropsychological test performance and symptom reporting. The terminology “diagnosis threat” derives from the concept of stereotype threat, when a group member shows dismal performance on a task opined to be difficult for the group (Ozen and Fernandes, 2011). Also, in cases of dissociative amnesia occurring after a mild traumatic brain injury (such as in the case of Charles), the so coined diagnosis threat itself was found to influence neuropsychological test performance (Ozen and Fernandes, 2011). Ninja behaved as if she were on the level of a first-year schoolgirl or even prior to that. In evaluating scores in symptom-validity-tests (such as the TOMM, the ASTM, or the Rey-15Item Test), neuropsychological and psychiatric guidelines recommend that the general intellectual behavior of the patient has to be taken into account (Heilbronner et al., 2009; Dressing et al., 2011; Walter, 2015). As a consequence, one either can argue that the patients manifested effort below their real ability, a hypothesis that would be in agreement with the ‘motivated forgetting hypothesis’, listed above, or that stressful life circumstances, which the individual is no longer able to cope with, led to mechanisms of a psychic and probably neural blockade (Markowitsch, 2002), and resulted in the overall grossly reduced cognitive performance (Fig. 3). As all the patients (or their parents – as in the case of Ninja) asked for therapeutic help, this is not unlikely (though the patients’ everyday performance appeared to be higher than their test performance suggested). Rebecca’s borderline results in Trial 1, but normal results in Trial 2 of the Test of Memory Malingering, provide a direct example for the argumentation that the memory impairment may be so severe that it initially falsely indicates feigning. _____________________ Insert Figure 3 about here _____________________ La belle indifference. A striking result – which, however, is more the rule than the exception – was the seemingly reduced concern of most of the patients with respect to their symptoms and future: Ninja was unable to continue even basic school (e.g., number counting only to 10), Karl, Charles, and Peter considered themselves to be unable to engage in a gainful form of employment, and Heidi had lost her job as a nurse and was holding a minor auxiliary working position. Ninja seemed to have no perspective to graduate from school. This lack of concern about their future has since Janet (1884, 1907) been termed indifference or la belle indifference and was observed in many other patients with dissociative amnesia (e.g., Reinhold and Markowitsch, 2009). However, as stated by Gould et al. (1985), la belle indifference “may also stem from a generalized apathy based on either subcortical or frontal dysfunction” (p. 596) (see the “executive deficit model” above). Seen in this

17 way, la belle indifference might also reflect what Locke et al. (2008) termed a plea for help and support. Young age (unripe personality). The idea that the behavior, in particular the neuropsychological test results, reflects a plea for help is reinforced by the young age of patients and the stressful events that happened to them in their life. It can be assumed that many of them initially grew up protected during childhood, but then unforeseeable circumstances occurred, which led them doubt that their life might continue as smoothly as it started. As they might not have developed a robust protective corset against adverse circumstances, they fell into resignation, a phenomenon named “learned helplessness” in psychology (M.E.P. Seligman, 1975) and attributed to dysfunction to the ventromedial prefrontal cortex and the amygdala (Maier and Seligman, 2016) and in consequence also to dysfunction of the hypothalamo-pituitary-adrenal system – the stress hormone axis, leading to impaired top-down inhibition of stress-responsive limbic and brainstem structures. The continuing stress then again might have induced a functional blockade, leading to a general deterioration in intellectual performance. Anterograde amnesia and retrograde amnesia outside the autobiographical range. Interestingly, all patients, but Peter, were impaired in the anterograde memory domain: Charles, Ninja and Heidi showed severe impairment, Karl and Rebecca, moderate to severe. In addition, Charles was ‘semanticizing’ those memories from his personal past, he still remembered, and Peter had semantic retrograde amnesia for his professional facts (e.g., Latin) (together with the complete loss of his episodic-autobiographical past). These results reinforce the idea that in patients with dissociative amnesia and related functional amnesic conditions (Markowitsch and Staniloiu, 2016) an anterograde episodicautobiographical memory impairment is found in addition. Such patients with combined retrograde and anterograde dissociative amnesia have been described previously (Markowitsch et al., 1998, 2000), in addition to more cursorily mentioned anterograde memory impairments in patients with the usual form of retrograde dissociative amnesia (e.g., Kritchevksy et al., 2004; Fujiwara et al., 2008). In the old literature, there were, however, several cases with combined anterograde and retrograde amnesia reported (Charcot, 1892; Janet, 1892; Souquet, 1893). As there are also patients with pure forms of anterograde dissociative amnesia (i.e., without retrograde amnesia) (Markowitsch et al., 1999; Markowitsch and Staniloiu, 2013; Staniloiu and Markowitsch, 2014; Smith et al., 2010), it may be concluded that there is sometimes more of gradient, rather than a dichotomy, between manifestations of memory disorders in patients with dissociative or functional amnesia. This makes sense when one interprets ‘functional amnesia’ in the way that the amnesia serves a function for the patient (namely to make him or her seeking out for help) (Markowitsch and Staniloiu, 2016). Related to the idea of gradient in memory loss is also the finding of a ‘semanticized’ retrieval of autobiographical events, such as in the case of Charles. Autobiographical memories are emotional memories which at the brain level involve amygdala activation (Sarter and Markowitsch, 1985a, b; Fink et al., 1996; Markowitsch and Staniloiu, 2011a; Stanley et al., 2017; Staniloiu and Markowitsch, 2019b). A hypometabolic activity of the anterior temporal lobes (especially of the right hemisphere), as seen in patients with dissociative amnesia (Staniloiu and Markowitsch, 2010; Staniloiu et al., 2011), can explain the retrieval block as such, but also the lack of emotional colorization in still retrieved past events. Reinhold and Markowitsch (2007, 2009) observed in patients with dissociative amnesia that their emotional processing skills were impaired and that their memories lack emotional colorization. Grilli and Verfaellie (2014, 2016) found that retrieval of semanticized memories may

18 either rely less on medial temporal lobe involvement or may even be processed by other neocortical areas. _____________________ Insert Figure 4 about here _____________________ On the other hand, Peter’s lack of remembrance of even the simplest Latin proverbs – in spite of having studied Latin in high school and at university – demonstrates that in addition to autobiographical and semantic-autobiographical material, also personal, emotionally connotated semantic facts can be affected by dissociative amnesia (cf. Fig. 4). This shows that not only buildings that one visited (Eiffel tower), or animals with which one had personal experiences (rhinoceros in the jungle), can gain a personal connotation, but also words making up a language or being part of a repertoire of specialist terms or of a scientific terminology (species names of the animal kingdom). As the patient probably incorporates them as having been acquired with particular personal effort (that is, in a more stressful milieu), and is under psychic pressure of being able to retrieve them in the future in order to fulfill professional demands, this repertoire is blocked or encapsulated as well under conditions of dissociative (psychogenic) amnesia. Consequently, it not only makes sense to follow Tulving’s division of memory into episodic or episodic-autobiographical memory on the hand, and semantic memory into the other (cf. Fig. 1 in Markowitsch and Staniloiu, 2012a, or Fig. 2 in Staniloiu and Markowitsch, 2014) – instead of subsuming both under the term ‘declarative memory’ (cf. Tulving and Markowitsch, 1998) – but also to specify semantic further (Fig. 4), at least when it comes to patients with dissociative or functional amnesia. As Figure 4 shows, episodic-autobiographical memory largely feeds episodes or events directly into autobiographical memory. Semantic memory can be split into three parts: The largest part – and that one which is normally subsumed under this term – is general world knowledge. But aside from this subsystem, there are two further ones: Semantic-autobiographical facts is one and contains personal facts such as the own birthday, birthplace and similar information, which usually is not emotionally embedded, but nevertheless autobiographical. In addition to this factual selfknowledge, trait self-knowledge (“I am usually rather shy.”) is found in this subsystem. Therefore, an arrow goes from this semantic subsystem to the autobiographical one. A third subsystem contains semantic facts with a personal and emotional connotation (e.g., animal names and Latin words in the case of Peter). Due to these attributes – which usually are found in autobiographical memories – there is also an arrow from this subsystem to the autographical one. So, while in general patients with neurological and with psychiatric disorders have problems principally in the episodic-autobiographical domain, but not or only mildly in semantic memory (and the other – “non-conscious” memory systems), this can change when it comes to semantic material with a personal and emotional connotation. 4. Evolution of dissociative amnesia and related dissociative disorders Pope et al. (2007) raised in the title of their publication the question: “Is dissociative amnesia a culture-bound syndrome”. They proposed that it is culture-bound and offered 1000 $ to anyone who would find a case from before 1800. They lost after the case was found in the protagonist, Nina, of the opera composed by the French Nicolas Dalayrac and played in 1786. Nevertheless, Pope et al. (2007) alerted to the fact that dissociative disorders – more than other psychiatric illnesses – are related to the social and cultural environment. Although little is known about the genetic

19 underpinnings of dissociative amnesia, in quantitative genetic studies a heritability rate of 50–60% was reported for dissociation, suggesting that it might be underpinned by a strong interplay between genetic factors and environment (Staniloiu and Markowitsch, 2014). In our experience (e.g., Staniloiu et al., 2018; Staniloiu and Markowitsch, 2017; Fujiwara et al., 2008) patients with dissociative amnesia and related diseases usually have had stressful or traumatic life situations and their amnesia often has its onset in the aftermath of a trauma or stressful life event. (In the present cases ‘car or other accident’ [Peter, Charles, Ninja], mobbing? [Karl], and (as a hypothesis) working in trauma surgery and the perspective of acquiring a neurodegenerative disorder to which her family seemed predisposed [Heidi].) Brain alterations. Since more than two decades, studies with functional brain imaging and later with volumetric measurements, diffusion tensor imaging and related methods, suggest changes in several brain regions in patients with dissociative disorders. As patient histories and time points of post-amnesia imaging differ, and as the methods applied are diverse, no uniformity in results can be expected. Nevertheless, already early, especially right hemispheric fronto-temporal hypometabolisms were detected in several studies (summarized in Staniloiu and Markowitsch, 2010, and in Staniloiu et al., 2011). The same hypometabolism, with the highest glucose reduction in the right prefrontal cortex, was detected in a group study with 14 patients with dissociative amnesia (Brand et al., 2009), but also in other studies (Glisky et al., 2000). Changes in this area were also found in interconnecting fibers such as the uncinate fascicle which serves as a bridge between the temporal (memory storing) and frontal (conscious retrieval regulating) areas (e.g., Tramoni et al., 2009). More recent studies also found hippocampal pathology (Chalavi et al., 2015) and changes in the parahippocampal gyri and the prefrontal cortex in dissociative patients in a hypo-aroused state (Reinders et al., 2014) (Our patient Rebecca similarly showed bilateral hippocampal pathology.) Whether these changes are the consequence of the disease or whether they already – at least partly – existed prior to disease onset, cannot easily be determined. However, as they all refer to areas which are memory-relevant and as memory was not seriously affected prior to disease onset, it is likely that most of the changes are a consequence of the disease onset (Brand and Markowitsch, 2010a; see esp. the Figure 13.1 showing the possibly involved brain regions). And as there exist patients who recovered from their amnesia (e.g., Lucchelli et al., 1995; Stuss and Guzman, 1988; Staniloiu and Markowitsch, 2018), a possible explanation is that there is a temporary blockage of these regions, provoked by the release of stress hormones (O’Brien; 1997; Markowitsch, 2003a), which may lead to a reduction in the neuropil (dendrites and axonal collaterals). If the somata are not affected (degenerated), this process is reversible, so that therapeutic steps should be reinforced (Staniloiu and Markowitsch, 2018). A study, using patients who had had transient global amnesia, even found for implicit learning processes impairment related to emotional stress (Nees et al., 2016). Purpose of memory blockade. It is obvious that these amnesic conditions serve a purpose – whether they are partly simulated or not (Brand and Markowitsch, 2010b; Markowitsch, 2000). As stated above they can be considered as a cry for help (Locke et al., 2008): The patient considers his or her life as not rewarding, but as increasingly full of obstacles which cannot be overcome. In this way the term ‘functional amnesia’ has its purpose (Markowitsch and Staniloiu, 2016) – it serves the function to protect patients from perceived adverse life conditions. As most of their other memory functions (aside from episodic-autobiographical and personal/emotional semantic memory) are preserved and also social skills, reading, writing, calculating and other skills are intact, they may lead a life without much negative obstacles, while before they might have led a life at the limits (or at

20 least their limits). Being usually unable to go to work is probably seen as an advantage, as they are no longer exposed to many responsibilities of everyday life. Even in the family they take on the patient role and therefore are no longer responsible for many duties. For the outsider such blocking mechanisms may be self-obstructive, but for the patient they are apparently not. There are many examples of disease conditions which look even more selfobstructive (or even self-destructive), especially in conversion disorders (e.g., “psychic blindness”; Freud, 1910) or in body integrity identity disorders (Oddo et al., 2010). The patient described in Markowitsch et al. (1999) is unchanged with respect to her amnesia up to the present. We know from other cultures, that there are many forms of dissociative conditions which are barely understandable or comprehensible for individuals from Western societies (R. Seligman and Kirmayer, 2008; Kirmayer and Ryder, 2016). But in our society as well, sometimes very bizarre forms of deviations from normality exist. O. Seidl (2008) wrote about a woman who “developed stigmata at the age of 29 and allegedly lived without any for 36 years” (p. 837), suffering from paralysis, deafness, and blindness. She developed stigmata on her extremities with bleeding together with “visions” of religious content. O. Seidl concluded that her behavior in nosological terms “would be classified today as dissociative disorders” (p. 837). In conclusion, it seems that for certain individuals the deviation to dissociation brings them mental fulfillment (Markowitsch and Schreier, 2019) and is an escape from a life which otherwise appears no longer rewarding or even tolerable to them. Tulving’s concept of autonoӫtic consciousness. Tulving and Markowitsch formulated in 1998 that episodic-autobiographical memory is accompanied “by a special kind of ‘autonoetic’ conscious awareness that is clearly different from the kind of conscious awareness (‘noetic’ awareness) that accompanies retrieval of declarative information” (p. 202). Tulving and Markowitsch (1998) relate this autonoetic consciousness to the remember/know distinction and relate this to ‘embeddedness’. Remembering always implies semantic knowing (but not vice versa) (Fig. 5). Retrieving the past requires an emotional appraisal of the recalled material – it is judged a positive or negative, going to the heart, or having been disgusting. For patients like Peter this implies that he also sees past information of an otherwise semantic nature as negatively connotated (the Latin language) and therefore blocks it from consciousness in the same way as he blocks personal events of his past. Therefore, we suggest expanding the term to episodic-autobiographical memory to include memories of a subjectively personal relevance, in particular to an emotional, affect-bound embedding. This idea is in line with the usually found involvement of affect-processing brain structures (such as the amygdala) in retrieving such material (Markowitsch and Staniloiu, 2011a, 2012a; Staniloiu and Markowitsch, 2019b). Of course, this widening of the concept of autonoetic consciousness (Nyberg et al., 2010; Szunar and Tulving, 2011) has implications for the personality of the affected individual. The individual with such an extended memory block is restricted in his or her repertoire from which an associating bridge to his or her personal past is possible. This may have implications for therapy and recovery, but also for personality dimensions as such, as there is – in the old term of Janet (1892) – a more extensive désagrégation psychologique (psychological decay) than in more pure cases of dissociative amnesia. Apparently, at the times of Janet such forms of amnesia were commonly described. Freund (1889) characterized them as “general memory weakness”. One also might argue that there is a higher degree of desynchronization between prefrontal regions, important for autonoetic consciousness, and the temporo-amygdalar system, important for evaluation and emotions (see Staniloiu and Markowitsch, 2012). Brand et al. (2009) had formulated

21 that in patients with dissociative amnesia the synchronization of “emotional and factual components of the personal past linked to the self” (p. 38) is no longer possible. This description holds for all our patients as well and points to the interweaving of episodic-autobiographical memory, autonoetic consciousness, emotion, and the self (Markowitsch, 2003b, 2013; Fujiwara and Markowitsch, 2005; Markowitsch and Staniloiu, 2011c, 2012b). Dissociative or psychogenic amnesic disorders can therefore be interpreted as “a malady of the constricted self” (Staniloiu et al., 2010, title). The deficits and in part somatic changes in some of our patients may reach beyond the traditionally attributed features to patients with dissociative amnesia, indicating that they may be a special sample with a chronic state of alterations in the conscious domain (see also the distinction of Harrison et al., 2017, into psychogenic amnesic patients with an early, acute form and those with a more persistent or chronic state). All of the patients described herein, have in a way lost their personal freedom and independence: Ninja is unable to attend a normal school, cannot learn sufficiently, and therefore will probably never be able to achieve her goal, to study medicine, which she wanted prior to amnesia onset. She is dependent on her parents and on a private teacher. Furthermore, she lost her ability to act and engage freely in her social and biological environment, due to her paralyzed arm and her urinary retention. Peter is dependent on his parents and wife, who found a therapist for him, help him to orient in his social environment and teach him about his personal past and about what had happened in the world. Karl as well is dependent on his parents who continue to provide him with a place to live (he never had left his parents’ house) and support him financially. Charles seems to have financial reserves from his firm, but at the time of our investigation was dissatisfied with his therapist (and probably vice versa) and impaired in many situations of everyday life. And Heidi needed therapeutic help, had lost her job, and was in many ways dependent on her husband’s help. We would like to emphasize that some of the cases described herein go with their symptomatology beyond that usually reserved for patients with dissociative or psychogenic amnesia. Especially the severity and diversity of deficits (e.g., case Ninja) and the tendency to score very low in symptom-validity tests (cases Ninja and Heidi) may result in skepticism of the reader, whether they just fake their amnesia of malinger in order to obtain secondary gains from their behavior. While we cannot proof to what degree their memory problems are valid, we can see their behavioral patterns as reflecting a manifestation of suffering which most people would not like to tolerate, if they were able to change it. Though the meaning of forgetting has been debated since more than 100 years (e.g., Breuer and Freud, 1895; Jung, 1905a, b; overview in Markowitsch and Brand, 2010), the fleeing of all our patients into amnesia, still remains the miracle of this kind of disease conditions. The present case descriptions also complement the theoretical contributions of Endel Tulving, on (a) the special, human-specific, character of episodic-autobiographical memory as such, and on (b) the striking similarities of past and future (prospective) memories (Szpunar and Tulving, 2011; Tulving and Szpunar, 2012), which also show similar activations on the brain level (Nyberg et al., 2010). Of relevance is in this respect Tulving’s (1995) SPI model. Tulving proposed that while encoding is assumed to be based on a hierarchical arrangement of memory systems from procedural and priming memory systems to the episodic-autobiographical memory system, retrieval allows independence in that way that no matter how the information was encoded, it can be retrieved in any memory system. Tulving termed this the SPI-model, where SPI refers to SERIAL encoding, PARALLEL processing (storage) and INDEPENDENT retrieval. The SPI model proposed by Tulving (1995) means that after brain damage or in cases with dissociative or functional forms of amnesia,

22 retrieval may still be possible based on familiarity judgments (via accessing the perceptual memory system representations), while it is blocked via the episodic-autobiographical memory system. Indeed, while Karl complained of “loss” of several skills (“procedural memory”), this could not be found objectively. Loss of skills in dissociative amnesia may represent difficulties with procedural discourse (semantic account of the procedure) or initiating or completing a task. Patients with retrograde dissociative amnesia show various degrees of impairments in familiarity judgments about people or situations that had been familiar in the past (see the case of Rebecca). They can also react to exposure to reminders of old mnemonic information in an implicit way (e.g. by changes in galvanic skin conduction, heart rate variability, behavior), by retrieving old information through the priming memory system.

5. Relations of the present cases to the nine models of dissociative amnesia The presented cases were chosen for their atypicality, in order to emphasize the heterogeneity of dissociative amnesic disorder with regards to their clinical presentation, comorbidity and mechanisms involved. Due to the type of consultations we are usually asked for undertaking, the sample we describe has followed a chronic course, which may be intimately related to variables such as comorbidity, lack of effort and indices suggestive of feigning. There is no single mechanism that can account for the triggering and maintaining of the amnesia in the presented cases, but rather a combination of mechanisms. The first two models that we presented on the beginning of our manuscript emphasize the psychological trauma or stressful life events as being primarily involved in the causality of dissociative amnesia. Stress is however a multifaceted construct, which entails exposure to stressors, subjective perception of psychological stress and biological and behavioral responses or markers of stress. We found antecedents of traumatic or stressful life experiences in several patients: Ninja developed dissociative (conversion) symptoms after sustaining two falls and a worsening of her symptoms after being a passenger in car that was involved in a motor vehicle accident. Peter dealt with an accident and his unsettled professional situation (given that he had to provide subsistence for his family) prior to the onset of his amnesia. The cognitive deficits of Karl, which were blended with symptoms of a neurocognitive neurosis, occurred on a background of fears of being unable to cope with a self-perceived stressful and uncontrollable environment. Charles dealt with private stressors (divorce, child) as well as professional ones (own firm, he longer could control). Heidi dealt with cognitive problems on a background of work-related stressors and dementia worry in the context of increased awareness of dementia due to her profession and family history. Rebecca dealt with stressors related to her divorce, children, gastrointestinal infection and assumed brain disease. Interestingly, all but Peter (who only was retrogradely amnesic) had a combination of retrograde and anterograde memory deficits. Therefore, both stress models may account for the patients, especially when considering that the affected brain regions in anterograde and retrograde amnesia overlap considerably (Staniloiu et al., 2011; Markowitsch and Staniloiu, 2012). In the six patients presented, we did not carry out laboratory investigations of biomarkers of stress. Previous research undertaken in humans has however provided evidence for the contribution of stress hormones in mnestic processes. Retrieval deficits of episodicautobiographical memory and semantic memory were recorded in healthy participants after the acute administration of glucocorticoids or psychosocial stressors. Several studies linked chronic glucocorticoid increases to poor performance on memory tasks. Most likely epigenetic factors (not yet identified) play a role in triggering stress hormone-mediated dissociative amnesia in predisposed individuals exposed to psychological trauma or stressful life events during certain windows of vulnerability (Lupien etal., 2009)

23 The executive deficit model (Kopelman, 2000, 2002; Harrison et al., 2017) is partly related to the retrieval blockade-stress models, as it assumes that “the combination of a severe precipitating crisis, depressed mood, and past experience of a transient neurological amnesia, as in a minor head injury, can trigger ‘frontal’ inhibitory (or ‘control’) mechanisms in autobiographical memory retrieval“ (p. 2508). It is, however, much more specific, as it requires several preceding factors (crisis, depressed moods, transient neurological amnesia/minor head injury) and holds only for processes of memory retrieval. In this restricted way it might solely hold for Peter, but not for the other five. In a less restrictive way, the model outlined in Figure 3 has some resemblance to the inhibitory prefrontal mechanisms (“executive control system”) of the executive deficit model. Furthermore, also in a more general way, we agree with Kopelman’s (2019) view that a “frontal ‘control’ system (in interaction with medial temporal/hippocampal systems)” is important for the “disrupted retrieval of ‘old’ memories” (Kopelman, in press; cf. also his Fig. 4, and McCormick et al., 2018). The motivated forgetting hypothesis has relations to the executive deficit model, as it assumes inhibitory control mechanisms in the prefrontal cortex and the medial temporal lobe (Anderson and Hanslmayr, 2014). The authors specifically point to the ventrolateral prefrontal cortex of the right hemisphere and thereby to the area which in our studies on patients with dissociative amnesia was reduced in activity as measured with glucose positron emission tomography (Brand et al., 2009). The idea of an ‘impairment in emotional colorization and first person autonoetic connection’ is more of a description of the state of an individual with dissociative amnesia than an explanatory model. The binding deficiency model may be partly involved in patients with hippocampal formation damage, such as perhaps in Rebecca (Rosenbaum et al., 2009). The fantasy model in dissociative amnesia builds up on the idea that patients with this condition may lack strong self-confidence and instead may be more susceptible to outside influences or intrusions of dream-like material in the reality, especially on a background of cognitive failures (e.g. executive dysfunctions). As Dalenberg et al. (2012, p. 553) wrote, “fantasy proneness and dissociation are likely to correlate”; nevertheless, their arguments against the fantasy proneness model in favor of the stress model in dissociative disorders are convincing to us (Dalenberg et al., 2012, 2014). An evaluation of the susceptibility for false memory syndrome (confabulations, intrusions, false memory recognition) in patients with functional or dissociative amnesia however is only in its incipient stage (Dalenberg et al., 2012; Markowitsch and Staniloiu, 2013). The loss of information model seems difficult to test in the six patients and is therefore not further considered. While socio-cognitive models are unlikely to solely account for the symptoms the presented patients, the symptomatology of several patients, such as Heidi, Charles and Ninja seems to be filtered through the socio-culturally and personally molded lenses through which they perceive the past, self and memory (Seligman and Kirmayer, 2008). Consequently, we see the first four models, which all are interrelated, as best suited for describing the kind of amnesias and other cognitive disturbances in the presented patients. We see, however, a hierarchy in that way that stress is the primary triggering mechanism, probably inducing executive deficits and motivational changes. These views are supported also by animal and human research that found trauma models to account the best for dissociative disorders. Nevertheless, little research has been carried out with other models or theories, such as the loss of information model or fantasy proneness model, calling for compelling alternative theories to be tested in the future (Dalenberg et al., 2012, 2014).

Declaration of interests

24

We declare no competing interests.

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35 Table 1 Age of described patients, premorbid intelligence, applied brain imaging, incidents triggering memory problems, kinds of memory problems, and possible past events having made them vulnerable. Case

Age

Brain imaging

Ninja

16

MRI: neg.

Peter

29

Karl

Immediate incident triggering memory problem(s)

Kind of memory problem(s)

Possible stressful events in the past

?

mild TBI

retrograde and anterograde EA and S’ amnesia

constellation of parental background; previous mild TBI

MRI: neg.

97

mild TBI

retrograde EA of total life and S’ amnesia

constellation of parental background; lack of professional success

26

MRI: neg. PET: neg.

93

entanglement of various problems in private and professional life

anterograde EA and partly retrograde EA amnesia

mocking in private and professional life

Charles

41

MRI: neg. 104

mild TBI

severe anterograde EA and retrograde EA memory impairments

stressful live (“always at the limits”) and personal social problems

Heidi

31

MRI: neg. 94 SPECT: neg. PET: neg.

idea of having Alzheimer’s Disease

severe anterograde EA amnesia and more minor retrograde EA memory impairments

continuous stress in everyday life

MRI: minor 101 changes in both hippocampi

suspicion of limbic encephalitis

anterograde EA amnesia and total retrograde EA

continuous stress in everyday life

Rebecca 35

IQ

EA: episodic-autobiographical; IQ: intelligence quotient; MRI: magnetic resonance imaging of the brain; PET: glucose positron emission tomography; S’: semantic memories with direct personal impact (school knowledge; university knowledge); SPECT: Single-photon-emissioned-computed tomography; ?: Intelligence estimation not measurable, as Ninja was too young, apparently too memory impaired, and insufficiently educated to apply the test. IQ estimation is throughout based on the Mehrfach-Wahl-Wortschatz-Test of Lehrl (2005), which has similarities to the National Adult Reading Test of Nelson and Willison (1991).

36 Figure legends NONE OF THE FIGURES SHOULD HAVE COLOR IN PRINT. Figure 1. Performance of patient Charles in the reproduction of the Rey-Osterrieth Figure by heart after 30 min. Figure 2. Performance of patient Heidi in the reproduction of the Rey-Osterrieth Figure by heart after 30 min. Figure 3. Model demonstrating the blockade of formation or retrieval of episodic-autobiographical memories (E) in dissociative amnesic conditions. F: features of information, R: representations of information in the brain. Only the white lines allow successful information processing. In condition 1 all processing of information is in synchrony, while in condition 2 the executive control system prevents conscious access of formed representations and in conditions already the formation of representations in the brain is blocked. (Adapted and modified after Figure 16.5 of Fujiwara and Markowitsch, 2003).

Figure 4. Relations between autobiographical memory and semantic memory. (For description see text). Figure 5. Relations between episodic-autobiographical and semantic memory according to Tulving’s (1995) SPI model. (S = serial encoding, P = parallel storage, I = independent retrieval). Information can be encoded into semantic memory independently of episodic-autobiographical memory, but muse be encoded into episodicautobiographical memory “through” semantic memory. Encoded and stored information is potentially available for retrieval from one of the two systems, or from both of them. (After Figure 1 of Tulving and Markowitsch, 1998).

37 Figure 1

38 Figure 2

39 Figure 3.

40 Figure 4

41

Figure 5

(1) (2) (3) (4) (5)

Dissociative amnesia (DA) occurs after traumatic or stressful life events Most dissociative amnesias are characterized by retrograde memory impairments The sole or preponderant impairment in DA involves the episodic memory Loss of personal identity highly suggests DA In dissociative amnesia routine structural brain imaging is unremarkable