Neuropsychol Rev DOI 10.1007/s11065-015-9284-y

REVIEW

The Still Enigmatic Syndrome of Transient Global Amnesia: Interactions Between Neurological and Psychopathological Factors Audrey Noël 1 & Peggy Quinette 2,3,4,5 & Mathieu Hainselin 2,3,4,5,6 & Jacques Dayan 2,3,4,5,7 & Fausto Viader 2,3,4,5 & Béatrice Desgranges 2,3,4,5 & Francis Eustache 2,3,4,5

Received: 5 December 2014 / Accepted: 30 March 2015 # Springer Science+Business Media New York 2015

Abstract Transient global amnesia (TGA) is a neurological syndrome that usually occurs in middle-aged or older people. It is characterized by the abrupt onset of profound anterograde amnesia, associated with more variable retrograde amnesia and repetitive questioning. The whole episode lasts no more than 24 h. Almost 60 years after its first descriptions, the etiology of TGA remains unknown. Until now, TGA has been described exclusively as a memory disorder, but there is a growing body of evidence to show that emotional and psychological factors (as anxious and depressive symptoms) are present at different times of TGA. Their role therefore needs to be clarified. First, these factors seem to play a part in triggering TGA, at least for a subgroup of patients, suggesting the existence of an emotional TGA subtype. Second, recent research shows that almost all the TGA patients displayed modifications of their emotional state during the episode, possibly linked to sudden memory loss. The level of depressive and anxious symptoms could even reach a pathological threshold in patients with the so-called “emotional TGA subtype”. Third, the persistence of these

* Francis Eustache [email protected] 1

CRPCC - EA 1285, University of Rennes 2, Rennes, France

2

UMR-S1077, INSERM, Caen, France

3

University of Caen-Basse Normandie, Caen, France

4

Ecole Pratique des Hautes Etudes, Caen, France

5

University Hospital, Caen, France

6

CRPCPO, EA 7273, Université de Picardie Jules Verne, Amiens, France

7

Guillaume Régnier University Hospital, Rennes, France

depressive and anxious symptoms after the end of the episode could account for lasting memory disorders in some patients. Finally, the analysis of these emotional syndrome and emotional factors and the recent data in neuroimaging could allow us to gain a better understanding of the pathophysiological mechanisms behind TGA. The aim of this review was thus to discuss whether the anxious and depressive symptoms are causative, resultant or coincidental of TGA. Keywords Transient global amnesia . Emotion . Memory . Pathophysiology . Psychopathological factors

Introduction The clinical features of transient global amnesia (TGA) are now well known to be a selective memory disorder that occurs in middle-aged or older people and lasts just a few hours (Hodges and Warlow 1990). It is characterized by the sudden onset of profound anterograde amnesia, usually accompanied by variable retrograde amnesia and repetitive questioning (Quinette et al. 2006b). Its mechanism is thought to be a functional disturbance of the hippocampus (Bartsch and Deuschl 2010). Apart from the amnesia, there is no neurological deficit. For decades, the neuropsychology of TGA has focused on the amnesic syndrome, and we therefore use this Introduction to summarize the findings in this area. Not all the memory systems are affected in TGA. For instance, the implicit forms of memory are preserved: patients can perform complex procedural activities (Evers et al. 2002; Guyotat and Courjon 1956) and even learn new skills, provided they do not involve episodic or working memory (Eustache et al. 1997; Goldenberg et al. 1991; Kazui et al. 1995). Similarly, researchers have reported normal perceptual (Kapur et al.

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1996; Kazui et al. 1995) and semantic priming (Eustache et al. 1997; Beauregard et al. 1997; Guillery et al. 2001) effects in TGA patients. More recently, Marin-Garcia et al. (2013) found new evidences for spared implicit learning during the acute phase of TGA. Indeed, they showed enhanced preference for previously exposed faces (also called mere exposure effect) in spite of the absence of explicit recognition of these faces. Concerning semantic memory, conceptual (Hodges 1994; Na et al. 2013), public (Evans et al. 1993; Hodges and Ward 1989; Kapur et al. 1998) and semantic personal (Evans et al. 1993; Guillery-Girard et al. 2004) knowledge is typically preserved. The slave systems of working memory (the phonological loop and visuospatial sketchpad, permitting the temporary storage and the rehearsal of verbal and visuospatial information, respectively) and its executive functions are also preserved in TGA (Quinette et al. 2003), although Quinette et al. (2006a) demonstrated a binding and storage deficit in the episodic buffer of working memory in a subgroup of TGA patients while suffering an episode. The most severely affected memory system in TGA is episodic memory. The anterograde amnesia (i.e., inability to memorize information that has occurred since the onset of the attack) is so extensive that all types of items (verbal and nonverbal), tasks (recall of stories, words, images, objects, etc.) and retrieval mode (immediate/delayed recall or recognition) are affected. Impairment of the anterograde component has been attributed to a deficit in encoding, storage, or both (Eustache et al. 1999; Quinette et al. 2006a). The retrograde amnesia (i.e., inability to recall past events) is more variable. It can range from a few days (Kritchevsky et al. 1988) to several years (Hodges and Ward 1989; Guillery et al. 2000). It stems from the disturbance of recovery processes, and once the episode has receded, TGA patients can again access their past memories. There are two recovery profiles after TGA (Guillery-Girard et al. 2004): either it follows Ribot’s gradient (i.e., starting with the oldest memories; Ribot 1881) or it reflects the depth of memory encoding (i.e., memories with the greatest emotional intensity are recovered first). Not only is the ability to recall past personal events disturbed, but also the ability to imagine future events (Juskenaite et al. 2014). TGA patients supply fewer details about imagined events, and the nature of their productions also differs from that of controls. To produce future events, 78 % of the controls and only 53 % of the patients relied on already planned or wished events before TGA. Another component of episodic memory, namely prospective memory (i.e., the ability to remember to perform an intended action at some point in the future) has also been assessed in TGA (Hainselin et al. 2011). Impairment of both the prospective (i.e., remembering that something has to be done) and the retrospective components (i.e., remembering what it is that has to be done at that time) of prospective memory occur. Finally, Hainselin et al. (2012) recently

showed that TGA patients are unable to pinpoint their memory impairment, although they are aware that something is wrong. The conspicuous repetitive and iterative questioning is probably linked to anterograde amnesia and mainly concerns the patients’ immediate context (the last thing they did, the reason why they are in hospital, etc.), reflecting their worries about their disease state (they know that something is wrong without knowing explicitly what it is). Thus, the content of repetitive questioning can be considered as an additional evidence of the residual and implicit awareness. In textbooks, no mention is made of emotional and emotional syndrome factors. However, Hodges (1991) has suggested that the dearth of descriptions of TGA cases prior to the 1950s could be due to erroneous classification of TGA as psychogenic or hysterical amnesia. Nowadays, TGA and psychogenic amnesia (or transient dissociative amnesia) are better known and it is quite easy to distinguish a possible emotionally-induced TGA from this other purely emotional syndrome/emotional syndrome of amnesia (Gil et al. 2010). Indeed, transient dissociative amnesia is mainly characterized by an extensive retrograde amnesia (complete loss of past memories from some days to several years), affecting the identity of patients and leading to episodes of runaways (patients suddenly disappears and are found wandering aimlessly). If the emotionalinduced TGA share some clinical (depressed and symptoms associated with amnesia, psychiatric history), neuropsychological (episodic memory impairment) and physiological (extensive brain dysfunction) features with transient dissociative amnesia, these two syndromes differ in numerous aspects. Indeed, in TGA, the memory disturbance is mainly characterized by profound anterograde amnesia (i.e., an inability to memorize new information), whereas this one is absent in transient dissociative amnesia. Moreover, in TGA, retrograde amnesia is more partial (only some episodic events are forgotten) than in transient dissociative amnesia and it never leads to a loss of identity. Finally, in TGA the memory disorders recede inside of 24 h, whereas in transient dissociative amnesia it can last several days, even many months. Even though TGA was not well defined and isolated at this time (i.e., prior to the 1950s), the role of emotion in this transient memory disorder was already considered to be central. However, most research on TGA has focused on its neuropsychology and pathophysiology. The aim of the present review is thus to take stock of the role of psychopathological factors (particularly of depressed and anxious symptoms) in TGA. But, before ruling on the place of these factors, we wish to clarify the concept of “psychopathology and psychopathological disorders”. On one hand, according to ICD-10 (1993), psychopathological or mental disorders are characterized by a psychological dysfunction associated with a distress feeling or a functional deterioration. The emotional disturbance observed in some patients during and after the episode of TGA could correspond to this very general definition of psychopathological or mental

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disorders. Indeed, TGA has been firstly described by two French medicine specialists (psychiatrist and neurologist, respectively) (Guyotat and Courjon 1956), which considered the disorder underpinned by different aetiologies and mainly a functional disorder. Moreover psychological triggering of TGA has been well evidenced. On the other hand, Robins and Guze (1970) stated that the validity of a psychiatric diagnosis can only be achieved in five phases: clinical description, laboratory studies, delimitation from other disorders, follow-up studies and family studies. These criteria are not fully met in descriptions of TGA. Moreover, the interaction between neurological and psychopathological factors may not be at play in all but only in a subgroup of TGA patients. Indeed, as no emotional and psychopathological factor (no history of psychopathological disorders, physical precipitants, a low increase of anxious and depressive symptoms during TGA) is reported in some patients, future researches must disentangle and deepen the knowledge of physiological mechanism to properly classify TGA subtypes. Finally, TGA does not fit the criteria of mental diseases such as those of anxious disorders or depression (described in the international classifications such as DSM 5 (2013) or ICD-10 (1993)). Thus, nowadays, TGA cannot be considered as a psychopathological disorder. It seems therefore more appropriate to try to learn whether the depressed and anxious symptoms that have been reported at different times of the TGA episode are more likely to be causative, resultant or simply coincidental of this disorder. We will begin by attempting to elucidate the role of emotional and psychological factors in triggering TGA. If these constitute predisposing factors in TGA, they could reflect the existence of a specific TGA subtype, characterized by psychological vulnerability (emotional TGA). Second, we will try to determine whether the abrupt change in patients’ emotional state can be considered as a genuine symptom of TGA (linked to brain dysfunction) or whether it is only the consequence of an awareness, even partial, of their disease state (they know that something is wrong without knowing what it is). Third, we will try to determine whether depressed and anxious symptoms can slow down the recovery process and thus explain the lasting memory disorders, albeit mild, that can still be found several months after an episode in some patients. Finally, we will attempt to determine whether an extensive analysis of emotional and psychological factors in TGA can provide a better understanding of the pathophysiological mechanisms behind TGA.

Can Emotional and Psychological Factors be Considered as Predisposing or Risk Factors for TGA? In this section, we wish to determine whether specific personality traits or psychiatric profile could constitute a risk factor for TGA. Even early observations in the French neurological

literature (Guyotat and Courjon 1956; Porot and Plenat 1977; Schott 1969) reported a particular psychological profile in TGA patients. For example, TGA often happens in hyperactive and overworked people (Guyotat and Courjon 1956; Schott 1969). According to Schott (1969), their need for action would hide or compensate for an anxious or phobic personality. Trillet et al. (1983) consider that one third of TGA patients would display a phobic personality. Moreover, they notice an obsessive personality in some patients too. Although these studies emphasized very early the presence of psychological and emotional factors in TGA, these ones may be considered with caution because some descriptions are prior to criteria for TGA published by Hodges and Warlow (1990) and then these studies possibly included patients with other diseases than TGA. In 1956, Bender formulated the hypothesis of a psychogenic origin in TGA, revisited some years later by Merriam et al. (1992) with the concept of emotional arousal-induced transient global amnesia. However, the first study focused on TGA patients’ personality was conducted by Inzitari et al. (1997). These authors found that agoraphobic behaviors (with avoidance of phobogenic situations before the episode) were more often reported by patients with TGA than by those with transient ischemic attack (TIA): 82 vs. 22 % of 51 patients included in each group. The same group (Pantoni et al. 2005) also showed that TGA patients more frequently had a past history of psychiatric disease than TIA patients (39 vs. 13 % of 51 included in each group). These results can suggest that personality traits or a psychiatric profile have a role of possible predisposing factors for at least one subset of TGA. To test this hypothesis, we conducted a hierarchical analysis on clinical data obtained in 63 patients that revealed three apparent clusters of variables in the dendrogram interpreted as three prototypical profiles of TGA, each associated with different risk factors (Quinette et al. 2006b). The first profile was characterized by a TGA episode that mainly occurred in men after a physical precipitant event. In women, it was associated with personality disorders, a history of anxiety and an emotional precipitant event. The last profile concerned the younger patients (below 56 years) with a history of headaches. In another study, Döhring et al. (2014) reported that TGA patients tended to handle stress less efficiently and less constructively than controls. These results support the idea that psychological vulnerability of some kind could make easier to develop TGA, as it is the case in other clinical conditions such as ulcers and heart disease (Niles et al. 2015). In TGA, this would concern only one subgroup of patients. Their psychological vulnerability could lead them to experience repeated and/or prolonged episodes of stress, or even favor the development of anxious or depressive disorders. As has already been demonstrated in other pathologies (in particular posttraumatic stress disorder), the latter could be responsible for changes in the hippocampus (Bremner 1999). In prolonged or repeated stressful episodes,

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the excessive release of glutamate could result in lesions to the hippocampus. These hippocampal insults linked to patients’ psychological profiles could contribute to make patients vulnerable to the occurrence of TGA.

Are Anxious and Depressive Symptoms a Consequence, a Simple Coincidence or a Symptom of TGA? Emotional and psychological factors might thus increase the chances in one subgroup of vulnerable individuals for developing TGA. But, these emotional and psychological factors are also present during the episode and their status merit to be discussed. Even in the initial descriptions, several authors (Kritchevsky et al. 1988; Laurent 1991; Schmidtke and Ehmsen 1998; Schott 1969) underlined abnormal behavior (patients unusually passive, quiet and even apathetic, depressive or on the contrary hyperactive displaying a psychomotor instability) combined with anxiety during the episode. Hodges and Warlow (1990) noticed outward signs of anxiety, agitation and even euphoria in 36 % of TGA patients. Accordingly, Inzitari et al. (1997) carried out a systematic investigation of the symptoms associated with TGA, which revealed that 37 % of TGA patients showed symptoms similar to those manifested during a panic attack, compared with only 10 % of patients with transient ischemic attack (TIA). We confirmed these results, showing that TGA is more frequently associated with the criteria for a panic attack during the episode (compared with a control population) (Quinette et al. 2006b). We therefore suggested that these symptoms (dizziness, nausea, chills or flushes, etc.) are somatic manifestations of anxiety linked to TGA. Taken together, these studies raise the question of whether depressive attitude and anxious signs should be regarded as fully-fledged symptoms of TGA. Several studies (Hainselin et al. 2011, 2012; Noël et al. 2008) have been carried out by our team to address this issue. In the first of these studies (Noël et al. 2008), we assessed the presence of anxiety and depressive symptoms during a TGA episode. Results showed that almost all the patients displayed a sudden change in mood and anxiety during the episode, but without necessarily reaching a pathological threshold. Hainselin et al. (2011, 2012) made the same observations. Several hypotheses may be considered to explain this sudden change. The context of a hospital admission could be the source of this anxiety. Indeed, the verbal leitmotive (stereotyped and repetitive questions that patients continually ask their family or medical staff) of TGA patients often focus on the immediate context i.e., on their presence in hospital and the reasons for their admission (Hainselin et al. 2012). However, this change in patients’ emotional state is also reported by their relatives outside the hospital context (they are already upset before they even reach hospital). In the same way, the signs of anxiety

manifested by their relatives can be regarded as a factor that aggravates the situation. It is therefore important to reassure patients and relatives about the benign nature of TGA; to limit factors that can increase the anxiety level, already highlighted (Noël et al. 2008). Moreover, it can be noticed that the increasing of anxiety and depressive symptoms is not necessarily a typical response of admitted patients in hospital, whatever the cause (i.e., in other pathologies than TGA). Besides, the emotional state of TGA patients differs from those with TIA patients for example (Inzitari et al. 1997). These anxious and depressive symptoms could be also due to the feeling of disorientation produced by anterograde amnesia. Indeed, it is not unusual for patients who are alone at home at the onset of the episode to contact their relatives and evoke a health problem without being able to define it. Recently, another study conducted by our team (Hainselin et al. 2012) showed that patients are unable to identify the nature of their memory deficits, even if they perform poorly on memory tests and are then confronted with their failures. Indeed, they may even overestimate their memory performances. However, even if they do not know that they are suffering from memory disorders, they are conscious of and worried about their disease state. They are able to analyze their environment and their own behavior, thus allowing them to remain aware of events. This growing awareness of their disease state can lead to an increase in their levels of depressive symptoms and anxiety. Finally, a last explanation could be given for abrupt change of patients’ emotional state. Brain dysfunction which causes memory disorders in TGA could lead to emotional impairment too. Indeed, several studies have revealed hypoperfusion or hypometabolism of regions implicated in anxiety/mood disorders such as the amygdala (Guillery et al. 2002) or the prefrontal cortex (Baron et al. 1994; Eustache et al. 1997), in particular the orbitofrontal cortex (Peer et al. 2014). Moreover, animal data suggest that the ventral part of hippocampus is involved in processing stress, emotion and affects (Fanselow and Dong, 2010). However, Döhring et al. (2014) failed to find any correlation between the location of lesions in the hippocampus (particularly the ventral part) and stress-related factors in TGA. In summary, all patients display an increase of anxious and/or depressive symptoms during TGA that is probably linked to the sudden and major memory loss which is bewildering for patients. A pathological threshold is reached only in some patients. These last could belong to subgroup of patients identified as having a history of psychopathological disorders (anxiety, depression or personality disorders before TGA). The emotional impact of TGA could therefore be more important for this subgroup. However, other studies are necessary to confirm this hypothesis. Considering that there is a heightened level of anxiety and/or depressive symptoms during TGA, the question then arises of whether these emotional changes can influence the memory impairment. The impact of anxiety and mood disorders can be viewed in two ways. First, depressive and anxious patients

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perform more poorly than controls on a variety of cognitive tasks (Andreoletti et al. 2006; Calvo and Eysenck 1996; Phillips et al. 2002; Ramponi et al. 2004). Similarly, in TGA, mood disorders have a deleterious effect on the anterograde component of episodic memory i.e., a decrease in recall abilities: in Noël et al’s study (2008), the patients who scored the highest on the mood scale (i.e., the most of depressive symptoms), had the poorest recognition performances, whatever the item’s valence—positive, negative, or neutral. Gallassi et al. (2006) observed a selective episodic memory deficit (sparing short-term memory and visual attention) in older patients with major depression. Moreover, according to these authors, the improvement in performance after treatment suggested that it was their depressive state at the time of assessment (state depression), and not a personality trait, that was responsible for their memory impairment. Our results (Noël et al. 2008) show that even the simple increasing of depressive mood at the time of assessment (without fulfilling the criteria of a clinical depression) can have a deleterious effect on memory performances. In the same way, state anxiety has also been found to affect certain features of episodic memory. As mentioned above, we found that TGA patients exhibited a prospective memory deficit (Hainselin et al. 2011). Although the impairment concerned both the prospective and retrospective components of prospective memory, the latter was more severely affected during the acute phase. This result is important because it may explain the verbal leitmotive observed in TGA. Patients may have residual knowledge about the fact that they have to do something (prospective component), but do not remember what it is they have to do (retrospective component). This situation also causes profound anxiety. Thus, it is not surprising that the anxiety level correlates with performances on a task assessing the retrospective component. State anxiety has also been found to have an impact on the enactment effect observed in TGA (Hainselin et al. 2014). In this study, patients during a TGA episode had to memorize an action (either read on a computer screen, carried out by experimenter, or performed by the patients themselves). The enactment effect resulted in increased recall when the actions had been performed by the patients themselves. However, this effect was smaller in the most anxious patients. This effect of anxiety on memory can be explained by the processing efficiency theory developed by Eysenck and Calvo (1992). According to these authors, anxious subjects are prone to distracting thoughts linked to worry. Thus, they are constantly in dual-task situations because distracting thoughts compete with cognitive tasks, notably those that place high demands on working memory capacity and are treated as secondary tasks. The prospective memory tasks require considerable strategic attentional resources, since the subjects must carry out an ongoing task (for example, to judge if the result of an addition is correct) and remember to perform an action when a cue appears (for example, to press a button when the addition is wrote in a specific color; see Ihle et al. 2013 for review). They must interrupt the

ongoing task to perform an action and to remember what action they must perform. In anxious subjects, one part of attentional resources would be allocated to distracting thoughts linked to worry and would be no longer sufficient to carry out tasks requiring a high degree of controlled cognitive processes, such as in prospective memory tasks (Harris and Cumming 2003). In enactment, an action is better recalled because enactment permits to enhance episodic integration in strengthening the link between the action verbs and object nouns (Kourmi-Nouri and Nilsson 2001). Enactment involves the working memory, and notably the binding processes. In anxious subjects, the attentional resources allocated to binding processes would be less available and efficient, thereby decreasing the enactment effect. TGA patients’ performances may also be characterized by a mood congruency effect, that is by the preferential processing of items linked to their emotional state, as shown in anxious individuals (Russo et al. 2001, 2006) and in negative mood induction procedures (Lewis et al. 2005). These phenomena led us to assess the influence of anxious and depressive symptoms on the memory impairments observed in TGA patients, using tasks featuring emotional items (Noël et al. 2008). We expected to observe a mood congruency effect on tasks assessing both the anterograde (i.e., enhanced processing of negative items in this recognition task) and retrograde (i.e., preferential production of negative memories) components of episodic memory. Regarding the anterograde component, we failed to find a mood congruency effect, possibly attributable to the profound anterograde amnesia resulting in a floor effect in the recognition tasks, whatever the valence of the items. By contrast, we did find a mood congruency effect in the retrograde memory task despite low performance. Patients supplied more negative memories than controls for the most recent life period (i.e., previous 12 months). Thus, we only obtained one indicator of a potential mood congruency effect in TGA. However, it may be that we did not choose the best tasks to highlight this effect. Implicit memory tasks would probably be more appropriate, as implicit memory is spared in TGA.

Can Anxious and Depressive Symptoms Slow Down the Recovery Process After the Episode? The delay necessary to a complete recovery after a TGA varies considerably from one study to another (Noël et al. 2011). The presence of anxious and depressive symptoms in some patients could explain these differences. One study (Noël et al. 2007) noted that 1 day after an episode, only patients who still displayed a high level of anxiety and depressive symptoms had persistent cognitive deficits in episodic memory, thus supporting Kessler’s hypothesis (Kessler et al. 2001) that prolonged cognitive impairments in TGA are due to psychopathological factors. More specifically, by using emotional material (positive, negative and neutral items), we showed that

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only TGA patients who were anxious or depressive had difficulty distinguishing targets from lures, and only did so in the case of negative items. Similarly, they produced more negative, less specific and less intense memories for the life period corresponding to the so-called reminiscence bump. We interpreted these data as evidence of a mood congruency effect, thus reinforcing the idea of a strong interaction between emotional and memory disorders in TGA. We also showed that TGA patients continued to display mild memory deficits several months after the episode. Even though their levels of anxiety and depressive symptoms seemed to have returned to their pre-TGA level (Noël et al. 2011), they continued to influence their cognitive performances (Guillery-Girard et al. 2006; Noël et al. 2011). More specifically, patients with the highest anxiety and depressive symptom levels also displayed the most impaired cognitive profile (Noël et al. 2011). Néri et al. (1995) had previously observed that most of the TGA patients with slight persistent episodic memory deficits were also depressed at the time of the examination. Even if the lasting memory disturbances observed after the episode seem to be linked to depressive and anxious symptoms, they can reflect either the negative effect of these depressive/anxious symptoms due to TGA episode on recovery process (a slowing down), or the return to a psychological and cognitive status previous to TGA episode in patients with depressive/anxious personality (mild memory impairment linked to patients’ personality previous to TGA).

Can the Analysis of Emotional and Psychological Factors Surrounding the Episode Help us to Clarify the Etiology of TGA? One of the most enigmatic questions in TGA concerns its etiology. Several hypotheses have been formulated, but none has been fully supported. However, analyzing the circumstances surrounding the episode, in particular the emotional events, could reveal the pathophysiological mechanisms precipitating TGA. Precipitating events are more frequent in TGA than in TIA (Inzitari et al. 1997; Rösler et al. 1999) and are usually divided into two broad categories: physical (e.g., physical effort, cold/hot bath, pain) and emotional (e.g., death, quarrel, announcement of bad news). These emotional precipitants constituted nearly half of all noted precipitants (Inzitari et al. 1997; Trillet 1990) and have spawned multiple hypotheses on the pathophysiology of TGA. Lewis (1998) emphasized that physical precipitants often correspond to activities that can lead to a Valsalva manoeuvre. This is responsible for increased thoracic pressure, preventing a normal blood flow and even leading to retrograde flow patterns from the jugular vein towards the brain. This venous congestion associated with jugular vein valve incompetence, which is frequently found in these patients (Modabbernia et al. 2012),

could cause hypoxia of the hippocampus. According to Sander and Sander (2005), the combination of intense emotional stress (emotional precipitant) and specific personality traits (e.g., anxious, phobic, depressive), could also induce venous congestion by causing hyperventilation (frequent reaction in psychopathological disorders or after a stressful event; Gardner 1996) and vasoconstriction, resulting in hemodynamic changes in the hippocampal region. However, no correlation has been found between intracranial venous flow and jugular valve insufficiency, thus reducing the plausibility of this factor in TGA (Akkawi et al. 2007). Bartsch and Deuschl (2010) proposed an additional argument against this hypothesis, by emphasizing that the presence of discrete hippocampal lesions is not compatible with an overall increase in intracranial venous pressure. In the latter case, we would expect to observe more extensive lesions in patients, caused by a thromboembolic event or a hematoma, for example. Moreover, another older vascular hypothesis suggested a mechanism similar to TIA, but several studies have shown that TGA patients do not have more vascular risk factors than controls (Mangla et al. 2014; Pantoni et al. 2005; Quinette et al. 2006b; Winbeck et al. 2005) and significantly less than TIA patients and have significantly lower rates of major vascular events and death than TIA patients (Pantoni et al. 2005). Nonetheless, Winbeck et al. (2005) found that TGA patients who displayed abnormalities in diffusion-weighted imaging (DWI) had a higher incidence of carotid atherosclerosis. Finally, the prevalence of past history of migraine in TGA patients has led to the postulation that the pathophysiological mechanism behind TGA is similar to that described in migraine with aura (i.e., cortical spreading depression). Besides, Lin et al. (2014) showed that patients with migraine had a greater risk of developing a TGA (at least twice as much) than controls without migraine or other headache disorders (matched in age, sex and cardiovascular comorbidities). In TGA, intense emotional stress could be responsible for this phenomenon, with an emotional shock leading to an excessive glutamate release triggering spreading depression and causing a functional ablation of the hippocampus (Sander and Sander 2005). This depolarization is thought to originate in the hippocampus. Repeated and/or prolonged episodes of stress, favoring the development of anxious or depressive disorders, presumably lead to successive releases of glutamate in the brain. The hippocampus is one of the most vulnerable brain regions to repeatedly high levels of glutamate (Bremner 1999). This hippocampal vulnerability, which could define one subgroup of patients in TGA, could be a factor favoring the spread of depression. This presumably spreads from the hippocampus across the cortical surface, which could explain the dysfunction of an extensive brain network demonstrated in the few positron emission tomography (PET) studies (Baron et al. 1994; Guillery et al. 2002). The spreading-depression theory, however, has still to be unquestionably supported, even in migraine.

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If there is as yet no consensus on the pathophysiological mechanisms behind TGA, over the past 10 years, the involvement of the hippocampus has received particular attention. Several neuroimaging studies (Bartsch et al. 2006; Bartsch and Deuschl 2010) using DWI MRI has shown hyperintense hippocampal signals in some TGA patients between 24 and 72 h after the onset of symptoms when symptoms have subsided. These abnormalities were limited to the CA1 field of the hippocampus, and were frequently found in only one hemisphere. Unilateral involvement, however, is not sufficient to result in a global amnesia and is not consistent with the fact that episodic memory disorders are only severe in the case of bilateral lesions (e.g., Patient HM– —Scoville and Milner 1957). Döhring et al. (2014) adopted an original approach to elucidate the pathophysiological mechanisms behind TGA. As animal studies had shown that the CA1 network is divided into functional compartments (with a dorsal part involved in cognitive function and a ventral part involved in the processing of emotion, affect and stress), they noted the location of lesions in the dorsal (24 %), ventral (29 %) and intermediate (52 %) compartments in TGA patients, and analyzed the association between the distribution of these lesions in the hippocampus and measures of emotional factors (stress, personality trait or coping strategy questionnaires and precipitants). However, they failed to find any association between stressful events, behavioral patterns and the distribution of lesions in TGA. Finally, a recent resting-state functional MRI study (Peer et al. 2014) showed a significant reduction in functional connectivity within an extensive bilateral brain network during the acute phase of TGA, which was reversible after recovery. This disturbance of connectivity affected not only regions directly linked to the hippocampus, such as frontocingulate, inferior temporal and medial occipital regions and deep structures (thalamus, putamen and pallidum), but also other regions involved in episodic memory functioning. These regions were mostly temporolimbic (notably the amygdala), but also prefrontal (in particularly the orbitofrontal cortex), which could contribute to the emotional symptoms observed during TGA. Although the DWI MRI studies tended to show isolated impairment of the hippocampus, Bartsch et al. (2011) have already suggested that a profound albeit transient impairment of the CA1 field of the hippocampus could lead to acute diaschisis and reduced connectivity within the episodic and autobiographical memory network.

Conclusion Overall, this review highlights the growing number of studies on the role of depressive and anxious symptoms in TGA. These factors seem to intervene at different moments in TGA (i.e., triggering, course and recovery). First, the idea of emotional arousal-induced TGA suggested by Merriam et al.

(1992) can be considered more seriously. Indeed, several studies showed that psychological profile of patients constitute one of risk factors for TGA, at least in a subgroup of patients (Quinette et al. 2006b). This therefore appears to be one of precursors of TGA. Besides, in other pathologies such as epileptic seizures (Jacoby et al. 2015) or multiple sclerosis flareup (Amtmann et al. 2015), the emotional factors play an important role, too. During the TGA, all patients display an increasing of anxious and/or depressive symptoms. This change of patients’ emotional state is probably linked to the sudden memory and orientation loss. But, in TGA patients having a history of identified psychopathological disorders, the level of anxious and depressive symptoms could reach pathological threshold during TGA. The emotional impact of TGA could therefore be more important for this subgroup. Regarding the post-TGA period, few arguments have so far been put forward to support the assumption that anxious and depressive symptoms influence recovery processes. Moreover, the presence of lasting memory impairment could simply reflect the return of a previous emotional and cognitive status prior to TGA. It should be noted that most studies have focused on cognitive disorders, but none have sought to link the presence of psychopathological disorders after the episode to persistent memory and brain disorders. Finally, psychological and emotional factors are at the core of several pathophysiological hypotheses. But, at this time no study supplied evidences at this end. In order to clarify these mechanisms, further studies need to be conducted both in neuroimaging (resting-state MRI, PET), to confirm the hypotheses of disconnection in TGA, and in neurobiology (measures of neuroendocrine responses), to support the role of stress-related factors in the triggering of TGA.

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