Participants

Ours is the largest ever neuropsychological study of participants experiencing a transient global amnesia episode. Between 2005 and 2007, 35 people with transient global amnesia were admitted to the emergency department of Caen University Hospital. The selection of participants was systematically carried out by senior neurologists, in line with a codified procedure. The clinical and neurological examinations of the individuals were all normal, except for memory disturbance. Brain computed tomography (CT) scans and electroencephalograms performed during or after the episode were also normal. Seventeen people were examined during the very acute phase. Eighteen others were recruited during the peri-acute phase, i.e. within 24 h of onset. The exact end of the acute phase is difficult to gauge. ^{Reference Quinette, Guillery-Girard, Dayan, de la Sayette, Marquis, Viader, Desgranges and Eustache2} Although the onset of the attack is usually easy to pinpoint because it is so sudden, recovery is gradual and there is no criterion to determine the point at which people start to recover. We estimated the end of the acute phase using several types of clinical data. When individuals still displayed memory disorders but no longer presented temporal disorientation or repetitive questioning, they were included in the peri-acute phase group. People in both groups (acute and peri-acute phases) were matched according to age and level of education (Table 1). All of them fulfilled the criteria for transient global amnesia, ^{Reference Hodges and Warlow5} and for six of them, the witness was present for much of the attack but not at the very beginning. In order to list precipitants, i.e. unusual events preceding the attack, we used questionnaires previously described in Quinette et al. ^{Reference Quinette, Guillery-Girard, Dayan, de la Sayette, Marquis, Viader, Desgranges and Eustache2} We systematically looked for the presence of risk factors that have previously been reported in the literature and which could supply information on the aetiology of such episodes (Table 1). A control group consisted of 26 strictly selected healthy people, matched with the two case groups according to age (control group mean age: 60.2 years (s.d.=7.3) and level of education (control group mean: 11.8 years (s.d.=3.7)).

Table 1

Clinical characteristics of individuals with transient global amnesia according to the stage at which the test was carried out

	Acute phase (n=17)	Peri-acute phase (n=18)
Gender, women/men	8/9	9/9
Age, years: mean (s.d.)	62.8 (6.3)	60.3 (9)
Level of education, years: mean (s.d.)	10.9 (3.4)	9.9 (3.7)
Duration, h: mean (s.d.)	7.6 (1.7)	3.7 (3.1)
Start of examination, h: mean (s.d.)a	4.8 (1.5)	10.7 (7.5)
Recurrences, n	4 (second episode) + 1 (third episode)	2 (second episode)
Precipitants, n
Stressful event	4	5
Physical effortb	8	4
Intercourse	1	4
Water contact	1	1
No precipitant	3	4
Risk factors, n
Transient ischaemic attack	1	0
High blood pressure	8	7
Hypercholesterolemia	12	4
Diabetes	3	0
Heart disease	1	0
Migraine	2	4
Psychiatric disordersc	3	7

All participants gave informed consent to the study, which was performed in compliance with the Declaration of Helsinki. This study was approved by the local ethical committee.

Psychopathological assessments

In order to determine whether anxiety and mood disorders could be considered to be predisposing factors, participants completed, the day after the episode, two questionnaires assessing anxious personality trait (State–Trait Anxiety Inventory (STAI)) ^{Reference Spielberger6} and the presence of a depressive state at least 2 weeks before the episode (abridged version of the Beck Depression Inventory (BDI) composed of 13 items). ^{Reference Beck, Rial and Rickets7} Two other psychopathological scales completed during the attack allowed us to measure the level of anxiety (first part of STAI) and depression (Adjective Mood Scale (or Befindlichkeits-Skala)), ^{Reference Von Zerssen, Koeller and Rey8} and to determine whether these disorders could be regarded as symptoms specific to this episode. Because transient global amnesia is a short-lived syndrome, we chose scales that did not take long to complete. Because we also thought that moods before and during the episode might be radically different, we used the Adjective Mood Scale, which was designed to measure brief variations in mood. This scale is a particularly sensitive measure of changes in depressive symptomatology and is correlated with other depression scales such as BDI. ^{Reference Moller9}

The Adjective Mood Scale has already been used to determine the links between current mood state and neuropsychological disorders, notably in psychogenic amnesia. ^{Reference Markowitsch, Kessler, Russ, Frolich, Schneider and Maurer10} In this scale, participants must choose between two contrasting adjectives, selecting the one which best characterises them at the time of the test. Another kind of answer is possible if neither adjective is relevant. According to the score, people are classified as relaxed (mean score 12.02), worried (mean score 19.32) or utterly depressed (mean score 34.40). The maximal score is 56.

Neuropsychological assessment

Statistical analysis

We compared the levels of anxiety and depression, and the cognitive performances of all three groups of participants: individuals examined in the acute and peri-acute phases of transient global amnesia and controls. Data were analysed using a one-way analysis of variance (ANOVA), with group as a between-participant factor. Post hoc analyses (Tukey test) were then used to conduct paired comparisons of group performances.

To determine the influence of psychological factors on memory disorders, we established correlations between the participants with scores on the psychopathological scales and their cognitive performances. To increase the statistical power, we considered all these participants as a single group (35 individuals) and reduced the number of cognitive variables, selecting the most representative and independent impaired cognitive scores on each task. A probability level of 0.05 was adopted for all analyses.

Psychopathological deficits

There was no significant difference between the three groups for the scores on the trait-STAI (F(2,58)=1.07, P=0.35) and BDI (F(2,58)<1), although there was one difference for the scores on the state-STAI (F(2,34)=4.70, P=0.01) and the Adjective Mood Scale (F(2,56)=11.82, P<0.001) (Table 2). The post hoc analysis revealed that only participants examined in the acute phase obtained higher scores than controls. There was no significant difference between those observed in the peri-acute phase and controls. There was no difference in the scores between the two groups with transient global amnesia.

Table 2

Scores obtained on the psychopathological scales for participants in the acute phase, in the peri-acute phase and in controls

	Acute phase (n=17), mean (s.d.)	Peri-acute phase (n=18), mean (s.d.)	Controls (n=26), mean (s.d.)
Trait STAI	44.2 (8.7)	50.0 (11.7)	46.3 (9.4)
Short version of BDI	2.6 (3)	3.1 (3.6)	2.5 (2.4)
State STAIa	59.3 (11.3)**	51.4 (16.3)	44.7 (6.5)
Adjective Mood Scale	23.9 (8.5)***	16.9 (9.2)	10.8 (7.8)

Effect of psychopathological disorders on memory impairments

Correlations between psychopathological and neuropsychological scores

We found a significant negative correlation between the trait anxiety score and the number of words produced in the fluency task. There are also significant negative correlations between the score on the Adjective Mood Scale and the three accuracy scores. All the correlations are reported in Table 3.

Table 3

Correlations between psychopathological scales and impaired neuropsychological scores in participants with transient global amnesia (n=35)

	State anxietya	Trait anxiety	BDI	Adjective Mood Scalea
Categorical fluency	-0.18	-0.46**	-0.19	-0.16
Accuracy scores (assessment of anterograde amnesia)
Positive items	-0.35	+0.15	-0.04	-0.38*
Negative items	-0.19	+0.27	-0.17	-0.37*
Neutral items	-0.38	+0.19	-0.03	-0.41*
Specificity scores (assessment of retrograde amnesia)
Life period: 18-30 years	+0.32	+0.06	+0.17	+0.03
Life period: past 10 years	-0.12	-0.24	-0.05	-0.32
Life period: past 12 months	+0.05	-0.13	-0.09	-0.04
Working memory
Backward visuospatial span	+0.04	+0.20	+0.04	-0.14
Letter—number sequence	+0.06	-0.20	-0.03	-0.06

Psychopathological disorders

Not only did almost all the participants with transient global amnesia display a sudden change in mood and anxiety levels during the episode, but these modifications of emotional state also followed the dynamic of the episode. As with memory disorders, we observed a deterioration in the emotional state during the acute phase, which subsequently improved during the peri-acute phase. These results suggest that the changes in mood and anxiety levels during the episode can be considered as symptoms. Clinical descriptions of individuals in the past have emphasised their particular emotional state: anxious attitude (verbal leitmotifs linked with their worry), tears, symptoms similar to those of a panic attack. ^{Reference Inzitari, Pantoni, Lamassa, Pallanti, Pracucci and Marini4} One possible explanation may be that transient global amnesia shares some physiopathological characteristics with anxiety and mood disorders. In addition to transitory hippocampal dysfunction, it is often associated with hypoperfusion or hypometabolism of the amygdale ^{Reference Guillery, Desgranges, de la Sayette, Landeau, Eustache and Baron21} or frontal regions, ^{Reference Baron, Petit-Taboué, Le Doze, Desgranges, Ravenel and Marchal22} which are also implicated in anxiety and mood disorders. ^{Reference Mayberg, Liotti, Brannan, McGinnis, Mahurin, Jerabek, Silva, Tekell, Martin, Lancaster and Fox23} The results of the group analysis of the scores on the two scales measuring the presence of trait anxiety and depressive symptoms prior to the episode show that the acute and peri-acute groups and controls obtained similar scores. This suggests that the anxiety personality trait and depressive symptoms are not predisposing factors for an episode. At first sight, these results would appear to contradict those of our previous study. ^{Reference Quinette, Guillery-Girard, Dayan, de la Sayette, Marquis, Viader, Desgranges and Eustache2} However, when we carried out individual analyses, we found that 16 of the 35 participants with transient global amnesia displayed a high level of anxiety (i.e. a score above 50 on the STAI) ^{Reference Spielberger6} and 5 of them showed depressed symptoms (i.e. a score above 8 on the abridged version of the BDI). ^{Reference Beck, Rial and Rickets7} Thus, the presence of these symptoms in some participants with transient global amnesia before the episode (and this was corroborated by relatives) could also have influenced the psychopathological and neuropsychological profiles of some individuals. However, we cannot completely exclude the possibility that the experience of an episode changed the self-judgement of people on the emotional state they felt during the days preceding it, meaning that this assessment would reflect the current rather than the previous emotional state.

Influence of psychopathological disorders on neuropsychological profile

First, we have highlighted a massive impairment of episodic memory associated with a slight executive deficit. During the peri-acute phase, these disorders decreased, but participants with transient global amnesia still displayed disturbances, especially of episodic memory.

During the acute phase, anterograde amnesia was characterised by a low recognition rate of items, whatever the emotional valence of these items. Moreover, even when participants did recognise items correctly, their responses were based solely on a feeling of uncertainty (Guess responses). The absence of both Remember and Know responses reflected the extent of their anterograde amnesia. During the peri-acute phase, even though individuals' performances improved, recognition was still disturbed. In particular, participants supplied fewer Remember responses than controls during the peri-acute phase; they had a considerable recollection deficit, although they were able to use the familiarity process (Know responses) as effectively as controls. Thus, even if performances improved, these relied more on semantic memory (feeling of familiarity) than on the residual capacities of episodic memory.

Regarding retrograde amnesia, our results confirmed that memories retrieved by those with transient global amnesia are neither specific nor detailed during the episode. ^{Reference Hodges and Ward24} The decline of retrograde amnesia was characterised by the recovery of memories from all but the most recent periods. This recovery of memories in chronological order, in accordance with Ribot's Law, ^{Reference Ribot25} has already been demonstrated in transient global amnesia ^{Reference Guillery-Girard, Desgranges, Urban, Piolino, de la Sayette and Eustache26} and other memory disorders. ^{Reference Kopelman27}

Our results also suggest minor impairment of executive functions. Contrary to the phonological loop and the visuospatial sketch-pad, the central executive of working memory was impaired during the episode. In a previous study, ^{Reference Quinette, Guillery-Girard, Noël, de la Sayette, Viader, Desgranges and Eustache28} we highlighted an abnormally rapid loss of verbal and visuospatial information when rehearsal was prevented. This explains why we found pathological scores on tasks that involved both the storage and handling of information. Moreover, the presence of another executive deficit, observed during the acute and peri-acute phases, was emphasised by the decreased production of responses on the categorical fluency task, which has previously been interpreted as an impairment of semantic memory retrieval strategies. ^{Reference Eustache, Desgranges, Petit-Taboué, de la Sayette, Piot, Sablé, Marchal and Baron29} This disturbance probably did not reflect a semantic memory disorder, as demonstrated by the preservation of conceptual knowledge we observed during an episode. ^{Reference Hodges30}

Second, we showed that cognitive performances were indeed affected by psychopathological disorders, as shown by significant correlations between accuracy scores and scores on the Adjective Mood Scale. However, although participants with transient global amnesia displayed a high level of anxiety at the time of the episode, this did not greatly affect neuropsychological disorders. Anxiety only contributed to the deficit in word production in the categorical fluency task. This impairment, which can be ascribed to impaired retrieval strategies in semantic memory, has also been observed in anxiety disorders ^{Reference Everhart and Harrison31} and can be linked to frontal lobe activity. ^{Reference Thibodeau, Jorgensen and Kim32} This reinforces the hypothesis that the deficit in production was because of the disruption of executive functions, at least in the more anxious individuals. Conversely, depressed mood disorders were found to influence memory performances: there was a deleterious effect of depressed emotion on memory that mainly concerned the anterograde component of episodic memory. We showed that the more pathological the scores assessing the current mood state, the poorer the recognition performances, whatever the valence of the items. This effect of depressed mood has also been observed in people with clinical or non-clinical depression, ^{Reference Airaksinen, Larsson, Lundberg and Forsell33} as in experimental negative mood induction, ^{Reference Ellis, Thomas, McFarland and Lane34} and could be explained by a depletion in attentional resources due to interfering activities. ^{Reference Trask and Sigmon35} A negative mood state is characterised by irrelevant thoughts which are in keeping with depressed emotion and which interfere with cognitive tasks. ^{Reference Seibert and Ellis36} Moreover, this aversive effect of negative mood state on cognitive performances would appear to be greater in elderly people than in young adults. ^{Reference Deptula, Singh and Pomara37} It may be a similar story for the verbal leitmotifs (often linked to worries) that are observed in transient global amnesia. Regarding retrograde amnesia, neither the participants' mood nor their anxiety level affected their ability to evoke episodic memories.

As almost all participants with transient global amnesia displayed a depressed mood state, we expected to observe greater processing of negative items in the recognition task and preferential production of negative memories in the autobiographical tasks, as has already been reported for depression. ^{Reference Ergis, Piolino and Mure38} Although this mood congruency effect was not actually observed in the recognition task, it may have been masked by the extensive anterograde amnesia. We did, however, find a mood congruency effect in the task assessing the retrograde component of episodic memory: participants with transient global amnesia supplied more negative memories than controls for the most recent life period, which was also the one most adversely affected by an episode.

Clinical implications and limitations of the study

Transient global amnesia causes a deterioration of mood and an increasing level of anxiety during an episode. These modifications of mood have a deleterious effect on memory performances. During the acute phase, the management of anxiety both in individuals experiencing an episode and relatives should be based on verbal reassurance. ^{Reference Harrison and Williams39} Concerning subclinical depression observed, other studies should be carried out to determine whether these individuals need short-term treatment. A follow-up study could supply further information on the psychological impact of the episode on everyday life. For relatives, medical staff must stress that transient global amnesia is a benign condition, and that the work-up is only intended to rule out more serious diseases such as stroke or epilepsy. Family members should also be reassured to prevent their anxiety from increasing that of their relatives with amnesia. Finally, as anxiety is more frequent in idiopathic than post-traumatic transient global amnesia, this symptom might be used as a diagnostic clue to distinguish both conditions when information about the start of the episode is lacking, but this needs to be confirmed in further studies.

We cannot exclude the possibility that psychopathological disorders present in some individuals before the episode also influenced memory performances. The evolution of these psychopathological disorders in the time course of the episode was not examined.

In conclusion, we recorded high anxiety levels and a depressed mood state during an episode. Trait but not state anxiety was correlated with categorical fluency, and transiently depressed mood was associated with impaired anterograde memory performances. Other studies have stressed the link between emotional precipitants and the onset of transient global amnesia and reported the presence of psychopathological disorders in some people before the episode, ^{Reference Quinette, Guillery-Girard, Dayan, de la Sayette, Marquis, Viader, Desgranges and Eustache2} suggesting that psychopathological disorders may constitute one of the predisposing factors for an episode. Other studies are therefore needed in order to explore in greater depth the role of emotional factors in transient global amnesia.