engagement of lateral and medial …functional imaging methods such as functional magnetic resonance...

Vrije Universiteit Brussel

Brain circuits for the retrieval of sad and happy autobiographic episodes

Markowitsch, H.; Vandekerckhove, Marie; Lanfermann, H.; Russ, M

Published in:Cortex

Publication date:2003

Document Version:Final published version

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Citation for published version (APA):Markowitsch, H., Vandekerckhove, M., Lanfermann, H., & Russ, M. (2003). Brain circuits for the retrieval of sadand happy autobiographic episodes. Cortex, 39(4), 643-665.

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ENGAGEMENT OF LATERAL AND MEDIAL PREFRONTALAREAS IN THE ECPHORY OF SAD AND HAPPY

AUTOBIOGRAPHICAL MEMORIES

Hans J. Markowitsch1, Marie M.P. Vandekerckhove1, Heinrich Lanfermann2 andMichael O. Russ3

(1University of Bielefeld, Physiological Psychology, Bielefeld; 2Institute ofNeuroradiology; 3Clinic of Neurology of the Johann Wolfgang Goethe University,

Frankfurt am Main, Germany)

ABSTRACT

Autobiographic memory is usually affect-laden, either positively or negatively. A centralquestion is whether the retrieval of both emotive forms of memory engages the same or adifferent neural net. To test this we studied 13 normal subjects with functional magneticresonance imaging while they retrieved a number of distinct episodes, all of which wereeither rated as strongly positive (happy) or strongly negative (sad) in affect. Comparing theretrieval of sad with that of happy episodes revealed activation in both lateral orbital corticessymmetrically (extending into the ventrolateral prefrontal cortex as well), together with asmall region in the right lateral temporal cortex and the left cerebellum. Vice versa,comparing the retrieval of happy with that of sad episodes revealed a major activation inthe left hippocampal region, bilateral (though more right-sided) activation in the medialorbitofrontal/subgenual cingulate and a left sided activation in the dorsolateral prefrontalactivation. These findings point to the importance of the orbitofrontal cortex for affect-laden information processing and to the existence of distinct neural nets for the re-activationof positively and negatively viewed autobiographic episodes.

INTRODUCTION

Memory is nowadays divided into several systems of which the episodic-autobiographic system is considered to be the most complex, requiring consciousreflection and allowing mental time travel into the past (Tulving andMarkowitsch, 1998). Due to its complexity, autobiographic memory isvulnerable to diverse forms of focal as well as diffuse brain damage and tovarious psychiatric problems, frequently related to stress, trauma, anddissociative disorders (Markowitsch, 1999, 2000).

Results from brain damaged patients (Kroll et al., 1997; Levine et al., 1998)and functional imaging studies (Fink et al., 1996) have pointed to a special roleof prefrontal regions in memory processing as well as in theory of mind (Stusset al., 2001), consciousness (Knight and Grabowecky, 2000; Wheeler et al.,1997), emotion processing (Baker et al., 1997), self-recognition and personalidentity (Keenan et al., 2000; Vogeley et al., 2001). This research ties to earlystudies, implicating particularly the orbitofrontal portion of the prefrontal lobesin personality dimensions (Harlow, 1848, 1869; Kleist, 1934; Welt, 1888). Afurther corroboration can be seen in discussions on metabolic reductions in thefrontal lobes of affective murderers (Raine et al., 1998) and on gray matter

Cortex, (2003) 39, 643-665

volume reductions in subjects with antisocial personality disorder (Raine et al.,2000). (Affective murderers are more impulsive, emotional and unplanned thanpredatory murderers.) Furthermore, morphological changes have been observedin the prefrontal and orbitofrontal regions of brains of patients with psychiatricdiseases, and impairments in social and moral behavior have been noted inpatients with damage to these regions (SW Anderson et al., 1999; Clark et al.,2001; Nies, 1999; Eslinger, 1999; Goldstein et al., 1999; Harrison, 1999;Nyffeler and Regard, 2001).

Orbitofrontal and adjacent subcallosal cortices receive input from (other)prefrontal and posterior cortical integration areas as well as from many limbicregions, representing the hierarchical apex of this system. It is involved in social,emotional, motivational, and self-regulatory processes and represents the site ofconvergence for extero- and interoceptive information (Bechara et al., 2000;Goel and Dolan, 2001; Rolls, 1999, 2000; Shammi and Stuss, 1999). Lateral andmedial portions of this basal frontal cortex have different networks ofconnectivity. The medial sector is particularly related to hippocampal andparahippocampal regions, and the posterior cingulate and retrosplenial areas,while the lateral section has strong connections with the amygdala, sensory andpremotor regions (Cavada et al., 2000).

Results of animal studies complement the findings on social functions of the(orbito-) frontal (and anterior temporal) cortex (Franzen and Myers, 1973). Theventral striatum may be seen as a subcortical extension of this anterior frontal-temporal circuit which Nauta (1979) termed the “expanded limbic system”. Thisregion has been linked to emotional information processing as well (Davidson,2000; Ohara et al., 1999; Thomas et al., 2001).

Elliot et al., (2000) suggested that the orbitofrontal cortex becomes activewhen there is insufficient information available to determine the appropriatecourse of action. Selection of stimuli, based on their familiarity and on a feelingof “rightness” are – according to these authors – related orbitofrontal functions.Further, decoding and readjusting the reinforcement value of stimuli seem to bean important function of the orbitofrontal cortex (Rolls, 1999), which thereforecan be characterized as involved in high level judgement, implicating theanticipation of consequences, empathy and decision making (Bechara et al.,2000).

Autobiographical memories involve many of these processes attributed(among other regions) to the orbitofrontal cortex. They are inherently personalmemories and therefore part of an individual’s personality – used to form thebasis of the self (Conway and Pleydell-Pearce, 2000). Secondly, they are usuallyof an emotive character, having positive or negative valence. Thirdly, theirretrieval or ecphory requires consciousness. (The term ‘ecphory’ is used todescribe the process by which retrieval cues interact with stored information sothat an image or a representation of the information in question appears,Tulving, 1983.)

A question of interest is, however, whether autobiographical memories of apositive (pleasant, happy) character recruit other portions of the frontal lobe thanautobiographical memories of a negative (sad, unhappy) character. There is ahuge literature on the influence of emotional valence on information encoding

644 Hans J. Markowitsch and Others

and retrieval (Bower, 1992; Brewer, 1988; Holmes, 1970). It is also intriguing toask whether, in addition to the likely engagement of frontal lobe regions, otherbrain areas are implicated differentially in the processing of sad versus happyold autobiographical memories, and whether processing episodes of a positiveand of a negative character involve a difference in brain laterality.

Regions of the limbic lobe, in particular portions of theprefrontal/orbitofrontal cortex, the ventral striatum and the amygdala areconsidered to process emotional information (Davidson, 2000; Davidson andIrwin, 1999; Mesulam, 2000; Morris and Dolan, 2001). The amygdala receivespreprocessed polysensory information and its left and right nuclear complexesrespond differently to different aspects of emotional stimuli (Markowitsch,1998/99), though frequently a bilateral activation can be measured withfunctional imaging methods such as functional magnetic resonance imaging(fMRI) (e.g., Royet et al., 2000; Sander and Scheich, 2001). There is evidencefor a strong engagement of both amygdalae to fearful or negative as opposed topositive stimuli (Adolphs, 1999; Adolphs et al., 1999; Davidson and Irwin,1999; Morris et al., 1998; Nader et al., 2000). Several careful analyses, however,challenged or specified (AK Anderson and Phelps, 1998; Davis, 1998) this view.Recent fMRI findings demonstrated significant and bilateral amygdalaactivations towards both positively and negatively valenced pictures and showedthat the arousal level modulated the amygdala response for negative, but not forpositive stimuli (Garavan et al., 2001). Furthermore it was found that theduration or frequency of exposure to emotional material may change amygdalarresponses (Phillips et al., 2001). Wright et al., (2001) suggested from their fMRIfindings to repeatedly presented emotional stimuli that the right amygdala is partof a dynamic emotional stimulus detection system and the left is specialized forsustained stimulus evaluations. (Related to their argumentation, Canli et al.,2000, suggested that amygdala activation reflects moment-to-moment subjectiveemotional experience.)

Aside from the relation of verbal material to the left and non-verbal to theright amygdala (Beauregard et al., 2001; Markowitsch, 1998/99), there arefurther laterality effects, some of which may have to do with the righthemispheric preponderance to attention mechanisms (Heilman and Van denAbell, 1980) and emotional expression (Borod et al., 1998; Cimino et al., 1991).Though there is some specific data in favor of lateralization effects between theamygdalae, results are not infrequently contradictory: Phelps et al. (2001)described, a specific activation of the left amygdala to the cognitiverepresentation of fear, while Abercrombie et al. (1998) stated that the metabolicrate in the right amygdala predicts negative affect in depressed patients.Similarly, Drevets (1998) found that depressed patients had higher blood flowrates in the left amygdala, while Abercrombie et al. (1998) observed them in theright amygdala. Adolphs et al. (2001) compared 20 patients with unilateralamygdala damage and one with bilateral damage to two groups of controlsubjects. They found differences only for the subject with bilateral amygdaladamage: she showed – compared to the controls – poorer memory for gist butsuperior memory for visual details.

Reviewing this literature, Markowitsch (1998/99) concluded that the left

Ecphorizing old memories 645

amygdala is more closely related to affective encoding with a higher affinity forlanguage and for detailed feature extraction, and the right amygdala to affectiveretrieval with a higher affinity for pictorial or image-related material.Furthermore, the right amygdala may be more strongly engaged than the left onein a fast, shallow or gross analysis of affect-related information.

Functional magnetic resonance imaging is used in normal human subjects toaddress these questions of interaction between memory, emotion, and functionalneuroanatomy. We proposed that especially regions modulating memory byproviding an affective flavor to it, would be activated. Furthermore, we assumedthat in general regions similar as in our previous report (Fink et al., 1996) mightbe engaged. In the study of Fink et al. ventral prefrontal and temporal regions,including amygdalar and hippocampal areas were activated. Recently in an fMRIstudy Cadoret and co-workers (2001) also found that the ventrolateral prefrontalcortex was activated during the retrieval of previously stored visualrepresentations. Other memory modulating regions, which might be activatedwithin the present design include the cingulate gyrus (Fink et al., 1996;Markowitsch, 2000; Markowitsch et al., 2000; Shah et al., 2001), basal forebrainregions (e.g., septal region, ventral striatum) (Mesulam, 2000; Von Cramon andMarkowitsch, 2000) and the precuneus – termed “the mind’s eye” by Fletcher etal. (1995) (Markowitsch et al., 2000; Shah et al., 2001).

The hippocampal region has also been consistently discussed, though morewith respect to memory processing (Eichenbaum, 2000) than with respect to theprocessing of affect. The possible engagement of hippocampal regions in retrievalprocesses is thus controversial (Maguire et al., 2001) – especially as it seems tobe impossible to distinguish between mere retrieval and retrieval accompanied bythe re-encoding of the retrieved information (Tulving and Markowitsch, 1997,1998). This is largely due to the unresolved nature of memory consolidation(McGaugh, 2000; Moscovitch and Nadel, 1998; Sara, 2000).

In the meantime, a considerable amount of literature on neuroimaging andemotion has accumulated. Because the central theme of the present investigationis on memory, only a short review will be given. Lane et al. (1997) reported ina PET study on pleasant and unpleasant emotions, elicited by pleasant, neutral,and unpleasant pictures, that unpleasant emotions activated the left amygdalaand hippocampus. Other functional imaging studies also found increased neuralactivity in the left amygdala while negative emotions were being processed(Breiter et al., 1996; Ketter et al., 1996; Morris et al., 1996; Phelps et al., 2001;Schneider et al., 1995), whereas other authors reported the opposite pattern oflateralization: positive emotions leading to an increased left hemisphericamygdaloid activition, and negative emotions to an increased right hemisphericone (Canli et al., 1998; Tabert et al., 2001; Zalla et al., 2000). Gender effectsmight contribute to differences in results, as Schneider et al. (2000) recentlyfound that only males demonstrated an amygdala activation during sadness, andCahill and co-workers (2001) demonstrated activation with enhanced memoryfor emotional films in males on the right and in females in the left amygdala.Similarly, brain activations differed in part between sexes when viewing eroticfilm excerpts (Karama et al., 2002). In a developmental study on amygdalaresponses to affective faces, only females showed a progressive increase in


prefrontal relative to amygdala activation in the left hemisphere with increasingage (Killgore et al., 2001).

A specific aspect of emotions was the target of an fMRI study of Beauregardet al. (2001). They wanted to compare inhibition of sexual arousal, elicited byviewing erotic stimuli, with responding in a normal manner. Standard viewingresulted in activity of structures of the expanded limbic system – right amygdala,right anterior temporal pole, hypothalamus – while inhibition evoked activity inthe right superior frontal and the right anterior cingulate gyri.

The present study was undertaken to study whether a person’s ownbiographical memories of different emotional valence (positive versus negative)lead to different metabolic changes on the brain level.

METHODS

Subjects

Subjects were 13 right-handed healthy volunteers (7 females) from theUniversities of Cologne and Frankfurt am Main (average age: 30 years; range:19-43 years). None had a history of previous neurological or psychiatric illnessesor syndromes. No gross brain abnormalities were found on magnetic resonance(MR) scans. All subjects were native German speakers. Informed consent wasobtained from each subject prior to participation in this study.

Procedure

Subjects were told that psychologists have been studying memory for manyyears, but that there is still a need for research on the brain representation ofautobiographical memory about pleasant and sad experiences. They were askedto retrieve autobiographic episodes of either a pleasant or a sad content, evokedby a fixed set of 36 key words, from the following periods of their life: (1) thefirst 12 years, (2) the period between years 12 and 18, (3) and from age 18 tothe present. This division into three time periods was done (a) to obtainhomogeneous episodes between subjects with respect to the past, and (b) inorder to structure the retrieval of episodes. As there were not enough individualepisodes to analyze per period, they were combined.

Subjects were encouraged to provide episodes with a degree of intensity ashigh as possible for both mood conditions. They were told that the investigatorswere not interested in particulars of the content, but in the general way in whichdifferent experiences are re-activated and memorized.

The episodes retrieved were sorted with respect to the two conditions.Subjects were asked to rate and comment on the intensity of their happy or sademotion for each episode provided and on the easiness with which it came totheir mind. Intensity and easiness had to be rated on scales between 1 and 10.Likewise, happiness or sadness had to be rated between 1 (neutral) and 10 foreach given episode.

In spite of obviously differing in content between individuals, all episodes


were carefully selected with respect to their emotionality and their latency forevocation. While we attempted to maintain a balanced number of positive andnegative episodes with respect to their intensity, this was not always possible.Likewise, it was not possible to maintain the same average of intensity acrosssubjects. Some individuals rated nearly everything as very intensive, while otherswere more moderate in their ratings. We obtained a mean intensity level of 7.8 forthe positive, and a mean intensity level of 6.7 for the negative condition.

These results correspond to those of previous reports studying positive andnegative autobiographical episodes, in which positive compared to negativeepisodes tended to be more intense, elaborated, and more easily accessed(Larsen, 1998). In line with this result, Raspotnig (1997) found that the imageryassociated with positive memories is more vivid than that related to negativememories. D’Argembeau et al. (2002) similarly found that positiveautobiographical episodes were more easily accessed, tended to be moreelaborated, and were more frequently rehearsed than negative autobiographicalepisodes. D’Argembeau et al. interpreted their findings as consistent with thegeneral positive view most people possess from themselves.

After the interview phase, subjects practiced using a computer program tobecome familiar with the key words and the time-constraints of the procedure.Subjects received the key words on a computer screen for 5 s and checkedwhether each key word immediately evoked the appropriate episode.

Brain scanning was done on the day of the interview; subjects wereinstructed to re-imagine their original episodes. The key words used in theinterview were presented for 5 s on a screen. The screen was completelydarkened for the next 20 s while subjects retrieved the triggered episode.Following an alternation (‘boxcar’) design, every task (imagination) period of 25s alternated with a rest condition of the same length (5 scans each for rest andtask). During the two experimental conditions sad and happy episodes had to beecphorized, that is subjects retrieved previously elicited memories from theirpast. During REST, subjects had to fixate a small cross centered on the screenwith a light gray background (similar to the one in the study of Fink et al.,1996). The higher luminance of the rest-screen indicated to the subjects that theywere to immediately stop the imaginations from the complete darkness phase.All 36 cues (18 sad, 18 pleasant) were arranged in 2 blocks, consisting of 6successive items of the same quality (first 6 sad, then 6 happy ones, in fixedorder), and 3 time periods (childhood, adolescence, recent past). The sequence ofsessions (120 scans each) was counterbalanced between subjects. Before startinga session, the display showed them the imaginative ‘life period’ to facilitateretrieval: “you are a child” (or ‘adolescent’, or ‘adult’).

After scanning, subjects were again asked to rate and comment on theirretrieved episodes (easiness of retrieval, emotional intensity of the episode).

The questions depicted in Table I were used.

fMRI procedure

Prior to the start of the experiment, subjects’ brains were scanned with MRIto exclude morphological-pathological abnormalities. All fMRI measurements


were performed on a 1.5 Tesla whole-body scanner (Siemens Vision) withstandard head coil and using a standard EPI sequence (TR = 5 s, TE = 66 ms,FA = 90°, FoV = 220; matrix 128 × 128, voxel size=1.64 × 1.64 × 5, scan time2 s for 15 slices, 5 mm slice thickness). All fMRI scans were realigned to theinitial scan to correct for any head movement. Between each of the 3 sessions of125 scans each (first 5 discarded) a short break was necessary for technicalreasons to restart the EPI sequence for the next 125 measurements. Subjectswere instructed to hold their position unchanged over sessions. Data analysiswas performed using SPM (Worsley and Friston, 1997). After realignment of all360 scans to the first scan, and spatial normalization to standard stereotacticspace (Friston et al., 1995), images were smoothed applying a Gaussian kernel


TABLE I

Questions Used to Trigger Emotive Episodes from the Past

A. NEGATIVE REMEMBRANCES FROM CHILDHOOD1. The first negative memory in your life that you remember truly.2. A situation in which you were very angry.3. A situation in which you experienced anxiety.4. A situation in which you were hurt.5. A negative memory about a friend.6. A sad memory

B. POSITIVE REMEMBRANCES FROM CHILDHOOD1. The first positive memory in your life that you remember truly.2. A positive event you can remember, for example a play situation.3. A birthday in your childhood.4. A positive memory about a good friend.5. A pleasant memory in which you played with others.6. A pleasant holiday situation.

C. NEGATIVE REMEMBRANCES FROM ADOLESCENCE1. A negative experience from your school-time.2. A close contact with another person, which evoked very awkward feelings.3. A very awkward situation in which you were alone.4. A negative experience evoking massive stress.5. A shameful situation.6. A conflict with someone close

D. POSITIVE REMEMBRANCES FROM ADOLESCENCE1. Feelings of being in love.2. A pleasant experience of success.3. A cheerful amusing adventure.4. A very agreeable situation with someone.5. A happy holiday.6. A very pleasant appointment.

E. NEGATIVE REMEMBRANCES FROM ADULTHOOD1. A situation in which you were very worried.2. A moment of deep sadness.3. The death of a beloved person.4. A situation in which you were exploited.5. A situation in which you were hurt.6. A situation in which you were jealous.

F. POSITIVE REMEMBRANCES FROM ADULTHOOD1. One of your happiest moments in the last years.2. A very motivating positive situation. 3. A happy moment.4. A really joyful situation.5. The memory of a very pleasant, intimate experience.6. A situation which made you very enthusiastic.

of 12 mm FWHM. Statistical analysis was then carried out in two stages. First,a fixed effect (within-subject) model was applied to the time series of everyindividual subject. After filtering (high-pass: 100 s, low-pass: hrf), andproportional scaling the images to overall grand mean, t-statistic maps (heightthreshold: t = 3.12) were generated for the contrasts (SAD > REST), (HAPPY >REST), (SAD > HAPPY) and (HAPPY > SAD) and a single contrast image waswritten out from the parameter estimates for each contrast and for every subject.Then, with one summary contrast ‘scan’ per subject, a second-level randomeffects analysis was conducted for these four contrasts, applying a one-sample-t-test model. This approach takes the between subjects variability into account andextends inferences from the subjects studied to the overall population effects.The resulting activation maps were superimposed to the MNI template brain ofSPM 99 (Figures 1 and 2).

Statistical analysis

All possible permutations of any two of the three conditions SAD, HAPPY,REST were analyzed, applying contrast calculation within the general linearmodel approach provided by the SPM 99 software (two-level random effectanalysis [Friston et al., 1995]). Performing a two-level random effects – secondlevel – analysis implies to include inter-individual variances in the tests ofsignificance. It further implies to report p-values uncorrected for the entirevolume.

RESULTS

Subjects provided in general affect-based episodes with easiness: The averagerating score was 7.2 for the intensity with which subjects rated the emotions onthe scale ranging between 1 (lowest intensity) and 10 (meaning highestintensity). Easiness of remembrance of a specific episode was scored 6.6 on theaverage (10 meaning absolutely no effort necessary or that the episode came‘automatically’ to mind).

The main results are a lateral orbitofrontal activation, when activating SADmemory episodes, and a subcallosal-anterior cingulate activation, whenactivating HAPPY ones. The terminology used for these regions differs:Sometimes, they are referred to as limbic frontal or frontolimbic cortex,sometimes as orbitofrontal or basal frontal regions, and some authors use theterm prefrontal even when addressing anterior cingulate and subcallosal regions(e.g., Gusnard et al., 2001; Simpson et al., 2001). The cingulate sulcus and para-cingulate gyrus are structurally variable, so that exact anatomical locations differbetween subjects (cf. Paus et al., 1996).

The most revealing comparisons were those between sad and pleasantepisodes (SAD > HAPPY; HAPPY > SAD). Figures 1 and 2 illustrate our mainresults.

The SAD > HAPPY contrast (after random effect analysis) revealed a majorsymmetrical activation of the lateral orbitofrontal cortices, possibly extending


into the ventrolateral prefrontal cortices (see Table II for coordinates), togetherwith smaller activated regions in the right lateral temporal cortex and the leftcerebellum (Figures 1 and 2; Table II). Vice versa, the comparison of theretrieval of pleasant episodes with that of sad ones (HAPPY > SAD condition)revealed a major activation in the left hippocampal region, a bilateral activation(with a preponderance to the right hemisphere, however) in the subgenualcingulate (Brodmann area 25) and a left dorsolateral activation of the prefrontalarea (Table II). The medial subcallosal activation was exactly below the genu ofthe corpus callosum (Figures 1 and 2). The levels of this activity were all highlysignificant (second-level random effects analysis; height threshold t = 3.93,puncorrected < .0001).

Comparisons of the activation conditions with the condition REST uncovered


Fig. 1 – Functional anatomy of the SAD >HAPPY (red) and the HAPPY > SAD (green)comparisons. A coronal, sagittal, and transverse plane of an arbitrary magnetic resonance image isshown at the level providing the most significant activations. SAD > HAPPY activations are foundbilaterally in the lateral orbitofrontal cortex and to a minor degree in the right temporal cortex. Viceversa, the HAPPY > SAD comparison revealed a strong bilateral medial orbitofrontal activation, aleft hippocampal and a left dorsolateral prefrontal activation.


TABLE II

Activated Regions in the Comparisons Employed

SAD > HAPPY COMPARISON X y z Z

Lateral orbitofrontal cortex, left – 52 24 – 2 3.52Lateral orbitofrontal cortex, right 54 34 – 6 3.79Lateral temporal cortex, right 64 – 28 – 12 3.90Cerebellum, left – 10 – 60 – 24 3.99

HAPPY > SAD COMPARISONMedial orbitofrontal cortex, right 14 26 – 10 3.77Medial orbitofrontal, left – 24 24 48 3.79Hippocampal region, left – 30 – 28 – 16 4.10Dorsolateral prefrontal cortex, left – 24 24 48 3.79

SAD > REST COMPARISONAnterior cingulate gyrus (area 24/32), left 12 20 26 4.89Lateral orbitofrontal cortex (area 47), left – 44 44 10 4.84Lenticular nucleus, right 28 10 2 4.81Cerebellum, medial 4 – 48 – 18 4.22

HAPPY > REST COMPARISONPosterior temporal gyrus (area 37), right 32 – 56 2 5.99Anterior cingulate gyrus (area 24/32), right 14 16 28 5.37Medial frontal gyrus, left – 16 20 48 5.19Superior frontal gyrus, left – 12 – 45 4 5.12Precuneus, left – 26 – 58 16 5.09Ventral pallidal/dorsal amygdalar region, left – 22 – 4 – 4 5.29

All these activations were highly significant, after second-level random effects analysis (height threshold t = 3.93,puncorrected < .0001).

Fig. 2 – Projections of activations onto representations of the standard stereotactic space asdefined by Talairach and Tournoux (1988) (“SPM-99 glass brains”). The top three maps show theactivations for the SAD > HAPPY, and the bottom tree for the HAPPY > SAD comparison.

(for second-level analyses) several significant activations for the comparisonsHAPPY > REST and SAD-REST (Table II; Figure 2). For the HAPPY > RESTcomparison, regions in the right posterior temporal and anterior cingulate cortex,in the left dorsolateral cortex, the medial frontal cortex, the left precuneus andthe left ventral pallidal – dorsal amygdalar region were activated; for the SAD-REST comparison, the left lateral orbital frontal cortex, the right anteriorcingulate cortex, the right lenticular nucleus and the medial cerebellar regionwere activated.

DISCUSSION

This study is a further step in tracing the functional anatomy of episodicmemory. It centers on old autobiographical information and emphasizes the linkbetween emotion and memory. There are several important aspects of theseresults: the activity patterns are very distinct and differ considerably betweennegatively and positively experienced episodes. With the exception of thecerebellar one, all activations involve the cerebral cortex and are largelyconfined to limbic or paralimbic regions. Within limbic structures, thehippocampal region was only activated during the retrieval of happy memories(but not significantly in the HAPPY > REST condition), suggesting that at leastunder the circumstances of data analysis (e.g., combining the three time periodstested), ecphorizing past episodes engages the hippocampal region only to aminor degree. This finding is in conformity with a recent study of our group,where we found a hippocampal engagement only for more recent, but not forremote old autobiographical memories (Piefke et al., 2003). As we combined inour present analysis memories from childhood and adulthood, a less prominenthippocampal activation remained which was only significant for the HAPPY >SAD condition. In line with our present findings of a left hippocampal activationfor the HAPPY > SAD, Piefke et al. (2003) had observed a left medial temporallobe and a left temporal pole activation for this same comparison, but – again inline with the present results – not for the other comparisons (e.g., not forSAD>HAPPY). Here, they observed activations in the right middle temporalgyrus which again corresponds to our present findings (cf. Table II). Also in thereport of Liotti et al. (2000), no hippocampal activations were found in relationto generated sadness or anxiousness provoking autobiographical memories.

Alternatively, the selective hippocampal engagement for the HAPPY > SADcondition might reflect a more intense re-encoding, elaboration and rehearsal ofaspects of the happy memories just retrieved, which would correspond to ourfinding of a higher level of intensity in association with the retrieval of positivememories (cf. Methods section and Buckner et al., 2001). Thirdly, future studiesneed to consider possible differences in neural activations related to gender(Cahill et al., 2001; Schneider et al., 2000; cf. below under the ‘amygdala’).

Differences in activation patterns between the HAPPY > SAD and theHAPPY > REST conditions possibly indicate the major visual and emotionalcomponents, which are seen in the comparison to rest, but not in that betweenthe two emotional memory conditions. Similarly, the cingulate activation, found


in the HAPPY > REST and SAD > REST may be related to emotional as wellas attentive mechanisms (George et al., 1995; Mayberg et al., 1999).Interestingly, this activation was right-hemispheric for the positive and left-hemispheric for the negative ones.

The orbitofrontal and subcallosal cortex thus appear to be a major hub forthe retrieval of emotional memories. The orbitofrontal cortex and itsimmediately adjacent prefrontal and anterior ventral cingulate regions figure asmajor trigger stations for ecphorizing emotionally colored episodes of the distantpast. Within this area there is a clear distinction between regions engaged in theretrieval or ecphory of positive and negative episodes of the distant past. Wewill comment on these findings.

The orbitofrontal-subcallosal area as a hub for emotional memory retrieval

The division of medial and lateral portions of the basal frontal cortex, asdescribed by Cavada et al. (2000), corresponds (a) to the selective medialsubgenual (and left hippocampal) activation when ecphorizing positively valuedepisodes, and (b) to the selective lateral orbitofrontal activation, whenremembering sad or unhappy episodes (it has repeatedly been stressed that theamygdala evaluates negative or particularly intense emotions to a higher degreethan positive ones; Canli et al., 2000; Markowitsch, 1998/99). Related to thispoint are the findings of Frey et al. (2000) of area 13 involvement in theprocessing of unpleasant auditory information and that of Simpson et al. (2001)of medial orbitofrontal/subgenual involvement during anticipatory anxiety.

In the literature on conscious reflection (Wheeler et al., 1997), attributionwithin personal theory of mind (Stuss et al., 2001), and on self-recognition,personal identity and self-referential mental activity (Gusnard et al., 2001;Keenan et al., 2000; Kircher et al., 2000; Miller et al., 2001) there are proposalsor links to the ventral (and medial) frontal lobe, and these proposals are fully inaccordance with our present observation of activations in exactly this portion ofthe brain. The interaction between memory and emotion consequently seems tobe central for the self (Markowitsch, in press).

We cannot determine whether the activation in the two disparate loci reflectsthe triggering of the respective episodes or is used to influence (e.g., suppress)the respective other circuit. In favor of this last hypothesis are observations ofZubieta et al. (1999), who found a medial frontal engagement in posttraumaticstress symptoms, and of Elliot et al. (2000), who suggested that activation of thelateral orbitofrontal cortex may reflect the suppression of previously rewardedresponses. (However, they also referred to an activation of the lateralorbitofrontal cortex when viewing an angry face.) For the first hypothesis, on theother hand, the work of Blood et al. (1999) is relevant who found that emotionalresponses to pleasant music correlated with medial orbitofrontal activation. Price(1999) referred to PET data which showed increased blood flow in the lateralorbitofrontal cortex in patients with unipolar depression (compared to normals)and decreased blood flow in medial frontal regions in bipolar, manic-depressivepatients, in their depressed phase, suggesting again a differential involvement ofthese two basal frontal sectors in emotional processing. Gusnard et al. (2001)


hypothesized from their findings with functional magnetic resonance imagingthat the region they term medial prefrontal cortex (and which with respect toanatomical co-ordinates closely resembles our medial anterior orbital/subcallosalarea) is engaged in aspects of the self (‘self-referential mental activity’), whichthey found by letting subjects determine which of presented pictures werepleasant or unpleasant.

There are a few results which may be viewed as at variance with ourfindings of a medial anterior cingulate/subcallosal activation when ecphorizingpositively valued episodes and a lateral orbitofrontal activation when ephorizingnegatively valued ones: In a PET-study Mayberg and co-workers (Mayberg etal., 1999; Liotti et al., 2000) found increases in sadness related activity in thesubgenual cingulate cortex, and Drevets et al. (1998) found that the volume ofthe subgenual prefrontal cortex is reduced in patients with major depressivedisorders. These observations might, however, indicate that this cortical region,in fact, processes positively valued information in normal, non-depressedsubjects. Alternatively, or in addition, it could process both positively andnegatively valued episodes, but with varying strength or engagement. Evidencefor this view was provided by Rolls (2000) and Ochsner et al. (2001). Rolls(2000) reviewed neuroimaging results which showed that “areas of theorbitofrontal cortex (and connected subgenual cingulate cortex) are activated bypleasant touch, by painful touch, by rewarding and aversive taste, and by odor”(p. 284). From their findings in a patient with bilateral anterior cingulotomy,Ochsner et al. suggested that one “of the anterior cingulate’s roles may be tomonitor on-line processing and signal the motivational significance of currentactions or cognitions” (p. 219), indicating a more general role of this cortex ininformation processing.

Recently, Lepage et al. (2000) also found anterior cingulate activationsduring memory retrieval tasks and proposed that neuronal activity in this regionis correlated with the maintenance of the episodic memory retrieval mode, acondition necessary for remembering past episodes. In this article, they alsoprovided a new interpretation of their HERA model (hemispheric encodingretrieval asymmetry) by writing that the previously assumed strict righthemispheric activation during episodic retrieval should be replaced by abilateral, though more prominently right hemispheric activation – a revisionfitting our present data.

In conclusion, spatially different and distinct portions of the human basalfrontal cortex seem to work as hubs within wider and primarily cortical netsengaged in ecphorizing old autobiographic episodes of a positive or negativecharacter.

Dorsal prefrontal cortex

As mentioned above, we found a left dorsolateral prefrontal activation(together with a left hippocampal one) during the retrieval of happy episodes.The left dorsolateral prefrontal cortex is engaged in numerous functions, aboveall, in encoding episodic and semantic information (Tulving et al., 1994; Noldeet al., 1998). It has also been suggested that this brain region is engaged in


‘working with meaning’ (Kapur et al., 1994), an interpretation fitting the presentdesign. As the retrieval of episodes is accompanied by their re-encoding, thismight be an explanation for the left do rsolateral activation. The selectiveactivation under the condition ‘HAPPY >SAD’ is most likely related to thesignificance threshold set.

Reduced activation of the dorsolateral prefrontal cortex has been found in avariety of psychiatric diseases such as in schizophrenia (Selemon et al., 1998);furthermore, dysfunction to the left dorsolateral prefrontal cortex is associatedwith clinical depression (Baxter, 1989; Martinot et al., 1990; Robinson, 1996).

Hippocampal formation

The hippocampal formation is that brain structure which first comes to mindin connection with memory. The engagement of the hippocampus inautobiographic information processing (Vargha-Khadem et al., 1997), and inparticular in conscious recollection (Heckers et al., 1998), and the fronto-hippocampal disconnection hypothesis in schizophrenia (Csernansky et al., 1998;Fletcher, 1998), all fit the combined prefrontal and hippocampal activation seenunder the condition HAPPY > SAD. Vargha-Khadem et al. (1997) demonstratedthat young patients without a hippocampus proper were unable to encode (andconsequently also unable to retrieve) autobiographical episodes, while they couldsuccessfully retrieve world knowledge which is independent of consciousreflection (Markowitsch, in press). An interaction between ventral prefrontal andhippocampal regions has been proposed both from anatomical (Lavenex andAmaral, 2000) and functional (Mesulam, 2000; Seamans et al., 1998) points ofview. It seems therefore possible to consider the principal activation pattern asreflecting neuronal circuitry for emotional evaluation of memorized episodes andpossibly even more so of those with a positive affective background.

Alternatively, or in addition, the hippocampal activation could indicate thatthis region indeed is implicated in information retrieval – at least for a limitedperiod of time (as we combined the three time periods we cannot determinewhether there is a greater activation for the retrieval of more recent as opposedto more remote memories) (cf. Moscovitch and Nadel, 1998). If this were true,it might be that the selective – left hemispheric – activation just becamesignificant, while the right hemispheric did not. Or, that retrieving old episodes(or old positively valued episodes) engages the hippocampal formation of theleft hemisphere.

The issue of laterality, where initially a right-hemispheric dominance wasseen (Fink et al., 1996; Tulving et al., 1994; Shallice et al., 1994) became muchless clear-cut over the last years (cf. Ojemann et al., 2002, for temporal areas,discussed below). The recent review of Lee and co-workers (2002) discusses thisissue extensively. These authors question the importance of language relatedmaterial for a left hemispheric activation (both for encoding and retrieval) andsuggest that a multitude of factors in various combinations will lead to a morepronounced left or right hemispheric activation. Similarly, Nolde et al. (1998)earlier had argued that more demanding or ‘reflective’ retrieval situations mayactivate regions of the left hemisphere to a greater extent than basic mnemonic


processes. Cabeza et al. (2002), on the other hand, stressed that it is not so muchthe reflection, but the generation of information during more demandingconditions (e.g., free recall as opposed to recognition) which activates the lefthemisphere. Other authors found that the retrieval of specific perceptualinformation (‘picture-like memories’) engages left-hemispheric more than right-hemispheric regions (Ranganath et al., 2000).

Cerebellum

The significant left hemispheric cerebellar activation corresponds to thefindings of others suggesting that the left cerebellum is particularly engaged inseveral nonmotor mental activities, including episodic memory retrieval(Andrease et al., 1999; Cabeza and Nyberg, 2000; Fink et al., 1996), andattribution or experience of emotion (Lane et al., 1997; Paradiso et al., 1999). Inthe study of Andreasen et al. (1999) subjects intentionally recalled a specificpast personal episodic memory. The authors suggested the participation of thecerebellum in an interactive cortical-cerebellar network initiating and monitoringthe conscious retrieval of episodic memory. Probably, therefore, cerebellarneurons provide a (sequencing) time code or a temporal programming toecphorized events.

Lateral temporal cortex

The selective engagement of a right-hemispheric region of the lateraltemporal gyrus during the retrieval of sad episodes can be interpreted differently:it more likely reflects a more controlled, less emotional access to unpleasant asopposed to pleasant past experiences. Sad as opposed to happy episodesprobably have different degrees of vividness, ‘mental visibility’, and self-attribution (Kircher et al., 2001); Kircher et al. (2001) suggested the righttemporal cortex to be associated with the semantic processing of sentences.Distantly related old work of Flor-Henry (1963) on patients with epilepsypointed out that psychotic (schizophrenic) behavior is more likely associatedwith dysfunction of the left (‘dominant’ in his words), than of the right temporallobe region, while vice versa dysfunction of the right temporal lobe is associatedwith depressive behavior. The temporal region probably reflects the particularengagement of a possible storage place for engrams (Chen et al., 1996;Miyashita et al., 1998; Sakai and Miyashita, 1994).

While there is not much controversy with respect to the importance of lateraltemporal regions for old memory processing (Phelps et al., 1997), the issue ofleft and right temporal lobe engagement and of a differential engagement duringpositively as opposed to negatively rated memories is a complex one. Thisbecomes especially evident when comparing studies relying on differentmethodological approaches (e.g., studying of brain damaged patients, functionalneuroimaging in healthy subjects, single-unit recordings in patients). Ojemannand co-workers (2002) recently discussed this issue, based on their resultsobtained from single cell recordings in the human lateral and inferior temporalcortex (see also Fletcher and Tyler, 2002). Ojemann et al. failed to find


hemispheric differences within lateral and inferior temporal cortices forencoding, storage, and retrieval processes of memory.

The tone of resignation formulated in the abstract of a recent functionalimaging study on positive and negative emotional material seems nevertheless toreflect the still open issues on laterality and precise topographical assignments:“The outcomes of imaginal studies of emotions seem to be largely dependent onthe conservativeness of the statistical analysis and very likely also on the methodof emotion induction” (Aalto et al., 2002, p. 67).

Amygdala

The amygdala can be regarded as that structure that attaches emotionalflavors to memories (Sarter and Markowitsch, 1985). Consequently, we mightwell expect it to be activated during the retrieval of old biographical memories(Dolan et al., 2000; Fink et al., 1996; Markowitsch, 1998/99; Markowitsch et al.,2000). Indeed, this was found when comparing retrieval of happy memories withthe rest condition. However, the comparisons of principal interest, namelyHAPPY > SAD and SAD > HAPPY, apparently cancelled out the amygdala’sactivation. Alternatively, or in addition, one could speculate about a habituationeffect (Wright et al., 2001). The male-female differences in amygdaloidactivation during memory retrieval (Cahill et al., 2001) and during sadness(Schneider et al., 2000) complicate the picture further. Together, these factorsmay have resulted in an insignificant activation of the amygdala during all butone condition of comparison. Aalto et al. (2002) studied possibleneuroanatomical substrates of amusement and sadness with PET. Similarly toour results, they failed to find amygdala activations in a strict explorativeanalysis and attributed the differences to earlier reports (who had observedamygdala activations) to differences in statistical and methodologicalapproaches.

Bi-hemispheric activations

The bi-hemispheric activations in the orbitofrontal cortex in the two principalcomparisons HAPPY>SAD and SAD>HAPPY may reflect the comparativelyhigh demands of the task, requiring the activity of neurons in the respectiveareas of both hemispheres. Similar bi-hemispheric activations have been foundin other memory retrieval paradigms (Ranganath and Paller, 2000). They mayalso be due to the combined visual and verbal portions of the retrieved episodes(Wagner et al., 1998).

CONCLUSIONS

This report provides evidence for an engagement of portions of theorbitofrontal/ventral prefrontal cortex in the retrieval of old, emotionally coloredepisodes. We demonstrate a differential activation towards past episodes thatwere viewed as clearly happy or otherwise positive in character and episodes


that were viewed as clearly of a sad or otherwise negative character. This studycomplements earlier ones in which it was found that the retrieval of old episodesactivates a temporo-frontal network of structures for which the expression“expanded limbic system” (Nauta, 1979) can be used as umbrella (Fink et al.,1996; Markowitsch et al., 2000). Areas especially within the prefrontal lobe canbe described as acting in a dynamic interplay between cognition and emotion(Simpson et al., 2001a, b).

From our findings it can be concluded that different anatomical networksengage in the ecphory of positively and negatively rated biographical events. Itcan furthermore be concluded that cortical structures provide a significantcontribution to the processing of affective memories.

While we are quite confident about the reliability and validity of the resultsobtained, some cautious remarks have to be made. The possibilities forcontrolling and equalizing responses between subjects are limited; subjectsprovide different statements which vary in contents as everyone has his or herown, individual background of experiences. Furthermore, when one subjectmakes a specific intensity rating of his or her experience this does not imply thatanother subject would have made the same rating towards the same experience.Individual backgrounds, personality variables, mood conditions etc. influenceratings. Fresh experiences may have more detail and vividness, old experienceson the other hand may still be remembered exactly because of their emotionalseverity. Gender may contribute to enhancing or diminishing possible neuralactivation effects towards affect-related information (Cahill et al., 2001; Killgoreet al., 2001; Schneider et al., 2000). Consequently, it cannot be excluded thatdifferent aspects of emotional and memory variables contribute differently inmale and female subjects to our finding of an anatomical separation of positivelyand negatively valued autobiographical episodes.

Acknowledgements. Supported by the Deutsche Forschungsgemeinschaft (Ma 795/24).M.M.P. Vandekerckhove performed this work in partial fulfillment of her dissertation. Wealso thank David Emmans for improvement in the English text.

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