Emotional processing in bipolar disorder: Behavioural and neuroimaging findings

International Review of Psychiatry, August 2009; 21(4): 357–367

Emotional processing in bipolar disorder: Behavioural and neuroimagingfindings

MICHELE WESSA & JULIA LINKE

Department of Cognitive and Clinical Neuroscience, Research Group ‘‘Emotional Processing in Bipolar Disorder’’, Central

Institute of Mental Health, Mannheim, Germany

AbstractExisting studies revealed that bipolar patients show an altered identification of emotional stimuli (e.g. facial expressions),however, so far modifications in early emotional processes and the regulation of emotions are less clear. In response toemotional stimuli bipolar patients show a dysfunction in a ventral-limbic brain network including the amygdala, insula,striatum, subgenual cingulate cortex, ventrolateral prefrontal cortex and orbitofrontal cortex. In most studies, a relativehypoactivity of dorsal brain structures, including the dorsolateral prefrontal cortex, the dorsal anterior cingulate and theposterior cingulate cortex, has been reported in bipolar patients. This imbalance between the two networks has beenproposed to underlie deficient emotion regulation in bipolar disorder.

Introduction

Bipolar disorder is associated with emotional dis-

turbances that may lead to impairments in cognitive

functioning (Strakowski, Adler, Holland, Mills, &

DelBello, 2004) and deficits in social behaviour and

interpersonal relationships (Kerr, Dunbar, & Bentall,

2003). Studies on emotional processing in bipolar

disorder have focused on the recognition of emo-

tional expressions and the reaction to overtly

presented emotional stimuli, showing impaired emo-

tion recognition and enhanced emotional reactivity

in bipolar patients. On the neural level, increased

limbic activation in symptomatic as well as in

remitted bipolar patients has been reported

(Strakowski, DelBello, & Adler, 2005).

In this article behavioural as well as neuroimaging

findings of emotional processing in bipolar patients

will be discussed in detail, following a general

model of different stages of emotional processing

(see Figure 1).

Stages of emotional processing and their

behavioural and neural correlates

Various theoretical accounts agree that emotional

processing includes different mechanisms that vary

with respect to the involvement of attentional and

cognitive resources. These mechanisms can be

roughly divided into (1) early emotional processing,

(2) emotional responses including transient, auto-

matic responses and the subjective emotional

experience and (3) expression of emotion and emo-

tion regulation depending on the respective context

(Davidson, Pizzagalli, Nitschke, & Kalin, 2003;

Gross, 2002; Hsu & Pessoa, 2007; Lazarus, 1991;

Phillips, Drevets, Rauch, & Lane, 2003a; Schaefer

et al., 2003). The inability to efficiently regulate or

inhibit emotional responses can result in reduced

goal- or task-directed behaviour (Simpson et al.,

2000; Vuilleumier, Armony, Driver, & Dolan, 2001)

and has been suggested to underlie affective dis-

orders, such as unipolar depression or bipolar disor-

der (Lane, 2006; Leppanen, 2006).

The sensory perception of a stimulus is crucially

dependent on the attention that is allocated to it

(Kouider & Dehaene, 2007; Pessoa, McKenna,

Gutierrez, & Ungerleider, 2002). Due to their

enhanced salience, motivationally significant stimuli

are processed with priority as they automatically

capture attention and more resources are allocated

for their perceptual processing (Bradley et al., 2003;

Ohman & Mineka, 2001). In healthy humans, an

increased attentional capture for and an enhanced

orientating response to affective stimuli has been

consistently demonstrated (Algom, Chajut, & Lev,

2004; Anderson, 2005; Mogg, Bradley, & Hallowell,

1994; Ohman, Flykt, & Esteves, 2001; Pourtois,

Grandjean, Sander, & Vuilleumier, 2004).

Particularly in affective disorders, a mood-congruent

bias for emotional stimuli has been observed (Jongen,

Smulders, Ranson, Arts, & Krabbendam, 2007;

Suslow, Junghanns, & Arolt, 2001), although this

Correspondence: Michele Wessa, PhD, Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Square J5, 68159 Mannheim,

Germany. Tel: þ49 621 1703 6008. E-mail: [email protected]

ISSN 0954–0261 print/ISSN 1369–1627 online � 2009 Institute of Psychiatry

DOI: 10.1080/09540260902962156

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finding has not been consistently reported (Bradley,

Mogg, & Lee, 1997; Bradley, Mogg, Millar, & White,

1995; see also second part of this review).

So far, the neural substrate of this attentional

bias is not completely understood. However, lesion

as well as neuroimaging studies have advanced the

understanding of the neural mechanisms underlying

the influence of emotion on attention. Anderson and

colleagues (Anderson, 2005; Anderson & Phelps,

2001) revealed that the left amygdala plays a critical

function in facilitating the perception of stimuli

with emotional significance, their enhanced sensory

perception and visual awareness (see also Duncan &

Barrett, 2007). Through its connections with pri-

mary and higher-order sensory brain areas (Amaral,

Price, Patkanen, & Carmichael, 1992), the amygdala

might have a strategic role in modulating perceptual

sensitivity to incoming information by ascribing

emotional value to the respective stimuli. This

notion is supported by neuroimaging studies that

show concomitantly increased activity in the amyg-

dala and the visual cortex and stimulus-specific

processing areas like the fusiform face area

(Sabatinelli, Bradley, Fitzsimmons, & Lang, 2005)

as well as increased functional coupling of the

amygdala with the fusiform and visual cortices

when fearful versus neutral faces are perceived

(Morris et al., 1998; Pessoa, Kastner, &

Ungerleider, 2002; Vuilleumier, Richardson,

Armony, Driver, & Dolan, 2004). Moreover, only

patients with combined hippocampal and amygdala

lesions did not show the expected neural activity in

the fusiform cortex to fearful relative to neutral

faces (Vuilleumier et al., 2004). This result supports

the hypothesis of Anderson and Phelps (2001) that

the amygdala provides a structure for the facilitation

of perception by affective value.

An automatic, transient emotional response and

subsequent subjective emotional experience, includ-

ing emotional expressive behaviours and heightened

autonomic reactivity, usually follows the enhanced

perception of emotional stimuli. The production of

these emotional states and emotional behaviours

has also been linked to the amygdala. Indeed, lesions

of the left amygdala resulted in significant changes

in social behaviour and a lack of emotional motor

and verbal behaviour (Zola-Morgan, Squire, Alvarez-

Royo, & Clower, 1991) as well as decreased auto-

nomic responses to emotionally salient stimuli and

deficient fear conditioning in monkeys (Gallagher,

Graham, & Holland, 1990). In humans, an absence

of conditioned fear (Weike et al., 2005) as well as

deficits in arousal-enhanced memory (Adolphs,

Cahill, Schul, & Babinsky, 1997) and in the evalu-

ation of non-verbal fear expressions (Anderson &

Phelps, 2000) have been observed in patients with

amygdala lesions. Although the amygdala is also

implicated in the experience of positive emotions

such as reward, other subcortical structures, such as

the basal ganglia (e.g. the ventral striatum) have been

shown to be more crucial here (Knutson, Fong,

Adams, Varner, & Hommer, 2001; Pagnoni, Zink,

Montague, & Berns, 2002). In addition to subcor-

tical brain structures, prefrontal cortical brain areas

(medial and ventrolateral prefrontal cortex, orbito-

frontal cortex, ventral anterior cingulate) and the

insular cortex have consistently been associated

with conscious emotional experience (Bush, Luu, &

ACC, vlPFC, OFC

dACC, dlPFC, OFC

ACC, dlPFC, vlPFC, mPFC, OFC

Pre-attentivestage

AmygdalaVentral visual

cortex

Attentionallocation

Parietal cortexfrontal eye

fieldsThalamus

Sensoryperception

Visualprocessing

areasAmygdala

Experience andexpression of

emotionHigh-level appraisal

Amygdala, InsulaOFC, vmPFCSubgenual CC

Emotion regulation

Transient and automatic emotional response

Amygdala, InsulaVentral striatumOFC, vmPFC

Emotionalvisual

stimulus

Suppression of theactivated emotion

Reappraisal of stimulus meaning

Inhibition of irrelevant emotional information

Early Emotional Processing Emotional Response Emotion Regulation

Figure 1. Successive and recurrent mechanisms in emotional processing. Broken arrows indicate an enhancing or suppressive effect; solid

arrows indicate different emotion regulation strategies at different time points during emotional processing. OFC, orbitofrontal cortex;

mPFC, medial prefrontal cortex; vmPFC, ventromedial prefrontal cortex; vlPFC, ventrolateral prefrontal cortex; dlPFC, dorsolateral

prefrontal cortex; dACC, dorsal anterior cingulate cortex; CC, cingulate cortex.

358 M. Wessa & J. Linke

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Posner, 2000; Dunn & Everitt, 1988; Lane, 2006;

Phillips et al., 2003a; Reiman et al., 1997).

The voluntary regulation of these emotions is

crucial for effective action selection and goal-directed

behaviour (Davidson et al., 2003; Ochsner et al.,

2004). However, when it does not serve an optimiza-

tion of outcome, the up- or down-regulation of

emotional responses might also be maladaptive,

as it is the case for mood and anxiety disorders

(Nolen-Hoeksema, 2000).

Several strategies might be useful in regulating

emotional states, which differ with respect to the

timing of emotion regulation (see Figure 1). This

includes response-focused emotion regulation, invol-

ving the suppression of the emotional response when

it has already been activated and antecedent-focused

emotion regulation, describing the reappraisal of

emotional stimuli (Gross, 1998). Compared to the

suppression of emotional responses, the reappraisal

of emotional cues was shown to be more effective in

reducing self-reported emotions and accompanying

physiological responses (Gross, 2002). Such ante-

cedent-focused strategies are for example detaching

oneself from the situation or the shift of attention

away from emotional stimuli and by this the inhibi-

tion of affective information that is not relevant to

the situation or task (Phillips et al., 2003a). Indeed,

a positive relationship between the ability to shift

attention away from negative or towards positive

stimuli and the successful management of anger and

distress could be shown in young children (Posner &

Rothbart, 2000).

On the neurobiological level, a modulation of

neural activity in the amygdala depending on the

enhancement or reduction of affective states has been

observed (Eippert et al., 2007; Ochsner et al., 2004).

Functional connectivity analyses revealed an inverse

relationship between ventromedial prefrontal and

amygdala activity when individuals reappraised the

affective meaning of a negative stimulus (Johnstone,

van Reekum, Urry, Kalin, & Davidson, 2007; Urry

et al., 2006). Furthermore, the up- and down-

regulation of emotions has been shown to activate

a prefrontal network (Beauregard, Levesque, &

Bourgouin, 2001; Eippert et al., 2007; Levesque

et al., 2003; Ochsner, Bunge, Gross, & Gabrieli,

2002), including the dorsal and ventral lateral

prefrontal cortex (PFC), the medial PFC and ante-

rior cingulate cortex (ACC). These brain regions

have also been implicated in cognitive control (Miller

& Cohen, 2001), emotional awareness (Lane et al.,

1998) and the online-monitoring of performance

(Botvinick, Braver, Barch, Carter, & Cohen, 2001).

The lateral PFC and orbitofrontal cortex (OFC)

seem to be specifically related to the down-regulation

of emotions (Kalisch, Wiech, Herrmann, & Dolan,

2006; Ochsner et al., 2004). The OFC has

been linked to the updating of context-sensitive

motivational significance of a stimulus (Bechara,

Damasio, H., & Damasio, A. R., 2000), supporting

the notion that reappraisal refers to the cognitive

reversal of a stimulus affective value, potentially by

altering stimulus-outcome relationships.

Likewise, the inhibition of task-irrelevant informa-

tion has been shown to activate the PFC, including

the ACC and the OFC (Casey et al., 1997; Horn,

Dolan, Elliott, Deakin, & Woodruff, 2003; Menon,

Adleman, White, Glover, & Reiss, 2001), with the

ventral ACC being specifically associated with the

inhibition of negative emotional information (Elliot,

Rubinsztein, Sahakian, & Dolan, 2000; Whalen

et al., 1998). The successful inhibition of emotional

distractors in a cognitive task was related to a

negative functional coupling between the superior

frontal cortex and the bilateral amygdala (Blair et al.,

2007), supporting the contribution of a fronto-limbic

interaction to emotion regulation.

The increased prefrontal activity during both

up- and down-regulation of emotional states and

the modulation of amygdala activity during emotion

regulation indicates that prefrontal regions do not

only exert an inhibitory influence on emotion-related

limbic activity, but also an excitatory effect on other

prefrontal neural networks. This aspect is particularly

interesting with respect to deficient emotion regula-

tion in mood disorders, as it might be related to both

an insufficient inhibition of emotional stimuli and

down-regulation of emotions in manic bipolar

patients and a lack of adaptive up-regulation of

positive emotions reflected by anhedonic states in

depressed patients.

Bipolar disorder and emotional processing

Early emotional processes

As described earlier, the attribution of salience to a

stimulus and the allocation of attentional resources

to this stimulus occur early in emotional processing.

Thus, the identification of deficits in these early

stages might be crucial for the understanding of

emotional processing in bipolar patients. However,

in bipolar patients these processes have so far not

been sufficiently investigated and the findings

obtained are very inconsistent. It has been suggested

that both mood states of bipolar disorder as well as

of unipolar depression are associated with a mood-

congruent attentional bias. This hypothesis is in line

with the associative network theory (Bower, 1992),

which proposes that the underlying affect or mood

acts as prime that activates mood congruent infor-

mation and retrieves it from memory. Indeed, some

studies have reported a mood-congruent attentional

bias in manic and depressed bipolar patients

Emotional processing in bipolar disorder 359

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(Lennox, Jacob, Calder, Lupson, & Bullmore, 2004;

Murphy et al., 1999). However, recent reports rather

indicate a mood-congruent cognitive bias only for

depressed, but not manic bipolar patients (Gray

et al., 2006) or even mood-incongruent bias in manic

and depressed patients (Chen et al., 2006). These

inconsistent findings might in part arise from differ-

ent methods and different stimulus material used to

determine attentional bias to emotional cues, ranging

from affective go/nogo tasks, the multimorph task,

during which facial expressions are gradually

morphed from neutral to emotional (e.g. fear,

happy) to explicit and implicit facial affect recogni-

tion tasks (Chen et al., 2006; Elliott et al., 2002,

2004; Lennox et al., 2004; Murphy et al., 1999).

Even when using tasks that are explicitly designed to

assess an attentional bias to emotional stimuli (e.g.

emotional Stroop test, emotional dot probe task) very

heterogeneous and inconclusive results have been

reported in bipolar patients. In a recent study, using

an emotional dot probe paradigm, an attentional bias

away from positive and depression-related words

in mildly depressed bipolar patients has been

reported (Jongen et al., 2007). In the same study,

euthymic bipolar patients showed an attentional bias

towards depression-related words and away from

positive words. An attentional bias towards fearful

faces in children with bipolar disorder and comorbid

anxiety disorder was observed in a visual dot probe

paradigm (Brotman et al., 2007), while highly

anxious individuals usually tend to avoid fearful

stimuli and thus direct their attention away from

such cues. Kerr and colleagues (Kerr, Scott, &

Phillips, 2005) have investigated the classical and

emotional Stroop test and observed generally

increased reaction times for all task conditions in

manic, depressed and euthymic bipolar patients

as well as patients with unipolar depression. In

line with these findings, Malhi and colleagues

(Malhi, Lagopoulos, Sachdev, Ivanovski, & Shnier,

2005) found no differential affective interference

effect on the emotional Stroop in remitted bipolar

patients as compared to healthy controls, but only

significantly dampened cortical and subcortical

neural responses to affective versus neutral words.

In contrast, in a sample of undergraduate students

hypomanic traits were associated with an attentional

bias towards depressive, but not euphoria-related

words (Bentall & Thompson, 1990). However, it

remains unclear to what extent these results can be

transferred to bipolar disorder. One recent emotional

Stroop study has reported an attentional bias towards

social-threat and manic-irritable words in children

of at least one parent with bipolar disorder as

compared to children without this family history

(Gotlib, Traill, Montoya, Joormann, & Chang,

2005). This suggests that an emotional bias might

represent a vulnerability marker for bipolar disorder.

On the neurobiological level, much less work has

been conducted with respect to attentional processes

of emotional information in bipolar patients.

In paediatric patients with bipolar disorder, Rich

and colleagues (2006) investigated the neural activa-

tion, when attention was directed to either emotional

(hostility, subjects’ fearfulness) or non-emotional

aspects of happy, angry, fearful and neutral faces

(nose width). Interestingly, a hyperactivation of the

amygdala occurred when attention was directed

towards emotional aspects of the stimuli but not

when directing the attention towards non-emotional

aspects of a face. A further study by the same group

(Rich et al., 2008) revealed a significantly reduced

temporal correlation in paediatric bipolar patients

between the left amygdala and temporal association

cortical regions (posterior cingulate/precuneus and

right fusiform gyrus/parahippocampal gyrus) that are

implicated in the processing of facial and social

stimuli. As these regions are thought to be the

‘gateway’ for cortical sensory input to the amygdala,

the result of a reduced connectivity between these

regions might explain the misinterpretation of neu-

tral as emotional stimuli.

In summary, the existing findings on early emo-

tional processing in bipolar patients are very heter-

ogeneous and allow no conclusive statements to date,

which can be mainly referred to the fact that previous

studies have used different experimental tasks

and have focused on either symptomatic or remitted

bipolar patients, but not on direct comparisons

between these groups. Future studies should there-

fore be designed to compare patients in different

symptomatic states and experimental paradigms that

have previously been used in healthy and patholog-

ical samples.

Affective response and evaluation

In bipolar patients, far more work has been

conducted on the recognition of emotions and the

reaction to emotional stimuli. A relatively consistent

finding is the impaired recognition of fear and disgust

in remitted and manic bipolar patients (Harmer,

Grayson, & Goodwin, 2002; Lembke & Ketter,

2002; Yurgelun-Todd et al., 2000), which has

recently been underlined by a differential brain

activation pattern in the amygdala and hippocampus

to fear and disgust in euthymic bipolar patients as

compared to healthy controls (Malhi et al., 2007)

such that euthymic patients responded largely to fear

but not to disgust whereas healthy controls

responded almost exclusively to disgust.

A more generalized deficit in identifying emotions

has been found in manic and remitted bipolar


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patients when being instructed to simply recognize

an emotion (Bozikas, Tonia, Fokas, Karavatos,

& Kosmidis, 2006; Getz, Shear, & Strakowski,

2003; Lembke & Ketter, 2002). In similar tasks,

adults and adolescent individuals with bipolar disor-

der have been shown to misinterpret neutral stimuli

as negative (Gur et al., 1992; McClure, Pope,

Hoberman, Pine, & Leibenluft, 2003). As previously

described, on a neural level children with bipolar

disorder show significantly increased limbic activity

to pictures of neutral faces and rate them significantly

more hostile relative to healthy children (Rich et al.,

2006). This result might be explained by a reduced

connectivity between the amygdala and temporal

association regions (Rich et al., 2008).

In neurobiological models of affective disorder

the hyperactivity of ventral-limbic brain structures,

including the amygdala, the subgenual cingulate

gyrus, the ventral PFC and OFC have been proposed

to contribute essentially to the observed emotional

disturbances (Mayberg, 1997; Phillips, Drevets,

Rauch, & Lane, 2003b; Blumberg, Chaney, &

Krystal, 2002). Empirical evidence for these models

comes from studies that show a generally hyperactive

limbic system either during resting states (Drevets

et al., 2002; Ketter et al., 2001) or during purely

cognitive tasks (Strakowski et al., 2004). With

respect to the early stages of emotional processing,

this general limbic hyperactivity might underlie the

hypothesized increased salience of emotional stimuli

in bipolar patients and the resulting enhanced

allocation of attentional resources to processing

emotional stimuli (Anderson & Phelps, 2001). This

binding of attentional resources has been proposed

to interfere with cognitive processing (Strakowski

et al., 2004) as seen in bipolar patients during both

symptomatic phases and in remission (Robinson &

Ferrier, 2006; Robinson et al., 2006) as well as in

patients with unipolar depression (Zakzanis, Leach,

& Kaplan, 1998).

In addition to the described general limbic hyper-

activity, an emotion-specific hyperactivity of ventral-

limbic brain structures such as the amygdala, the

insula, the anterior cingulate cortex and the orbito-

frontal cortex has been repeatedly reported in adult

depressed and euthymic bipolar patients (Altshuler

et al., 2005; Elliot, Rubinsztein, Sahakian, & Dolan,

2002; Lawrence et al., 2004; Malhi et al., 2004; Wessa

et al., 2007; Yurgelun-Todd et al., 2000). Three

studies that used a similar emotional go/nogo task

revealed an increased activity in the bilateral orbito-

frontal cortex to emotional as compared to neutral

task conditions in manic and euthymic bipolar

patients and depressed patients relative to healthy

controls (Elliott et al., 2002, 2004; Wessa et al.,

2007). In euthymic and depressed bipolar patients,

Lawrence and colleagues (2004) equally showed an

increased activation of the prefrontal cortex, more

precisely the ventral prefrontal cortex, as well as the

ventral striatum, thalamus and hippocampus in

response to both positive and negative emotional

facial expressions in comparison to healthy controls.

Increased subcortical activation in limbic as well as

thalamic brain regions on the presentation of emo-

tional stimuli have also been found in patients with

manic and depressive symptoms (Yurgelun-Todd

et al., 2000) as well as in patients with bipolar

depression (Malhi et al., 2004).

A hyperactivation of limbic brain areas in response

to negative and positive faces has also been observed

in paediatric bipolar patients (Chang et al., 2004;

Dickstein et al., 2007; Pavuluri, O’Connor, Harral,

& Sweeney, 2007). More specifically, Pavuluri and

colleagues (2007) reported a reduced activation in

the ventral PFC together with an increased activity

in the right ACC, the amygdala, the paralimbic

cortex, the fusiform gyrus (during the presentation of

angry faces) and the posterior parietal cortex (during

the presentation of happy faces). Accordingly,

paediatric patients with bipolar disorder displayed

greater activation in the ACC and the left amygdala

as well as less activation in the ventrolateral PFC

and dorsolateral PFC in a word-matching paradigm,

where subjects had to match the colour of a neutral,

positively or negatively valenced word with one of

two coloured circles below (Pavuluri, O’Connor,

Harral, & Sweeney, 2008). These results in paedia-

tric bipolar patients are supported by a more recent

study in adult patients, showing a reduced connec-

tivity between the ventrolateral PFC and the amyg-

dala in manic bipolar patients as compared to healthy

controls when perceiving or labelling emotional faces

(Foland et al., 2008). In line with the previously

mentioned neurobiological models of affective dis-

orders (Blumberg et al., 2002; Mayberg, 1997;

Phillips et al., 2003b), the described results suggest

that the reduced activity in the PFC in bipolar

patients might reflect diminished top-down control,

which causes the hyperactivation in the amygdala and

paralimbic areas.

Whereas the reaction to primary emotional stim-

uli such as fear, anger, disgust and happiness has been

investigated in bipolar patients, studies on the reac-

tion to secondary emotional cues such as reward and

punishment has only been scarcely touched, although

altered reward processing has recently been hypothe-

sized to represent an important mechanism of the

alternating phases of mania and depression (Hasler,

Drevets, Gould, Gottesman, & Manji, 2006). In

addition, functional as well as structural cerebral

alterations have been observed in brain regions

involved in reward processing and decision making.

Differential emotional responses to winning and

losing have been observed in depressed (Ernst et al.,


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2004) but not euthymic paediatric bipolar patients

(Rich et al., 2005) in a reward-related decision-

making paradigm. Additionally, adult bipolar

patients revealed dysfunctional reward learning,

which in part reflected an increased sensitivity to

single rewards of the disadvantageous stimulus

(Pizzagalli, Goetz, Ostacher, Iosifescu, & Perlis,

2008) and made more errors on uncertain task

trials as well as more risky decisions (Clark, Iversen,

& Goodwin, 2001; Minassian, Paulus, & Perry,

2004; Murphy et al., 2001). In line, an increased

responsiveness to immediate reward but impaired

integration of reinforcement information was also

observed in patients with major depressive disorders

(Pizzagalli, Iosifescu, Hallett, Ratner, & Fava, 2008).

In addition, adults with unipolar depression have

been reported to show a reduced positive affect

to rewarding outcomes and lower engagement in

rewarding activities (Epstein et al., 2006; Forbes &

Dahl, 2005; Must et al., 2006). On a neural level,

these impairments in reward-processing and reward-

related behaviour in depressed patients are accom-

panied by reduced neural responses to highly

rewarding events, notably in the anterior cingulate

cortex, bilateral caudate and bilateral inferior orbito-

frontal cortex (Forbes et al., 2006), an activation

pattern that is consistent with decreased emotional

reactivity to positive stimuli (Epstein et al., 2006).

In the only study, investigating the neural correlates

of impaired reward processing in manic bipolar

patients with positron-emission-tomography (PET)

no behavioural task impairments in manic patients

was observed but an increased task-related activity

in the anterior cingulate cortex and inferior frontal

gyrus as well as decreased neural responses in the

frontal polar region, close to the orbitofrontal cortex

as compared to healthy controls (Rubinsztein et al.,

2001). To date, no study directly investigated pro-

cesses of reward-related decision making in adult

bipolar patients during remission.

In sum, a large body of literature investigating

the neural response to primary emotional stimuli

in bipolar patients supports the neurobiological

model of bipolar disorder, assuming an increased

ventral-limbic activity and decreased activation of

dorsal brain structures as well as a reduced con-

nectivity between these two neural networks. Until

now, less evidence has emerged for emotional

reactions to secondary emotional stimuli such as

reward and punishment, although these processes

might be at the core of bipolar disorder.

Emotion regulation

The inability to effectively regulate emotions within

an adequate range and adapted to the respective

context has been proposed to be at the core of

affective disorders (Phillips et al., 2003b). Only

recently, Philips and colleagues proposed a theoret-

ical framework to investigate emotion regulation in

bipolar disorder with paradigms designed to assess

the neural correlates of the automatic and voluntary

regulation of emotions.

So far, only few studies investigated emotion

regulation abilities in bipolar disorders, mostly

focusing on the inhibition of emotion-related infor-

mation. Manic bipolar patients have been reported to

show more difficulties to inhibit emotional stimuli

in an affective go/nogo task (Lyon, Startup, &

Bentall, 1999; Murphy et al., 1999). Similarly, an

inability to inhibit emotional distractor stimuli or

task-irrelevant emotional information have been

observed in dysphoric and depressed individuals

(Gilboa-Schechtman, Ben-Artzi, Jeczemien, Marom,

& Hermesh, 2004; Joormann, 2004). However,

recent affective go/nogo fMRI studies did not

show any performance deficits in manic, depressive

and euthymic bipolar patients, but altered neural

activation patterns, i.e. an enhanced orbitofrontal

activity during the inhibition of verbal or facial

emotional stimuli (Elliott et al., 2002, 2004; Wessa

et al., 2007).

Until now, no study has investigated different

strategies of emotion regulation (e.g. suppression

of already activated emotional responses, reappraisal

of emotional stimuli) in bipolar patients, although

the identification of deficient emotion regulation

in bipolar patients would guide cognitive therapeutic

strategies that ground on the idea that cogni-

tion (e.g. reappraisal) can significantly influence

emotions.

The hypothesis of impaired emotion regulation in

bipolar patients is fostered by neurobiological models

for bipolar disorder (Blumberg et al., 2002; Phillips

et al., 2003b), proposing a hypoactive dorsal-

cognitive network (dorsal ACC, dorsal PFC, inferior

parietal cortex) that fails to inhibit ventral-limbic

activity and that is related to the reappraisal of

emotions in healthy controls (Ochsner et al., 2004).

Dysfunctions of the rostral ACC and the medial

PFC, which are thought to represent an interface

between low- and high-level appraisal of emotional

information (Kalisch et al., 2006), might further

contribute to deficient regulatory mechanisms in

emotional and cognitive processing. Indeed, patients

with bipolar disorder display a decreased prefrontal

glucose metabolism at rest (Ketter et al., 2001)

and reduced activity in the prefrontal cortex

during cognitive tasks (Gruber, Rogowska, &

Yurgelun-Todd, 2004; Lagopoulos, Ivanovski, &

Malhi, 2007). In patients with major depressive

disorder, happy mood induction was associated with

a reduced autonomic activity and increased activity

in the ventromedial PFC (Keedwell, Andrews,


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Williams, Brammer, & Phillips, 2005), a region that

has previously been implicated in the regulation of

emotions (Phillips et al., 2003a). In contrast, sad

mood induction in this study was related to decreased

ventromedial prefrontal activity, a finding that has

been equally observed in euthymic and depressed

patients with bipolar disorder (Kruger, Seminowicz,

Goldapple, Kennedy, & Mayberg, 2003).

Whereas studies explicitly investigating the capac-

ity to voluntarily regulate emotions still lacking in

patients with bipolar disorder, two studies investi-

gated the neural correlates of emotion regulation

through reappraisal strategies in patients with major

depression and reported increased dorsal ACC

activity in depressed versus healthy individuals

when they decreased emotional responses to sad

films (Beauregard, Paquette, & Levesque, 2006) as

well as decreased functional coupling between

the ventromedial PFC and the amygdala during the

down-regulation of negative stimuli (Johnstone et al.,

2007). These findings point to abnormal emotion

regulation in patients with major depression.

Medication effects on neural functioning associated

with emotional processing

Some new interesting studies have investigated

whether pharmacotherapy used in bipolar patients

effects the functioning of the neural circuit that

is involved in emotional processing and that is

hypothesized to be dysfunctional in bipolar patients.

This approach seems very fruitful as it allows

important insights about the therapeutic mechanisms

of pharmacotherapy but also psychotherapy.

Indeed, several studies in healthy controls and

bipolar patients could show significant effects of

antidepressants and mood stabilizers on neural

activity in cortico-limbic brain structures relevant

for emotional processing. A series of studies from

the workgroup of Harmer (Miskowiak et al., 2007;

Norbury, Mackay, Cowen, Goodwin, & Harmer,

2007, 2008) has shown that singular doses and short-

term treatments with an antidepressant (reboxetine)

modulates the neural substrates of emotional proces-

sing (e.g. amygdala response to fearful faces) in

healthy volunteers. From these results a reversal of

the negative bias in depressed patients by antide-

pressants could be hypothesized. In depressed

patients, an increase in functional coupling between

the amygdala and prefrontal cortical areas (e.g.

anterior cingulate cortex) has been found after

8 weeks of treatment with fluoxetine (Chen et al.,

2008). In addition, an adaptive up-regulation of

anterior cingulate activity has been suggested to be

a predictor of the treatment response in depression

(Walsh et al., 2007). Interestingly, Frangou and

colleagues (Haldane et al., 2008; Jogia, Haldane,

Cobb, Kumari, & Frangou, 2008) recently reported

an enhanced function within a neural circuit involved

in affect recognition, mainly in the prefrontal cortex

and cingulate gyrus, in patients after 12 weeks

of lamotrigine treatment.

Conclusion

Numerous studies have investigated the behavioural

and neural correlates of emotional processing in

patients with bipolar disorder. Among these studies

an altered response to various emotional stimuli

together with an increased neural activity in a

ventral-limbic pathway including the amygdala, the

orbitofrontal and ventrolateral prefrontal cortex and

the subgenual cingulate cortex has been consistently

shown. These functional alterations might be at the

basis of an impaired emotion regulation in bipolar

patients; however, to date, very little research has

been conducted on the regulation of emotional

information and their neural correlates, although

these processes might be critical for the development

of bipolar disorder and the shifting between the

different illness phases.

The most heterogeneous results have been

reported for early attentional emotional processes.

Although some of the existing findings point to a

mood-congruent bias for emotional information in

bipolar patients, no final conclusion can be drawn

from the existing results. The heterogeneity of results

not only for these early emotional processes but

behavioural and neuroimaging findings in bipolar

patients in general might arise from the investigation

of different samples including (1) patients in different

symptomatic states, (2) patients with bipolar I and II

disorder, (3) different medications and (4) life time

as well as current psychiatric comorbidities. These

confounding factors can only be controlled when

investigating large samples that allow comparing

subgroups of patients, an aim that calls for multi-

centre studies.

Future directions

Perspectively, studies regarding the identification of

mood-related state markers and trait markers of the

pathology and studies focusing on the specificity of

disturbances in emotional processes for bipolar

disorder are needed to further delineate specific

biomarkers of bipolar disorders.

Acknowledgements

The authors’ research was supported by the

Deutsche Forschungsgemeinschaft (We 3638/3-1;

SFB636/C6).


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Declaration of interest: The authors report no

conflicts of interest. The authors alone are respon-

sible for the content and writing of the paper.

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Emotional processing in bipolar disorder: Behavioural and neuroimaging findings

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