Emotion and its disorders - Semantic Scholar · Emotion and its disorders Hugo Critchley Wellcome...

Emotion and its disorders

Hugo CritchleyWellcome Department of Imaging Neuroscience, Institute of Neurology, University College London,London, UK

Emotional processes are crucial to the control of human behaviour and anchored to acommon foundation in motivational mechanisms where emotional cues have intrinsicre-inforcement values. Emotions per se are transient events, produced in response toexternal or self-generated emotive stimuli, and typically characterized by attention tothe stimulus, involuntary arousal reactions and changes in motor behaviour, sub-jective feeling states and subsequent biasing of behaviour. Primary emotions, such ashappiness and fear, correspond motivationally with approach or withdrawalresponses. In humans, feeling-states and subjective emotional experiences reflectcognitive contextual awareness of emotional responses and may be embellished intosecondary emotions, such as guilt or relief. This review addresses the application ofneuroimaging techniques to understanding the neural mechanisms supporting theseaspects of emotional experience.

Processing of emotional cues

Processing of communicative emotional expressions

A rich vocabulary of communication exists in expressions of emotion asconveyed by changes in facial muscles, autonomic changes in skin andpupil, speech prosody, stance and movements. The ability to perceiveand interpret emotional expressions is essential for adaptive socialbehaviour. Information from faces is particularly communicative.Neuroimaging experiments have identified a region of visual (fusiform)cortex selectively activated when processing faces1. Connecting regionsof lateral temporal association cortex are implicated in processingmouth movements and gaze-direction that contribute to processingemotional expressions2. These specialized cortical representations offacial information connect to regions where emotional valence isextracted, or attributed to, face identity and expression. Functionalneuroimaging evidence lends some support to the theoretical constructthat emotional expressions are processed along distinct neural pathwaysthat reflect motivational meaning. For example, amygdala activity ismodulated by threatening stimuli, or by processing fearful (facial orvocal) expressions of others (Fig. 1A)3–5, whereas facial expressions of

British Medical Bulletin 2003; 65: 35–47DOI 10.1093/bmb/ldg65.035

The British Council 2003

Correspondence to: Dr Hugo Critchley,

Wellcome Department ofImaging Neuroscience,Institute of Neurology,

University CollegeLondon,

12 Queen Square, London WC1N 3BG, UK

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disgust enhance activity in anterior insula and basal ganglia,anatomically related to autonomic and gustatory centres5. Distinctprocessing streams allow for differing emotions to be coupled adaptivelywith distinct behavioural response repertoires and the visceromotorresponses that facilitate them, e.g. freeze or escape in the presence of

Imaging neuroscience: clinical frontiers for diagnosis and management

British Medical Bulletin 2003;65

Fig. 1 (A) Amygdala responses in the processing of fearful faces, in a PET study by Morris et al3. Face stimuli werederived from the Ekman series of prototypical facial expressions, but electronically manipulated to provide a rangeof stimuli along the fearful/happy dimension. The greater the degree of fear expressed in the facial expression, thegreater regional blood flow in left amygdala, associated with increased neural activity. (B) Amygdala responses tounseen fear. In another PET study by Morris et al12. One of two angry faces (CS+) was conditioned to indicate threatthrough pairing with an aversive white noise, the other angry face (CS–) was not paired with any aversive stimulus.A backward masking procedure was used to present subliminally these faces: by rapidly presenting (30 ms) the CS+or CS– face then covering it with a neutral face (45 ms), subjects see only the neutral face and are unaware that theysaw an angry face. However, skin conductance responses (SCR) are nevertheless greater to the unseen CS+ comparedto the unseen CS–. Greater activity in the right amygdala is also observed to the masked CS+ compared to themasked CS– face, consistent with emotional processing independent of awareness.

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threat, exhale and vomit to contamination implicit in disgust. However,there is still uncertainty as to the extent of such neuro-anatomical segregation:Amygdala activity may increase to give expressions of happiness and sadnessas well as fear6–8, and insula activity is reported during processing of threatand sadness, in addition to focal anterior activity associated with disgust5,9,10.

The Jamesian model of emotional processing is that of a reflex: An‘exciting’ stimulus automatically elicits a motor or autonomic response(subjective emotional experience, or feeling state, is a secondaryinterpretation of bodily response11 that may be contextually influenced).The automatic ‘unconscious’ elicitation of emotion has been examinedusing functional imaging using subliminal presentation of face-stimuli(using backward masking and rapid presentation, the subject is not awareof the emotive stimulus; see Fig. 1). When an ‘unseen’ face represents apotential threat, the stimulus still evokes amygdala activation (and a bodilyarousal response)12–14. A subcortical route is implicated in mediating thisunconscious processing of emotional stimulus, by-passing temporal lobeand insula cortices associated with conscious awareness and detailedfeature-processing of the stimuli13,14. These observations provide keyempirical evidence for a causal, automatic, link between stimulus andemotional response. The evidence for two processing pathways toamygdala is consistent with observations in animal experiments. Sincesurvival is dependent on a rapid response, a fast (subcortical) pathwayevokes alertness and escape behaviour to minimally processed, potentiallythreatening, stimuli; a second pathway via cortex provides for a moredetailed representation of the potential threat, enabling correction orreinforcement of the immediate fear response (Fig. 1B).

Stereotypical feature relationships underlie emotion-related processingof facial expression. Thus, line drawings of faces with happy and angryfacial expressions are sufficient to evoke differential amygdala activity15.The amygdala also responds differentially to upright versus inverted‘Thatcher illusion faces’16. In this model, a face can be made to lookbizarre and ‘emotionally threatening’ by inverting facial features such asmouth and eyes. The emotional charge of the face is much reduced if thesame manipulated face is presented upside-down, because componentfeatures are no longer processed within their global context. Differentialamygdala activity to these manipulations indicate that a global integrationof feature relationships is necessary for processing emotional facialexpression.

In experiments examining auditory processing of emotional signals,low-level qualities, in this case prosody, are again the primary source ofemotional information within speech3,4,7. Non-speech intonations ofemotional states (groans, squeals, etc) modulate activity to similar brainregions that are modulated by facial expressions of the same emotion,strengthening the evidence for emotional processing along distinct lines2,3.



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In summary, neuroimaging experiments suggest partial segregation ofstreams for the processing of communicative emotional signals. Suchprocessing may occur independently of awareness, drawing from low-levelglobal stimulus representations in addition to more detailed corticalprocessing of expression. The identification of dedicated cortical systems fordetailed representations of faces and facial features which are coupled withboth emotional responses and conscious awareness provides a further level atwhich communicative emotional signals may exert an influence on cognitiveprocessing and social interactions.

Processing of other emotive stimuli

Complex environmental and social stimuli may evoke emotions by virtueof their direct or implicit motivational meanings. Facial cues, such as eye-gaze, beauty and more elusive judgements of social potential, also share themotivational properties of ‘primary re-inforcers’. The perception ofattractive faces is associated with enhanced activity in ‘reward centres’,such as ventral striatum, which is maximal when eye gaze is directed at theviewer17. Interestingly, in ‘romantic love’, the face of a loved one evokes apattern of striatal, cingulate and insular activity similar that associatedwith obsessive compulsive disorder18. Negative judgements of emotionalattributes may evoke activity associated with implied threat, for example,faces rated by a viewer to be more ‘untrustworthy’ evoke greater amygdalaactivity, independent of attention to this facial quality19.

Complex visual scenes and even individual words may be ratedaccording to emotive power or emotional content. A set of pictures, theInternational Affective Picture System (IAPS), comprises of a large range ofscenes that vary in their emotional valence (positive and negative) and theirevocation of subjective arousal. In a combined fMRI and MEG study,negative pictures activated medial orbitofrontal cortex whereas positivepictures preferentially activated lateral orbitofrontal cortex20. The MEGdata indicated a more rapid processing of emotional pictures, particularlythose with negative content, than non-emotional pictures. Amygdalaresponses are reportedly enhanced by emotional words and positiveemotional words that also activate reward-related regions of ventralstriatum7. In contrast, perception of humour is reported to activate medialprefrontal cortex21. In perhaps what is a canonical neuroimagingexperiment of emotion, a recent fMRI study used a direct measure ofsexual arousal as a regressor of interest when male subjects watchedpornography or sport films. Regional activity within insula, basal gangliaand cingulate cortex, as well as visual and somatosensory cortices co-varied positively with sexual arousal22. It is noteworthy that much lessactivity was attributable to the stimuli themselves compared to activitydirectly correlated with physiological changes.



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Pain, itch and tickle as emotional stimuli

Emotion (reflecting a contextual interpretation of valence) is an importantcontributing factor to the difference between strong somatosensorystimulation and pain, or even light touch and tickle. There is a detailedreview of pain research by Jones23. The presence of subjective pain isassociated with consistently reported activity increases within in the ‘painmatrix’. This set of regions includes hypothalamus and thalamus,somatosensory and parietal cortices and, importantly from the emotionalperspective, also anterior cingulate, insula, lateral and medial prefrontalcortex23,24. Anterior cingulate cortex in particular may integrate painfulexperience with attention, arousal and subjective emotional state.However, even within anterior cingulate cortex, pain-related activity can bedissociated from activity related to stimulus intensity, implicating older,limbic cingulate regions in representations of pain25.

Disorders of processing emotional stimuli

Neuropsychological studies of patients with focal brain lesions haveprovided the basis of understanding many brain processes involved inemotion and emotional disorder. On this foundation, neuroimagingresearch has added powerful insights into central correlates of disordersof emotion, even where structural changes in brain anatomy are notobviously apparent. For example, some of the social and emotionaldeficits associated with autism may partly derive from inattention to, oraberrant processing of, emotional stimuli, particularly communicativeexpressions. When processing emotional expressions, deficits in activitywithin amygdala26,27 and fusiform cortex27 have been observed in peoplewith autistic symptoms. Subtle structural morphometric abnormalitieshave been observed in autistic individuals in brain regions associatedwith processing of emotional cues, including amygdala, cingulate andlateral temporal cortex28. Abnormal mechanisms in the processing ofemotional cues are also proposed to underlie behavioural features ofother ‘emotional’ disorders, such as developmental psychopathy29 whereamygdala dysfunction during processing of distress signals is implicatedin this disorder of empathy.

Representation of internal feeling states

Subjective emotional states

Mood states have variously been induced in healthy subjects bypresentations of emotional stimuli (such as facial expressions, emotivemusic, IAPS pictures, or subjective recall of emotional experiences) where



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the subject is instructed to experience (and rate) with the depicted orremembered emotion. Attention to subjective mood state increases activitywithin rostral anterior cingulate30. Subjective states of sadness, happinessand disgust induced by film or by recall have been associated withactivation of medial prefrontal cortex and thalamus. Participation ofsomatosensory cortex and insula has also been observed during recollectionemotional experiences, consistent with an importance of somaticrepresentations to emotional feeling states31. Negative mood states havebeen associated with increases in insula and amygdala activity, consistentwith processing aversive material. Sadness has been associated with activityin anterior insula and happiness by subgenual cingulate activity32. Symptomprovocation in people with simple phobias or obsessive-compulsivedisorder (OCD) have many similarities with mood induction studies and, ingeneral, increased activity is observed in orbitofrontal cortex, insula,amygdala and basal ganglia, regions implicated in fear, aversion, arousaland compulsive responses.

Subjective emotional states can be directly experimentally manipulatedto produce changes in emotional behaviour, attention and arousal. Thismay involve inducing motivational change (e.g. thirst or hunger) oremploying selective neurochemical interventions that can target specificallyemotional mechanisms. Tryptophan depletion, resulting in serotonergicdysfunction, can transiently depress an individual’s mood, which in turn isassociated with decreased activity in anterior cingulate, orbitofrontalcortex and basal ganglia33. In general, pharmacological interventions havebeen an under-used methodology to probe interactions between subjectiveemotion state and neurochemical mechanisms.

Feelings and arousal states

The role of bodily arousal states has been emphasized in many theories ofemotion11. Neuroimaging studies have tended to under-emphasize theobservation that brain regions implicated in emotional processing areinvolved at some level in control of autonomic responses and peripheralarousal states. However, some studies have attempted to map directlyregional brain activity associated with peripheral autonomic responses.These studies implicate anterior cingulate, medial prefrontal, and insulacortices in generation and representation states of autonomic arousal (Fig.2). Moreover, these regions support interactions between autonomicactivity and cognitive processing, for example during reward-anticipation,cognitive effort and stimulus awareness14,35,36. Regional representations ofbodily arousal, particularly where modulated by (experimental) context,may be the substrate of ‘feeling states’ and also mediate the influence ofarousal on attentional processes14,16,35.



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Disorders of subjective emotional state and arousal

Affective (mood) disorders are characterized by feeling states: (i) depressionby feelings of sadness; (ii) hypomania by feelings of elation; and (iii)happiness and anxiety disorders by fear37. These mood disorders are alsoassociated with changes in saliency of perceived cues, cognitive andmnemonic performance, motor and arousal states, which may confoundinterpretation of functional imaging experiments. Differences in brainmorphology have been related to predisposition to mood disorder (forexample, ventromedial prefrontal cortex abnormalities in forms ofdepression37 or anterior cingulate associations with anxiety38). More



Fig. 2 Activity related to electrodermal arousal. Galvanic skin conductance was recorded continuously while subjectsperformed a gambling task. Activity attributable to task performance, including rewards and punishments wasexcluded from this analysis. Activity varying continuously with electrodermal arousal is presented to the left. The upperfigure on the right represents activity related to the generation and feedback representation of discrete skinconductance responses (peaks in electrodermal activity), which were modelled as events, with a 4 s delay added tomodel the feedback representation. The lower figure depicts medial prefrontal cortical activity co-varying with theamplitude of these discrete skin conductance events. Electrodermal arousal is thus associated with modulation ofregions implicated in emotional/motivational (medial and ventrolateral prefrontal cortex) processes and attention(parietal and extrastriate visual cortex). fMRI study by Critchley et al35

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selective disorders of subjective feeling states may include paranoid feelings,depersonalization and somatization. In depersonalization disorder, acharacteristic feature is a sense of emotional detachment. Functional imagingfindings include reductions in activity with insula cortex, adjacent to areasimplicated in integrating emotional awareness and arousal39.

Emotional and motivational learning

Primary re-inforcement and satiation

Emotion is conceptually rooted in the processing of reward andpunishment40. Primary rewards satisfy intrinsic drives necessary forsurvival, and elicit positive emotional states. Proxy awards such as money,pictures of money, points score and tick marks share similar re-inforcingqualities in humans. Areas including orbitofrontal cortex and ventralstriatum are activated by primary rewards such as pleasant tastes, and byexpectation of these rewards41, but these areas are also activated by abstractrewards such as the promise or depiction of money42. Satiety experimentsprovide a powerful manipulation of an individual’s motivational state,which directly impacts on the reward-value of stimuli. Activity inorbitofrontal cortex (and amygdala) is enhanced by pictures of foods, onlywhen hungry43, reflecting the differences in reward. Memory of these foodstimuli is also greater when hungry and correlated with amygdala andorbitofrontal activity at the time of presentation43. These interventionalexperiments provide strong evidence for participation of humanorbitofrontal cortex and ventral striatum in immediate, prospective andmnemonic processing of rewards.

Motivational learning

Trial-by-trial imaging studies of reward-related learning have demon-strated differential involvement of human medial and orbitofrontal cortexin representing rewarding and punishing stimuli, in distinguishing betweendifferent degrees of rewards and in re-learning different stimulus-rewardassociations41,42. The learning of threat and punishment has been exploredusing fear conditioning9. When a stimulus is paired with shock orpunishment, learning results. Fear responses are subsequently produced bythe previously innocuous stimulus. Enhanced amygdala activity isassociated with fear conditioning where a face stimulus (CS+) is pairedwith an aversive event such as a burst of white noise (US)9,12,14. This mayoccur independently of conscious awareness12–14 and may rapidly habituateonce learning is established9. Associated increases in insula and anterior



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cingulate activity do not show the same degree of habituation to learnedthreats, suggesting these regions may selectively mediate attentional andarousal responses to threat9.

Attention to, encoding, and recall of emotional material

Attention is preferentially directed towards emotive stimuli perhaps tofacilitate processing and behavioural reactions. Attention and arousal areoften correlated and many similar brain regions have been implicated intheir control, such as anterior cingulate, parietal and insula cortices4,34–36.The distracting effect of emotional stimuli (faces associated with threat) ona spatial attention task was examined using fMRI44. Predictably, amygdalaresponses were associated with threat, independent of attention, whereasmedial prefrontal, orbitofrontal and parietal cortices were implicated inemotional modulation of attention44. ‘Oddballs’ are stimuli that stand outfrom others by virtue of different characteristic; for example, in a list ofwords, infrequent rare emotional words are remembered more reliablythan non-emotional words in the set (Fig. 3). Amygdala activity isenhanced during encoding of these emotional oddballs45. When recallingsuch emotional word stimuli, there is enhanced activity in prefrontal cortexand hippocampus (areas normally activated to a lesser extent by retrievalof non-emotional episodic memory) and additional activity withinamygdala and orbitofrontal cortex, which would have responded to theemotional material at encoding46. These two levels of emotional influenceon recall suggest dissociable modulatory mechanisms for adaptiveenhancement of emotional memories.

Disorders of emotional learning

Emotional and social problems are often conceptualized within theframework of re-inforcement-related behaviours, based on observationsof deficits consequent to focal brain damage including orbitofrontalcortex and amygdala40,47. Neuroimaging studies continue to providemechanistic insights into the functional contributions of discrete brainregions to adaptive behaviours. Along these lines, neuroimaging studieshave also described microscopic or functional abnormalities in similarregions in patients or offenders with disturbed social and emotionalbehaviour48,49. The mechanisms explored in studies of fear conditioning andemotional learning have direct implications for understanding thedevelopment, maintenance, and potential treatment of emotional disorderssuch as phobias, post-traumatic stress disorder, and related anxietydisorders. Additionally, differences in brain morphology may underlie



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individual predisposition to development of anxiety-related disorders37,38.As with OCD50, neuroimaging studies may provide an empirical index oftreatment responsiveness in these emotional disorders.

Future developments in neuroimaging studies of emotion

In recent years, two developments have had a great impact on functionalimaging studies of emotion: event-related fMRI and subject monitoring.



Fig. 3 There is enhanced memory for emotional information. The figure shows regions activeduring encoding of emotional ‘oddballs’ from a study by Strange et al45. Subjects werescanned reading word lists in which some stimuli ‘stood out’ (i.e. were oddballs) by virtue ofbeing emotionally, semantically or perceptually different. When viewing the emotional words,there was enhanced activity in amygdala and inferior prefrontal cortex. This activity correlatedwith whether the word was subsequently recalled. The location of amygdala and prefrontalgroup differences during processing emotional oddballs, relative to control stimuli is shown inthe brain sections on the left. The bar charts to the right illustrate that this enhanced activitywas associated with emotional, not perceptual or semantic ‘deviance’. Beneath are examplesof the stimuli showing emotional (E), perceptual (P) and semantic (S) oddballs.

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Event-related fMRI has enabled quantification of trial-by-trialrelationship of a stimulus (or response) to evoked regional brain activity,in contrast to blocked fMRI or PET studies. In the context of emotionstudies, this has overcome many confounds related to habituation andfluctuating attention and arousal. Subject monitoring during scanningcan now be safely achieved at temporal resolutions high enough forcombined EEG/fMRI studies, and monitoring changes in autonomicactivity have already enabled both on-line indexing of emotionalprocessing and dissociation of arousal-related activity from cognitiveaspects of emotional processing. The range of analytical methodsavailable for processing functional imaging data should provide for amore detailed definition of neurophysiological mechanisms underlyingemotion; for example, effective connectivity analysis to test formodulatory influences on region-to-region interactions. Nevertheless,interventional studies and the use of patient models provide perhaps themost powerful means of exploring theoretical issues, and the field offunctional neuropharmacology remains rather undeveloped with respectto fMRI studies of emotion. MRI advances must be set within thecontext of other modalities of magnetic resonance imaging. Acomprehensive understanding of the neurology of emotion must includedetailed structural and neurochemical descriptions. These may beachievable with development and implementation of techniques such asdiffusion tensor imaging of axonal tracts, combined with neurochemicalinformation from chemical shift imaging or spectroscopy. Thesemethods, combined with functional data obtained from synchronousfMRI and EEG, remain an obtainable goal for the study of healthyemotional processing and emotional disorders.

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