Emotion Perception 2

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Neurobiology of Emotion Perception II: Implicationsfor Major Psychiatric Disorders

Mary L. Phillips, Wayne C. Drevets, Scott L. Rauch, and Richard Lane

To date, there has been little investigation of the neuro-biological basis of emotion processing abnormalities in

psychiatric populations. We have previously discussed twoneural systems: 1) a ventral system, including the amyg-dala, insula, ventral striatum, ventral anterior cingulategyrus, and prefrontal cortex, for identification of theemotional significance of a stimulus, production of affec-tive states, and automatic regulation of emotional re-

sponses; and 2) a dorsal system, including the hippocam-pus, dorsal anterior cingulate gyrus, and prefrontalcortex, for the effortful regulation of affective states andsubsequent behavior. In this critical review, we haveexamined evidence from studies employing a variety oftechniques for distinct patterns of structural and func-tional abnormalities in these neural systems in schizophre-nia, bipolar disorder, and major depressive disorder. Ineach psychiatric disorder, the pattern of abnormalitiesmay be associated with specific symptoms, includingemotional flattening, anhedonia, and persecutory delu-sions in schizophrenia, prominent mood swings, emotionallability, and distractibility in bipolar disorder duringdepression and mania, and with depressed mood and

anhedonia in major depressive disorder. We suggest thatdistinct patterns of structural and functional abnormalitiesin neural systems important for emotion processing areassociated with specific symptoms of schizophrenia andbipolar and major depressive disorder. Biol Psychiatry2003;54:515528 2003 Society of Biological Psychiatry

Key Words: Emotion, neuroanatomy, schizophrenia, bi-polar disorder, depression

Introduction

Until recently, there has been little investigation of theneurobiological basis of the abnormalities in emotionprocessing present in different psychiatric populations.

Furthermore, there has been little attempt to compare the

severity and nature of these abnormalities across different

psychiatric disorders. In a previous review (Phillips et al

2003), we examined the findings from recent animal,

human lesion, and functional neuroimaging studies to

identify the neural bases of the different neuropsycholog-

ical processes important to the understanding of normal

human emotional behavior. Findings suggest that these

processes may be dependent upon the functioning of twoneural systems: a ventral system important for the identi-

fication of the emotional significance of a stimulus, the

production of affective states; and a dorsal system impor-

tant for executive function, including selective attention,

planning, and effortful regulation of affective states (Fig-

ure 1). Abnormalities in emotion perception may be

associated with abnormal triggering of emotional re-

sponses that lead to clinical phenomena unrelated to

exteroceptive perception (e.g., depressed or manic mood)

that dominate the clinical picture. In this critical review,

we have examined the evidence from studies employing a

variety of techniques for the presence of specific abnor-malities in these systems in major psychiatric illnesses,

including schizophrenia, bipolar disorder, and major de-

pressive disorder.

Schizophrenia

Evidence for Impaired Cognitive and EmotionProcessing in Schizophrenia

Bleuler (1950) defined schizophrenia as essentially a

splitting of thoughts (cognition) from feelings (emotion),

and a flattening of affect and anhedonia have beenrecognized as core features of the disorder since its first

description. Furthermore, schizophrenic patients often ap-

pear to misinterpret social cues and exhibit poor social

skills, with symptoms such as persecutory delusions often

emerging as misinterpretations of social interactions and

events, frequently revolving around a persons relationship

to others and role in society rather than neutral or

impersonal themes (Young and Bentall 1995).

One of the most commonly reported neuropsychologi-

cal impairments in patients with schizophrenia is impaired

From the Division of Psychological Medicine (MLP), Institute of Psychiatry,London, United Kingdom; Mood and Anxiety Disorders Program (WCD),National Institute of Mental Health, Bethesda, Maryland; MassachusettsGeneral Hospital (SLR), Charlestown, Massachusetts; and Department ofPsychiatry (RL), University of Arizona College of Medicine, Tucson, Arizona.

Address reprint requests to Mary L. Phillips, Institute of Psychiatry, Division ofPsychological Medicine, De Crespigny Park, Denmark Hill, London SE5 8AF,United Kingdom.

Received July 8, 2002; revised December 26, 2002; accepted January 10, 2003.

2003 Society of Biological Psychiatry 0006-3223/03/$30.00doi:10.1016/S0006-3223(03)00171-9
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executive function, including deficits in performance on

tasks of selective attention and working memory (Gold-

man-Rakic 1994). There is accumulating evidence toindicate that specific abnormalities in emotion identifica-

tion and emotional behavior are also associated with the

poor social function observed in patients with schizophre-

nia. Impaired recognition of facial (Edwards et al 2001;

Feinberg et al 1986; Whittaker et al 2001) and prosodic

(Edwards et al 2001) emotion, dysfunctional emotional

experience (Flack et al 1998), and a positive correlation

between emotion recognition and negative and positive

symptomatology (Kohler et al 2000) have been demon-

strated in these patients. In one study, however, no

impairment in facial expression identification was re-

ported (Flack et al 1997). Other studies have demonstratedan association between emotion identification and more

generalized task performance deficits (Kerr and Neale

1993) and between emotion identification deficits and

chronicity of illness (Mueser et al 1997).

Other findings have suggested a greater differential

impairment in negative affect recognition (Bell et al 1997),

the superior ability of paranoid compared with nonpara-

noid patients in negative affect identification (Kline et al

1992), and a positive association between the severity of

psychotic symptoms and the ability to recognize unpleas-

ant odors (Crespo-Facorro et al 2001). Furthermore, when

examined case by case, although no universal emotional

identification deficits were demonstrated in schizophrenic

patients (Evangeli and Broks 2000), emotions thought to

rely on intact amygdala function (particularly fear) were

most consistently affected. Additionally, schizophrenic

patients with persecutory delusions were reported as dem-

onstrating specific abnormalities in their viewing strate-

gies for social scenes depicting ambiguous rather than

overtly threatening information (Phillips et al 2000). It istherefore possible that schizophrenic patients identify

stimuli that are ambiguous in their emotional content as

more emotive and threatening than stimuli that depict

overt fear or threat.

A strong association has been reported in schizophrenia

between social outcome and the ability to accurately

recognize emotions displayed by others (Green et al 2000).

Impairments in the ability to monitor the source of willed

intentions, so that self- and nonself-originated intentions

become indistinguishable, and deficient understanding of

the behavior and intentions of others (theory of mind;

Figure 1. Schematic diagram depicting neural structures impor-

tant for the three processes underlying emotion perception. A

predominantly ventral system is important for the identification

of the emotional significance of a stimulus, the production of anaffective state, which may be associated with autonomic re-

sponse regulation (depicted in pale gray), whereas a predomi-

nantly dorsal system (depicted in dark gray) is important for the

effortful regulation of the resulting affective states. A reciprocal

functional relationship may exist between these two neural

systems (depicted by the curved arrows). DLPFC, dorsolateral

prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; ACG,

anterior cingulate gyrus; VLPFC, ventrolateral prefrontal cortex.

Figure 2. Schematic model for the neural basis of the observed

deficits in emotion perception and behavior in schizophrenia.

The color coding for the ventral and dorsal neural systems is as

in Figure 1. Structural and functional abnormalities within theventral system, including the amygdala, anterior insula, and

ventral striatum, may result in a restriction of the range of

emotions identifiable, a decreased range of subsequent affective

states and behaviors, and a misinterpretation as threatening of

nonthreatening and ambiguous stimuli. These phenomena may

be perpetuated by impairments in reasoning, contextual process-

ing, and effortful regulation of affective states (reduced size of

the curved arrow representing the regulation of the ventral by the

dorsal system), resulting from structural and functional abnor-

malities within the hippocampus and dorsal prefrontal cortical

regions. This pattern of abnormalities may be associated with

specific symptoms, including emotional flattening, anhedonia,

and persecutory delusions. DLPFC, dorsolateral prefrontal cor-tex; DMPFC, dorsomedial prefrontal cortex; ACG, anterior

cingulate gyrus; VLPFC, ventrolateral prefrontal cortex.

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Premack and Woodruff 1978), have been postulated as

possible causes for psychotic symptoms and the social

dysfunction of patients with schizophrenia (Corcoran et al

1997; Frith 1992). Other studies have demonstrated that

schizophrenic patients with prominent delusions have

abnormal reasoning styles, appearing unable to resist theirabnormal beliefs and unable to re-evaluate the evidence

for their conclusions (Garety et al 1991).

Taken together, these findings suggest that specific

abnormalities in the identification of emotionally salient

information, together with misinterpretation of the inten-

tions of others and impaired evaluation or regulation of the

resulting belief systems and emotional behavior, may

underlie some of the symptoms and poor social perfor-

mance reported in patients with schizophrenia.

Evidence for Structural and Functional

Neuroanatomic Abnormalities in Regions Importantfor Emotion Processing in Patients withSchizophrenia

Abnormal neural circuitry in schizophrenia, involving

dysfunctional prefrontalthalamic and temporolimbic or

cerebellar connections, has been emphasized by previous

authors (Andreasen et al 1998; Weinberger 1997). A

disruption in connectivity between nodes in prefrontal

cortex, the thalamus, and the cerebellum has been associ-

ated with cognitive dysmetria, a difficulty in prioritiz-

ing, processing, coordinating, and responding to informa-

tion, which may account for many of the diverse

symptoms of schizophrenia (Andreasen et al 1998).Many studies have reported in schizophrenic patients

structural and functional abnormalities in dorsolateral

prefrontal cortex and dorsal anterior cingulate gyrus,

regions important for selective attention and planning and

implicated in the previous review (Phillips et al 2003) in

the effortful regulation of affective states and emotional

behavior. Neuropathologic findings indicate reduced cor-

tical neuronal size and reduced glial cell density in frontal

cortex (Benes et al 1991; Rajkowska et al 1998). Although

there are inconsistent findings regarding the presence of

volume reductions within the prefrontal (Goldman-Rakic

and Selemon 1997; Lawrie and Abukmeil 1998; Pearlsonand Marsh 1999; Wright et al 2000) and, more specifi-

cally, dorsolateral prefrontal cortex in patients with

schizophrenia (Zuffante et al 2001), several studies have

demonstrated reduced blood flow and reduced activation

of dorsal prefrontal cortex and dorsal anterior cingulate

gyrus in these patients during the performance of tasks of

executive function (Andreasen et al 1997; Carter et al

1998; Goldman-Rakic and Selemon 1997; Hazlett et al

2000; Haznedar et al 1997).

These neuropsychological and structural and functional

neuroanatomic abnormalities within dorsal prefrontal cor-

tical regions have been associated in particular with

psychomotor poverty syndrome and negative symptoms

(Heckers et al 1999; Liddle and Morris 1991). Interest-

ingly, the reduced activation within the dorsal anterior

cingulate gyrus observed during performance of a paced

verbal fluency task in unmedicated schizophrenic patientshas been demonstrated to be reversed after challenge with

apomorphine, a dopamine agonist (Fletcher et al 1996).

This finding suggests that the pattern of hypofrontal

activity observed in schizophrenic patients during perfor-

mance of executive tasks may be a result of dysfunctional

dopaminergic activity, although this matter requires fur-

ther clarification.

With regard to medial temporal lobe structures, includ-

ing the amygdala and hippocampus, there have been

several reports of abnormal neuronal cell integrity (Falkai

and Bogerts 1986; Nasrallah et al 1994) and volume

reductions (Altshuler et al 2000; Heckers 2001; Lawrieand Abukmeil 1998; Nelson et al 1998; Shenton et al

1992; Wright et al 2000) in these regions, an association

between amygdalar lesions and psychotic symptoms

(Fudge et al 1998), and an inverse correlation between left

amygdalar volumes and thought disorder and between left

anterior and posterior hippocam-pal volumes and positive

and negative symptom scores, respectively (Rajarethinam

et al 2002). Although there have been inconsistent findings

of no differences in amygdalar (e.g., Altshuler et al 2000;

Chance et al 2002) or hippocampal (Laasko et al 2001)

volumes between patients and control subjects, volumetric

abnormalities in these regions have been demonstrated in

first-degree relatives (Seidman et al 1999). Although there

have been inconsistent findings regarding thalamic size in

patients with schizophrenia (Andreasen et al 1990; Gur et

al 1998), in a recent meta-analysis, a significant, small-to-

moderate effect size was demonstrated for thalamic size

reduction in these patients compared with nonpsychiatric

and nonneurologic control subjects (Konick and Friedman

2001). Other studies have reported decreased insular size

in schizophrenic patients (Crespo-Facorro et al 2000;

Wright et al 2000). The relative contribution of medication

to these structural neural abnormalities in schizophrenicpatients remains to be clarified.

Hippocampal dysfunction has been reported in schizo-

phrenic patients, with increased activity at rest (e.g.,

Medoff et al 2001) but decreased hippocampal activity

during memory task performance (e.g., Benes and Berretta

2000; Heckers and Konrad 2002). There have been few

studies examining neural responses to emotional stimuli in

these patients, however. The delusions and hallucinations

of reality distortion syndrome have been associated with a

specific pattern of abnormal cerebral flow involving over-

activity of the left medial temporal lobe (Liddle et al

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1992). Studies have demonstrated, however, that schizo-

phrenic patients fail to activate the amygdala in response

to fearful facial expressions (Phillips et al 1999), aversive

scenes (Taylor et al 2002), and during sad mood induction

(Schneider et al 1998). Schizophrenic patients also show

decreased amygdalar activation during facial emotiondiscrimination (Gur et al 2002), although they may show

amygdalar activation in response to happy faces (Kosaka

et al 2002).

Additionally, regional cerebral blood flow to the ante-

rior insula, nucleus accumbens, and parahippocampal

gyrus failed to increase in response to unpleasant odors in

a group of schizophrenic patients, despite their subjective

experience of these stimuli as unpleasant (Crespo-Facorro

et al 2001). In schizophrenic patients with prominent

persecutory delusions, however, amygdalar activation has

been reported in response to ambiguous emotive stimuli

comprising fearful faces and neutral sounds, but not toovertly fearful stimuli, comprising fearful faces and fearful

sounds (Parker et al, unpublished data).

These findings suggest an impaired response of the

amygdala, anterior insula, and ventral striatum, regions

important for the identification of the emotional signifi-

cance of a stimulus, to overt displays of emotions, and

particularly fear, in schizophrenic patients. Findings also

suggest an enhanced amygdalar response to ambiguous

stimuli, however. One possibility is that there is a lowering

of the threshold at which these regions respond to ambig-

uous stimuli but an attenuation of their responses to overt

displays of emotion, although this requires further study.

Is There an Abnormal Functional Neuroanatomy ofEmotion Processing in Schizophrenia?

Findings indicate that the misinterpretation of others

intentions and positive symptoms, such as persecutory

delusions, emotional flattening or anhedonia, and the poor

social functioning evident in patients with schizophrenia,

may be related to impaired recognition of emotion. Addi-

tionally, there may be a tendency for ambiguous stimuli to

be misinterpreted as threatening, particularly in patients

with prominent persecutory delusions. Studies employingneuroimaging techniques have demonstrated in schizo-

phrenic patients structural and functional abnormalities

within ventral and dorsal neural systems important for

emotion processing, although inconsistent findings have

been noted.

How are these emotion processing and structural and

functional neurobiological abnormalities associated with

symptoms in schizophrenic patients? Structural and func-

tional abnormalities in regions important for the appraisal

and identification of positive and negative emotional

stimuli and production of affective states, including the

amygdala, anterior insula, and ventral striatum, may result

in a restriction of the range of positive and negative

emotions identifiable. They may also be associated with a

misinterpretation as threatening of nonthreatening and

ambiguous stimuli and with a decreased range of subse-

quent affective states and behaviors. Specific negativesymptoms, including emotional flattening and anhedonia,

positive symptoms, including persecutory delusions, and

impaired social function could arise from these abnormal-

ities in emotion processing. Structural and functional

abnormalities in the hippocampus and dorsal prefrontal

cortical regions, resulting in impairments in reasoning,

contextual processing, and effortful regulation of affective

states, may then perpetuate these abnormalities and symp-

toms (Figure 2).

Bipolar Disorder

Evidence for Impaired Cognitive and EmotionProcessing in Bipolar Disorder

Many of the symptoms experienced by patients with

bipolar disorder, including irritability, distractibility, and

emotional lability, would appear to be associated with

abnormalities in emotion processing, including the expe-

rience of emotions of inappropriately high intensity in

relation to the context in which they occur, and an inability

to regulate mood. Impaired performance on cognitive

tasks, including those of selective attention and working

memory, has been demonstrated in manic (Bulbena andBerrios 1993; Bearden et al 2001) and depressed bipolar

patients (Borkowska and Rybakowski 2001) and also

within remitted patients (Wilder-Willis et al 2001). Other

studies have reported relatively spared (Clark et al 2002;

Paradiso et al 1997; van Gorp et al 1998) or little

generalized impairment (Sapin et al 1987) in remitted

patients on these tasks.

Studies have reported in bipolar patients impaired rec-

ognition of happy and sad facial expressions (Rubinow

and Post 1992), increased biases toward the identification

of stimuli as emotional rather than neutral, and particularly

negative, in depressed bipolar patients (Gur et al 1992;Lyon et al 1999; Murphy et al 1999), and in manic

patients, increased negative and positive biases (Lyon et al

1999; Murphy et al 1999). In euthymic bipolar patents,

enhanced disgust (Harmer et al 2002), and impaired

fearful facial expression identification (Yurgelun-Todd et

al 2000) have been demonstrated. Other studies have

indicated that the performance of schizophrenic patients

on these tasks is more impaired than that of bipolar

patients (Addington and Addington 1998). Despite these

findings, there has been little examination of performance

on these tasks at different phases of illness in bipolar



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disorder. It has therefore been difficult to determine

whether the cognitive and emotional processing abnormal-

ities demonstrated by bipolar patients represent state or

trait effects.

Evidence for Structural and FunctionalNeuroanatomic Abnormalities in Regions Importantfor Emotion Processing in Patients with BipolarDisorder

Findings from neuropathologic studies have indicated

decreased glial cell number and density and reduced

neuronal cell density in prefrontal cortex (Rajkowska et al

2001), reduced glial cell number and density in the

subgenual anterior cingulate gyrus (Ongur et al 1998;

Rajkowska 2002), and entorhinal and hippocampal

changes, including a reduction and dysgenesis of various

neuronal cell lines (Benes et al 1998) in bipolar disorder.Studies employing structural neuroimaging techniques

have demonstrated reductions in prefrontal and subgenual

cingulate cortical volumes (Drevets et al 1997; Hirayasu et

al 1999; Lopez-Larson et al 2002), reductions asymmetry,

and increases in right and left temporal lobe volumes

(Altshuler et al 2000; Harvey et al 1994), and, predomi-

nantly, increases in amygdalar volumes (Altshuler et al

1998; Strakowski et al 1999).There have been additional

reports of increased caudate volume (Aylward et al 1994)

but inconsistent findings regarding thalamic volumes

(Caetano et al 2001; Dasari et al 1999; Strakowski et al

1999). These studies have been unable to distinguish be-tween abnormalities caused by and/or associated with the

depressive, euthymic, and manic phases of the disorder.

Although long-term use of lithium has been associated

with increase in volume of the subgenual cingulate gyrus

(Harrison 2002; Manji et al 2000), the effect of medication

on the development of these structural neural abnormali-

ties remains unclear.

In depressed bipolar patients, compared with healthy

volunteers, executive task performance and at-rest studies

have demonstrated reduced metabolism in dorsolateral and

dorsomedial prefrontal cortical regions (Baxter et al 1989;

Ketter et al 2001) but increased metabolism within theright amygdala and thalamus (Ketter et al 2001). Reduced

prefrontal and caudate metabolism to aversive stimulation

(Buchsbaum et al 1986) and inconsistent findings of

decreased (Drevets et al 1997) but also increased (Kruger

et al, unpublished data) blood flow in rostral/ventral and

subgenual anterior cingulate gyrus have been demon-

strated during rest and sad mood induction, respectively.

In manic patients compared with healthy volunteers,

studies have demonstrated decreases in prefrontal

(OConnell et al 1995) and ventromedial prefrontal (or-

bitofrontal) cortical activity (Blumberg et al 1999) and

increases in dorsal anterior cingulate gyral (Blumberg et al

2000; Goodwin et al 1997; Rubinsztein et al 2001) and

ventral striatal (Blumberg et al 2000; OConnell et al

1995) activity during performance of executive tasks,

gambling, and at rest, with dorsal anterior cingulate gyral

activity correlating positively with mania ratings (Good-win et al 1997; Rubinsztein et al 2001) but also increasing

more during easy versus difficult decision making (Rubin-

sztein et al 2001). The latter suggests that dorsal anterior

cingulate gyral activation in manic patients is negatively

correlated with task difficulty, although this requires

clarification. Overall, this pattern of results may reflect a

tendency in patients who are able to perform these tasks

successfully to attempt to regulate in an effortful manner

inappropriate affective states and behaviors resulting from

increased sensitivity to emotionally salient environmental

information. Future studies examining neural responses

both to emotional stimuli and during cognitive task per-formance in a single group of manic patients may help to

clarify the neural basis of the impairment in the regulation

of emotional behavior and mood, and the relationship

between this and cognitive task performance in these

patients.

There have been conflicting findings regarding baso-

temporal regions, including the amygdala, in manic pa-

tients at rest (Gyulai et al 1997; OConnell et al 1995). No

study has examined neural responses to emotional stimuli

in these patients. Neuroleptic medication levels have been

positively correlated with mean regional cerebral blood

flow at rest (Silfverskiold and Risberg 1989) and prefron-tal cortical activation during decision-making in manic

patients (Rubinsztein et al 2001), although the effect of

medication on cerebral activity in these patients requires

further study.

In the few studies examining neural correlates of task

performance in euthymic patients, findings indicate fewer

functional neuroanatomic abnormalities compared with

symptomatic patients during executive task performance

(Baxter et al 1989; Blumberg et al 1999, 2000). Addition-

ally, increased amygdalar and reduced prefrontal cortical

activation has been reported to facial expressions of fear

(Yurgelun-Todd et al 2000).Differences in functional neuroimaging techniques,

medication status, and in the type of cognitive task

performed by patients during scanning procedures may

have contributed to the discrepancies in some of the

findings from these studies. The results indicate, however,

that structural and functional abnormalities in prefrontal

cortex, the subgenual anterior cingulate gyrus, the amyg-

dala, and ventral striatum are present in patients with

bipolar disorder, and functional abnormalities exist in

these structures in manic and depressed phases of

illness.

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Is There an Abnormal Functional Neuroanatomy ofEmotion Processing in Bipolar Disorder?

The evidence to date indicates that although bipolar

patients demonstrate abnormalities in executive function,

they are less impaired than schizophrenic patients in the

identification of emotional stimuli. In bipolar patients,

there are reports of structural abnormalities in neural

regions important for emotion processing: within the

amygdala, important for the identification of the emotional

significance of a stimulus; within the subgenual region of

the anterior cingulate gyrus and orbitofrontal cortex,

important for the production of affective states; and within

dorsolateral prefrontal cortical regions, important for the

performance of non-emotional, cognitive tasks and impli-

cated in the effortful regulation of affective states and

emotional behavior.

How are these emotion processing and structural and

functional neurobiological abnormalities associated withsymptoms in bipolar patients? It may be speculated that

the findings in bipolar patients of enlarged rather than

decreased amygdalar volumes and enhanced rather than

reduced activity within the amygdala, subgenual cingulate

gyrus, and ventral striatum, together with reduced prefron-

tal cortical volumes and metabolism, indicate an oversen-

sitive but dysfunctional neural system for identification of

emotional significance and production of affective states,

and an impaired system for the effortful regulation of

the subsequent emotional behavior. Specific symptoms

of both the depressed and manic phases of illness in

bipolar disorder, including prominent mood swings,emotional lability, and distractibility, may then be

associated with these abnormalities in emotion process-

ing (Figure 3). To date, however, no information is

available regarding the functional neuroanatomy of the

switch process to and from euthymia or between mania

and depression.

Major Depressive Disorder

Evidence for Impaired Cognitive and Emotion

Processing in Major Depressive DisorderStudies have reported impaired executive function in

patients with major depressive disorder (Elliott 1998;

Murphy et al 2001), with positive correlations with de-

pression severity (Smith 1994) and illness duration

(Borkowska and Rybakowski 2001), and studies have

suggested either no difference (Goldberg et al 1993;

Sweeney et al 2000) or fewer impairments in these

compared with depressed bipolar patients (Borkowska and

Rybakowski 2001; Wolfe et al 1987). Studies have also

demonstrated a persistence of impairments in euthymic

patients with major depressive disorder (Austin et al 2001)

and more severe impairment in these than in euthymic

bipolar patients (Paradiso et al 1997).

Other studies have reported in patients with major

depressive disorder generalized and specific impairments

in the identification of emotional stimuli (Rubinow and

Post 1992), negative emotional biases (Bradley et al 1996;Murphy et al 1999; Williams et al 1996), and negative or

reduced positive attentional biases during facial expres-

sion identification (David and Cutting 1990; Gur et al

1992; Surguladze et al, in press).

Evidence for Structural and FunctionalNeuroanatomic Abnormalities in Regions Importantfor Emotion Processing in Patients with MajorDepressive Disorder

Similar neuropathologic abnormalities have been demon-

strated in patients with major depressive disorder andthose with bipolar disorder. Findings from postmortem

studies have indicated reduced density and number of glial

cells in the amygdala (Bowley et al 2002), the subgenual

anterior cingulate gyrus and orbitofrontal cortex (Cotter et

al 2001; Drevets et al 1998; Ongur et al 1998), and the

dorsolateral prefrontal cortex (Rajkowska et al 1999,

2001), and reduced neuronal cell density in the ventrolat-

eral and dorsolateral prefrontal cortex (Rajkowska et al

1999, 2001), in patients with major depression. Neuro-

pathologic abnormalities have also been reported in these

patients in the entorhinal cortex (Bernstein et al 1998).

Studies employing structural neuroimaging methodshave demonstrated in patients with major depressive

disorder volume reductions in the prefrontal cortex (Cof-

fey et al 1993; Goodwin et al 1997), including the

orbitofrontal cortex (Bremner et al 2002), and the sub-

genual region of the anterior cingulate gyrus (Botteron et

al 2002; Drevets et al 1997), as well as the hippocampus

(Bremner et al 2000; Sheline et al 1999), the putamen

(Husain et al 1991), the caudate nucleus (Krishnan et al

1992), and the amygdala (Sheline et al 1998). Discrepant

findings of no significant volume reductions in the hip-

pocampus and amygdala (Ashtari et al 1999; Pantel et al

1997) and striatal structures (Lenze and Sheline 1999)may be due to differences in medication status of patients,

acquisition paradigms, and image resolution (Sheline

2000).

Studies employing functional neuroimaging techniques

have consistently demonstrated in patients during a major

depressive episode reductions in metabolism and blood

flow within dorsomedial and dorsolateral prefrontal corti-

ces (Baxter et al 1989; Bench et al 1993; Buchsbaum et al

1997; Soares and Mann 1997) but increased metabolism

and blood flow within the ventrolateral prefrontal cortex

(Drevets et al 1992). Reduced ventromedial prefrontal



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cortical activity to feedback on planning and guessing

tasks (Elliot et al 1998) but no functional impairment in

this region during gambling (Rubinsztein et al 2001) have

also been reported. Increased activity within rostral ante-

rior cingulate gyrus and orbitofrontal cortical activity to

negative emotional stimuli during an affective go-no-gotask(Elliot et al 2002), and decreased activity within these

regions (Buchsbaum et al 1997; Drevets et al 1997) has

been demonstrated. Subsequent reports, however, have

demonstrated that if the reduction in subgenual cingulate

gyral volumes in patients with major depressive disorder is

corrected, then the effect is a relative increase rather than

decrease in activity within this region (Drevets 1999,

2000).

Increased blood flow within the amygdala (Drevets et al

1992), thalamus (Drevets et al 1992), and ventral limbic

regions, including the anterior insula and ventral striatum

(Mayberg et al 1999), and a positive correlation betweenamygdalar metabolism and the severity of depressed mood

(Abercrombie et al 1998; Drevets et al 1992) have been

reported in patients with major depressive disorder. Addi-

tionally in these patients, studies have reported to masked

presentation of fearful faces increased activation within

the left amygdala, which then normalizes after treatment

with antidepressant medication (Sheline et al 2001), and

decreased attenuation of the amygdalar response to nega-

tive words (Siegle et al 2002). Interestingly, there are

compatible findings in healthy volunteers during the in-

duction of sad mood of increased regional cerebral blood

flow within the insula and subgenual anterior cingulategyrus, and decreased regional cerebral blood flow within

the dorsomedial prefrontal cortex (Mayberg et al 1999).

Recovery from a major depressive episode after suc-

cessful treatment has been associated predominantly with

increased metabolism and blood flow within dorsomedial

and dorsolateral prefrontal cortices (Baxter et al 1989;

Brody et al 1999; Buchsbaum et al 1997; Kennedy et al

2001; Mayberg et al 1999, 2000) and the dorsal anterior

cingulate gyrus (Kennedy et al 2001). Studies examining

the effect of pharmacologic and interpersonal therapies on

prefrontal activity in patients with major depressive dis-

order have either failed to demonstrate increased prefron-tal blood flow (Martin et al 2001) or have reported

decreased prefrontal metabolism (Brody et al 2001) after

these treatments.

Other changes reported after treatment include reduced

metabolism in the ventral/subgenual cingulate gyrus (Dre-

vets et al 2002; Mayberg et al 1999, 2000) and in other

regions important for the generation of emotional states,

including the thalamus, ventral striatum, and insula (May-

berg et al 1999, 2000; Nobler et al 1994; Smith et al 1999).

Within the hippocampus, increased metabolism has been

associated with 1-week treatment with fluoxetine, whereas

decreased metabolism has been associated with a response

to 6 weeks of treatment with this medication (Mayberg et

al 2000).

There are discrepant findings regarding the role of the

pregenual/rostral anterior cingulate gyrus in major depres-

sion. Although there are reports of increased activity inthis region during depressive episodes (Drevets 1999),

metabolism has been demonstrated to be abnormally

decreased in this region in depressed patients who had

poor responses to treatment (Mayberg et al 1997). Fur-

thermore, although a response to medication at 6 weeks of

treatment with selective serotonin reuptake inhibitor med-

ication is associated with decreased regional cerebral

blood flow in the subgenual anterior cingulate gyrus

(Mayberg et al 1999, 2000), this is also associated with

increased regional cerebral blood flow in the pregenual

anterior cingulate gyrus (rostral region of Brodmann Area

24; Mayberg et al 1999, 2000). Decreased regional cere-bral blood flow within this region has also been demon-

strated in healthy volunteers during the induction of sad

mood (Mayberg et al 1999).

There are also inconsistent findings regarding changes in

activity within the ventrolateral prefrontal cortex on recovery

from a major depressive episode (Brody et al 1999, 2001;

Drevets et al 1992; Nobler et al 1994). It has been

suggested that whereas pharmacologic interventions may

have a direct effect in reducing activity within regions

important for the generation of emotional states, including

the limbic structures described above, resulting in a

relaxation of activity within the ventrolateral prefrontalcortex, nonpharmacologic interventions may serve to in-

crease activity within the ventrolateral prefrontal cortex to

enhance the role of this structure in the regulation of

emotional behavior (Drevets 2000).

Despite some of the inconsistencies in these findings,

taken together they suggest a reciprocal functional rela-

tionship between a ventral neural system, implicated in the

production of both normal and abnormal affective states,

and a dorsal neural system, implicated in the performance

of cognitive tasks and the effortful regulation of affective

states (Mayberg et al 1999). The specific nature of the

roles of the pregenual anterior cingulate gyrus and ventro-lateral prefrontal cortex in the induction of sad mood, as

well as in the generation of and recovery from depression,

requires further clarification.

Conclusion: Is There an Abnormal FunctionalNeuroanatomy Underlying Major DepressiveDisorder?

Findings indicate impaired executive and emotional pro-

cessing in patients with major depression. These impair-

ments appear to be less severe than those observed in

http://-/?-http://-/?-


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bipolar patients and may involve a bias toward the

identification of emotional information as negative or sad.

Studies have demonstrated structural abnormalities, and

predominantly volume reductions, within many of the

regions implicated in emotion processing: within the

amygdala and ventral striatum, important for the identifi-

cation of the emotional significance of stimuli; within the

subgenual cingulate gyrus, important for the production ofaffective states and behavior; and within prefrontal corti-

cal regions and hippocampus, implicated in the effortful

regulation of this behavior. Studies have also demon-

strated in patients during a major depressive episode

increased activity within regions important for the identi-

fication of emotional stimuli and generation of emotional

behavior, including the subgenual cingulate gyrus, ventro-

lateral prefrontal cortex, the amygdala, anterior insula,

ventral striatum, and thalamus, and decreased activity

within regions implicated in the effortful regulation of

emotional behavior, including dorsomedial and dorsolat-

eral prefrontal cortices. This pattern of activity reverses

after recovery from a depressive episode, with increased

activity within dorsomedial and dorsolateral prefrontal

cortices and decreased activity within the subgenual cin-

gulate gyrus, hippocampus, thalamus, ventral striatum,

and insula.

How are these structural and functional neurobiological

abnormalities associated with the symptoms of patients with

major depression? In these patients, volume reductions

within regions such as the amygdala, important for theidentification of the emotional significance of a stimulus and

production of affective states, may result in a restriction of the

range of emotions identifiable and experienced, as in patients

with schizophrenia. In patients with major depression, how-

ever, reports suggest increased rather than decreased function

within these regions during episodes of illness. The combi-

nation of these structural and functional abnormalities may

therefore result in a restricted emotional range, but with a bias

toward the predominant role of the amygdala in the identifi-

cation of negative rather than positive emotions. Thus, rather

than identify and experience a reduced range of emotions


deficits in emotion perception and behavior, and the relationship

between these and the symptoms of bipolar disorder. The color

coding and relative sizes of the figure components of the figure

define features described for Figure 2. Enlarged rather than

decreased amygdalar volumes and enhanced rather than reduced

activity within the ventral system suggest a dysfunctional in-

crease in the sensitivity of this system to identify emotional

significance and produce affective states. Impaired effortful

regulation of subsequent emotional behaviors (reduced size of

the curved arrow representing the regulation of the ventral by the

dorsal system) might result from decreases in prefrontal cortical

volumes and activity within the dorsal system. Specific symp-

toms of both depressed and manic phases of illness in bipolar

disorder, including prominent mood swings, emotional lability,

and distractibility may be associated with these abnormalities.DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial

prefrontal cortex; ACG, anterior cingulate gyrus; VLPFC, ven-

trolateral prefrontal cortex.


deficits in emotion perception and behavior, and the relationship

between these and the symptoms of patients with major depres-sion. The color coding is as in Figure 2. Volume reductions

within the amygdala and other components of the ventral neural

system, together with increased rather than decreased activity

within these regions during illness, may result in a restricted

emotional range, biased toward the predominant role of the

amygdala in the perception of negative rather than positive

emotions. Structural and functional impairments within regions

of the dorsal system, associated with impairments in executive

function and effortful regulation of emotional behavior (reduced

size of the curved arrow representing the regulation of the ventral

by the dorsal system), may perpetuate these phenomena, result-

ing in depressed mood and anhedonia. DLPFC, dorsolateral

prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; ACG,anterior cingulate gyrus; VLPFC, ventrolateral prefrontal cortex.



9/14


10/14

together with a bias toward the identification of all emotion-

ally salient stimuli as threatening, as in patients with schizo-

phrenia, or rather than demonstrate a lowered threshold for

the identification of emotional significance and production of

affective states, as in patients with bipolar disorder, patients

with major depression may experience an increased tendencyto identify stimuli as emotional and experience affective

states, but within a predominantly negative context. This may

then result in the production of depressed mood and anhedo-

nia. The structural and functional impairments in dorsolateral

and dorsomedial prefrontal cortices apparent in these pa-

tients, and associated impairments in executive function and

effortful regulation of affective states and behavior, may then

perpetuate the depressed mood and anhedonia (Figure 4).

A Neuroanatomic Explanation ofAbnormalities in Emotion Perception inSchizophrenia and Affective Disorders

To date, few studies have aimed to examine the nature of

the functional and structural neuroanatomic abnormalities

associated with the presence of symptoms in psychiatric

disorders. In this critical review, we have examined the

evidence for the presence of specific abnormalities in

ventral and dorsal neural systems implicated in emotion

processing in schizophrenia, bipolar disorder, and major

depressive disorder. We have suggested that different

patterns of structural and functional abnormalities, partic-

ularly within the ventral system, exist within these disor-ders and are responsible for the generation of specific

symptoms (Table 1). In particular, we have speculated that

in schizophrenia, the pattern of structural and functional

neural abnormalities in ventral and dorsal systems is

associated with a restriction of the range of positive and

negative emotions identifiable and a misinterpretation of

all emotional stimuli as threatening, which may, in turn,

result in specific negative and positive symptoms charac-

teristic of the disorder, including emotional flattening,

anhedonia, and persecutory delusions, and impaired social

function. In bipolar disorder, we suggest that the pattern of

abnormalities is associated with an oversensitive butdysfunctional neural system for identification of emotional

significance and production of affective states, together

with impaired regulation of subsequent emotional behav-

iors, resulting in prominent mood swings, emotional labil-

ity, and distractibility. In major depressive disorder, we

suggest that the pattern of reduced volume but increased

rather than decreased function within components of the

ventral system during depressed episodes indicates a bias

of this system toward the identification specifically of

negative rather than emotional material per se, resulting in

depressed mood and anhedonia, rather than the restricted

range of affective states observed in schizophrenia or the

emotional lability in bipolar disorder.

Future studies should aim to examine more closely the

effects of different treatments on functional and structural

neuroanatomic abnormalities in these and other psychiat-

ric populations. Studies employing imaging paradigms andmethods of analysis examining more closely functional

relationships between neural regions important for emo-

tion processing, and those combining neuroimaging with

electrophysiologic, neurochemical, and genetic ap-

proaches, will help to clarify further the nature of the

distinguishing neurobiological features of each of these

disorders.

References

Abercrombie HC, Schaefer SM, Larson CL, Oakes TR, Lingren

KA, Holden JE, et al (1998): Metabolic rate in the rightamygdala predicts negative affect in depressed patients.Neuroreport 9:33013307.

Altshuler LL, Bartzokis G, Grieder T, Curran J, Jimenez T,Leight K, et al (2000): An MRI study of temporal lobestructures in men with bipolar disorder or schizophrenia. BiolPsychiatry 48:147162.

Altshuler LL, Bartzokis G, Grieder T, Curran J, Mintz J (1998):Amygdala enlargement in bipolar disorder and hippocampalreduction in schizophrenia: An MRI study demonstratingneuroanatomic specificity. Arch Gen Psychiatry 55:663664.

Andreasen NC, Ehrhardt JC, Swayzee VW, Alliger RJ, Yuh RT,Cohen G, et al (1990): Magnetic resonance imaging the brainin schizophrenia: The pathophysiologic significance of struc-tural abnormalities. Arch Gen Psychiatry 47:3544.

Andreasen NC, OLeary DS, Flaum M, Nopoulos P, WatkinsGL, Boles Ponto LL, et al (1997): Hypofrontality in schizo-phrenia: Distributed dysfunctional circuits in neuroleptic-naive patients. Lancet 349:1730 1734.

Andreasen NC, Paradiso S, OLeary DS (1998): Cognitivedysmetria as an integrative theory of schizophrenia: A dys-function in cortical-subcortical-cerebellar circuitry? Schizo-phr Bull 24:203218.

Ashtari M, Greenwald BS, Kramer-Ginsberg E, Hu J, Wu H,Patel M, et al (1999): Hippocampal/amygdala volumes ingeriatric depression. Psychol Med 29:629 638.

Austin MP, Mitchell P, Goodwin GM (2001): Cognitive deficits

in depression. Possible implicaitons for funcitonal neuropa-thology. Br J Psychiatry 178:200 206.

Aylward EH, Roberts-Twillie JV, Barta PE, Kumar AJ, HarrisGJ, Geer M, et al (1994): Basal ganglia volumes and whitematter hyperintensities in patients with bipolar disorder. Am JPsychiatry 151:687693.

Baxter LR, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH,Selin CE, et al (1989): Reduction of prefrontal cortex glucosemetabolism common to three types of depression. Arch GenPsychiatry 46:243250.

Bearden CE, Hoffman KM, Canon TD (2001): The neuropsy-chology and neuroanatomy of bipolar affective disorder: Acritical review. Bipolar Disord 3:106 150.



11/14

Bell M, Bryson G, Lysaker P (1997): Positive and negative affectrecognition in schizophrenia: A comparison with substanceabuse and normal control subjects. Psychiatr Res 73:7382.

Bench CJ, Friston KJ, Brown RG, Frackowiak RS, Dolan RJ(1993): Regional cerebral blood flow in depression measuredby positron emission tomography: The relationship with

clinical dimensions. Psychol Med 23:579 590.

Benes FM, Berretta S (2000): Amygdalo-entorhinal inputs to thehippocampal formation in relation to schizophrenia. Ann N YAcad Sci 911:293304.

Benes FM, Kwok EW, Vincent SL, Todtenkopf MS (1998): Areduction of nonpyramidal cells in sector CA2 of schizo-phrenics and manic depressives. Biol Psychiatry 44:88 97.

Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL(1991): Deficits in small interneurons in prefrontal andcingulate cortices in schizophrenic and schizoaffective pa-tients. Arch Gen Psychiatry 48:996 1001.

Bernstein HG, Krell D, Baumann B, Danos P, Falkai P, Diek-mann S, et al (1998): Morphometric studies of the entorhinal

cortex in neuropsychiatric patients and control subjects:Clusters of heterotopically displaced lamina II neurons arenot indicative of schizophrenia. Schizophr Res 33:125132.

Bleuler E (1950): Dementia Praecox or the Group of Schizo-phrenias. New York, NY: International University Press.

Blumberg HP, Stern E, Martinez D, Ricketts S, de Asis J, WhiteT, et al (2000): Increased anterior cingulate and caudateactivity in bipolar mania. Biol Psychiatry 48:19451952.

Blumberg HP, Stern E, Ricketts S, Martinez D, de Asis J, WhiteT, et al (1999): Rostral and orbital prefrontal cortex dysfunc-tion in the manic state of bipolar disorder. Am J Psychiatry156:19861988.

Borkowska A, Rybakowski JK (2001): Neuropsychological fron-

tal lobe tests indicate that bipolar depressed patients are moreimpaired than unipolar. Bipolar Disord 3:88 94.

Botteron K, Raichle M, Drevets WC, Heath A, Todd RD (2002):Volumetric reduction in left subgenual prefrontal cortex inearly onset depression. Biol Psychiatry 51:342344.

Bowley MP, Drevets WC, Ongur D, Price JL (2002): Low glialcell numbers in the amygdala in major depressive disorder.Biol Psychiatry 52:404 412.

Bradley BP, Mogg K, Millar N (1996): Implicit memory bias inclinical and non-clinical depression. Behav Res Ther34:865879.

Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL,Charney DS (2000): Hippocampal volume reduction in major

depression. Am J Psychiatry 157:115118.Bremner JD, Vythilingham M, Vermetten E, Nazeer A, Adil J,

Khan S, et al (2002): Reduced volume of orbitofrontal cortexin major depression. Biol Psychiatry 51:273279.

Brody AL, Saxena S, Silverman DH, Alborzian S, Fairbanks LA,Phelps ME, et al (1999): Brain metabolic changes in majordepressive disorder from pre- to post-treatment with parox-etine. Psychiatry Res 91:127139.

Brody AL, Saxena S, Stoessel P, Gillies LA, Fairbanks LA,Alborzian S, et al (2001): Regional brain metabolic changesin patients with major depression treated with either parox-etine or interpersonal therapy: Preliminary findings. Arch GenPsychiatry 58:631640.

Buchsbaum MS, Wu J, DeLisi LE, Holcomb H, Kessler R,Johnson J, et al (1986): Frontal cortex and basal gangliametabolic rates assessed by positron emission tomographywith [18F] 2-deoxyglucose in affective illness. J AffectDisord 10:137152.

Buchsbaum MS, Wu J, Siegel V, Hackett E, Trenary M, Abel L,et al (1997): Effect of sertraline on regional metabolic rate inpatients with affective disorder. Biol Psychiatry 41:1522.

Bulbena A, Berrios GE (1993): Cognitive function in theaffective disorders: A prospecitve study. Psychopathology26:6 12.

Caetano SC, Sassi R, Brambilla P, Harenski K, Nicoletti M,Mallinger AG, et al (2001): MRI study of thalamic volumesin bipolar and unipolar patients and healthy individuals.Psychiatry Res 108:161168.

Carter CS, Perlstein W, Ganguli R, Brar J, Mintun M, Cohen JD(1998): Functional hypofrontality and working memory dys-function in schizophrenia. Am J Psychiatry 155:12851287.

Chance SA, Esiri MM, Crow TJ (2002): Amygdala volume inschizophrenia: Post-mortem study and review of magneticimaging findings. Br J Psychiatry 180:331338.

Clark L, Iversen SD, Goodwin GM (2002): Sustained attentiondeficit in bipolar disorder. Br J Psychiatry 180:313319.

Coffey CE, Wilkinson WE, Weiner RD, Parashos IA, Djang WT,Webb MC, et al (1993): Quantitative cerebral anatomy indepression: A controlled magnetic resonance imaging study.Arch Gen Psychiatry 50:716.

Corcoran R, Cahill C, Frith CD (1997): The appreciation ofvisual jokes in people with schizophrenia: A study of men-talizing ability. Schizophr Res 24:319 327.

Cotter D, Mackay D, Landau S, Kerwin R, Everall I (2001):

Reduced glial cell density and neuronal size in the anteriorcingulate cortex in major depressive disorder. Arch GenPsychiatry 58:545553.

Crespo-Facorro B, Kim J, Andreasen NC, OLeary DS, BockholtHJ, Magnotta V (2000): Insular cortex abnormalities inschizophrenia: A structural magnetic resonance imagingstudy of first-episode patients. Schizophr Res 46:35 43.

Crespo-Facorro B, Paradiso S, Andreasen NC, OLeary DS,Watkins GL, Ponto LLB, et al (2001): Neural mechanisms ofanhedonia in schizophrenia. JAMA 286:427435.

Dasari M, Friedman L, Jesberger J, Stuve TA, Findling RL,Swales TP, et al (1999): A magnetic resonance imaging studyof thalamic area in adolescent patients with either schizophre-nia or bipolar disorder as compared to healthy controls.Psychiatry Res 91:155162.

David AS, Cutting J (1990): Affect, affective disorder andschizophrenia: A neuropsychological investigation of righthemisphere function. Br J Psychiatry 156:491495.

Drevets WC (1999): Prefrontal cortical-amygdalar metabolism inmajor depression. Ann N Y Acad Sci 877:614 637.

Drevets WC (2000): Neuroimaging studies of mood disorders.Biol Psychiatry 48:813829.

Drevets WC, Bogers W, Raichle ME (2002): Functional anatom-ical correlates of antidepressant drug treatment assessed usingPET measures of regional glucose metabolism. Eur Neuro-psychopharmacol 12:527544.



12/14

Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, VannierM, et al (1997): Subgenual prefrontal cortex abnormalities inmood disorders. Nature 386:824827.

Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST,Raichle ME (1992): A functional anatomical study of unipo-lar depression. J Neurosci 12:3268 3641.

Edwards J, Pattison PE, Jackson HJ, Wales RJ (2001): Facialaffect and affective prosody recognition in first-episodeschizophrenia. Schizophr Res 48:235253.

Elliott R (1998): The neuropsychological profile in unipolardepression. Trends Cognit Sci 2:447454.

Elliott R, Rubinsztein JS, Sahakian BJ, Dolan RJ (2002): Theneural basis of mood-congruent processing biases in depres-sion. Arch Gen Psychiatry 59:597604.

Evangeli M, Broks P (2000): Face processing in schizophrenia:Parallels with the effects of amygdala damage. Cognit Neu-ropsychiatry 5:81104.

Falkai P, Bogerts B (1986): Cell loss in the hippocampus ofschizophrenics. Eur Arch Psychiatry Neurol Sci 236:154 161.

Feinberg TE, Rifkin A, Scaffer C, Walker E (1986): Facialdiscrimination and emotional recognition in schizophreniaand affective disorders. Arch Gen Psychiatry 43:276 279.

Flack WF Jr, Cavallaro LA, Laird JD, Miller DR (1997):Accurate encoding and decoding of emotional facial expres-sions in schizophrenia. Psychiatry 60:197210.

Flack WF Jr, Laird JD, Cavallaro LA (1998): Emotional expres-sion and feeling in schizophrenia: Effects of specific expres-sive behaviours on emotional experiences. J Clin Psychol55:120.

Fletcher PC, Frith CD, Grasby PM, Friston KJ, Dolan RJ (1996):Local and distributed effects of apomorphine in fronto-

temporal function in acute unmedicated schizophrenia. J Neu-rosci 16:70557070.

Frith C (1992): The Cognitive Neuropsychology of Schizophre-nia. Hove, UK: Lawrence Erlbaum Associates.

Fudge JL, Powers JM, Haber SN, Caine ED (1998): Consideringthe role of the amygdala in psychotic illness: A clinicopath-ological correlation. J Neuropsychiatry Clin Neurosci10:383394.

Garety PA, Hemsley DR, Wessely S (1991): Reasoning indeluded schizophrenic and paranoid patients. Biases in per-formance on a probablilistic inference task. J Nerv Ment Dis179:194 201.

Goldberg TE, Gold JM, Greenberg R, Griffin S, Schulz SC, Pickar

D, et al (1993): Contrasts between patients with affectivedisorders and patients with schizophrenia on a neuropsycholog-ical test battery. Am J Psychiatry 150:13551362.

Goldman-Rakic PS (1994): Working memory dysfunction inschizophrenia. J Neuropsychiatry Clin Neurosci 6:348 357.

Goldman-Rakic PS, Selemon LD (1997): Functional and ana-tomical aspects of prefrontal pathology in schizophrenia.Schizophr Bull 23:437458.

Goodwin GM, Cavanagh JT, Glabus MF, Kehoe RF, OCarrollRE, Ebmeier KP (1997): Uptake of 99 mTc-exametazimeshown by single photon emission computed tomographybefore and after lithium withdrawal in bipolar patients:Associations with mania. Br J Psychiatry 170:426 430.

Green MF, Kern RS, Robertson MJ, Sergi MJ, Kee KS (2000):Relevance of neurocognitive deficits for functional outcomein schizophrenia. In: Sharma T, Harvey P, editors. Cognitionin Schizophrenia. Oxford: Oxford University Press, 178 192.

Gur RC, Erwin RJ, Gur RE, Zwil AS, Heimberg C, Kraemer HC(1992): Facial emotion discrimination: II. Behavioral findings

in depression. Psychiatry Res 42:241251.

Gur RE, McGrath C, Chan RM, Schroeder L, Turner T, TuretskyBI, et al (2002): An fMRI study of facial emotion processingin patients with schizophrenia. Am J Psychiatry 159:19921999.

Gur RW, Maany V, Mozley D, Swanson C, Bilker W, Gur RC(1998): Subcortical MRI volumes in neuroleptic-naive andtreated patients with schizophrenia. Am J Psychiatry155:17111717.

Gyulai L, Alavi A, Broich K, Reilley J, Ball WB, Whybrow PC(1997): I-123 iofetamine single-photon computed emissiontomography in rapid cycling bipolar disorder: A clinicalstudy. Biol Psychiatry 41:152161.

Harmer CJ, Grayson L, Goodwin GM (2002): Enhanced recog-nition of disgust in bipolar illness. Biol Psychiatry 51:298 304.

Harrison PJ (2002): The neuropathology of primary mooddisorder. Brain 125:14281449.

Harvey I, Persaud R, Ron MA, Baker G, Murray RM (1994):Volumetric MRI measurements in bipolars compared withschizophrenics and healthy controls. Psychol Med 24:689 699.

Haznedar MM, Buchsbaum MS, Luu C, Hazlett EA, Siegel BVJr, Lohr J, et al (1997): Decreased anterior cingulate gyrusmetabolic rate in schizophrenia. Am J Psychiatry 154:682684.

Heckers S (2001): Neuroimaging studies of the hippocampus inschizophrenia. Hippocampus 11:520 528.

Heckers S, Goff D, Schacter DL, Savage CR, Fischman AJ,Alpert NM, et al (1999): Functional imaging of memoryretrieval in deficit vs nondeficit schizophrenia. Arch GenPsychiatry 56:11171123.

Heckers S, Konrad C (2002): Hippocampal neurons in schizo-phrenia. J Neural Transm 109:891905.

Heckers S, Rauch SL, Goff D, Savage CR, Schacter DL,Fischman AJ, et al (1998): Impaired recruitment of thehippocampus during conscious recollection in schizophrenia.Nat Neurosci 1:318 23.

Hirayasu H, Shenton ME, Salisbury DF, Kwon JS, Wible CG,Fischer IA, et al (1999): Subgenual cingulate cortex volume

in first-episode psychosis. Am J Psychiatry 156:10911093.

Husain MM, McDonald WM, Doraiswamy PM, Fliegel GS, NaC, Escalona PR, et al (1991): A magnetic resonance imagingstudy of putamen nuclei in major depression. Psychiatry Res40:9599.

Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH,McCann S, et al (2001): Changes in regional brain glucosemetabolism measured with positron emission tomographyafter paroxetine treatment of major depression. Am J Psychi-atry 158:899 905.

Kerr SL, Neale JM (1993): Emotion perception in schizophrenia:Specific deficit or further evidence of generalized poorperformance? J Abnorm Psychol 102:312318.



13/14

Ketter TA, Kimbrell TA, George MS, Dunn RT, Speer AM,Benson BE, et al (2001): Effects of mood and subtype oncerebral glucose metabolism in treatment-resistant bipolardisorder. Biol Psychiatry 49:97109.

Kline JS, Smith JE, Ellis HC (1992): Paranoid and nonparanoidschizophrenic processing of facially displayed affect. J Psy-

chiatr Res 26:169 182.

Kohler CG, Bilker W, Hagendoorn M, Gur RE, Gur RC (2000):Emotion recognition deficit in schizophrenia: Associationwith symptomatology and cognition. Biol Psychiatry 48:127136.

Konick LC, Friedman L (2001): Meta-analysis of thalamic sizein schizophrenia. Biol Psychiatry 49:28 38.

Kosaka H, Omori M, Murata T, Iidaka T, Yamada H, Okada T,et al (2002): Differential amygdala response during facialrecognition in patients with schizophrenia: An fMRI study.Schizophr Res 57:8795.

Krishnan KR, McDonald WM, Escalona PR, Doraiswamy PM,Na C, Husain MM, et al (1992): Magnetic resonance imaging

of the caudate nuclei in depression. Preliminary observations.Arch Gen Psychiatry 49:553557.

Laasko MP, Tiihonen J, Syvalahti E, Vilkman H, Laakso A,Alakare B, et al (2001): A morphometric MRI study of thehippocampus in first-episode, neuroleptic-naive schizophre-nia. Schizophr Res 50:37.

Lawrie SM, Abukmeil SS (1998): Brain abnormality in schizo-phrenia: A systematic and quantitative review of volumetricmagnetic resonance imaging studies. Br J Psychiatry172:110 120.

Lenze EJ, Sheline YI (1999): Absence of striatal volume differ-ences between depressed subjects with no comorbid medicalillness and matched comparison subjects. Am J Psychiatry156:19891991.

Liddle PF, Friston KJ, Frith CD (1992): Patterns of cerebralblood flow in schizophrenia. Br J Psychiatry 160:179 186.

Liddle PF, Morris DL (1991): Schizophrenia syndromes andfrontal lobe performance. Br J Psychiatry 158:340345.

Lopez-Larson MP, DelBello MP, Zimmerman ME, SchwiersML, Strakowski SM (2002): Regional prefrontal gray andwhite matter abnormalities in bipolar disorder. Biol Psychia-try 52:93100.

Lyon HM, Startup M, Bentall RP (1999): Social cognition andthe manic defense: Attributions, selective attention, andself-schema in bipolar affective disorder. J Abnorm Psychol108:273282.

Manji HK, Moore GJ, Chen G (2000): Clinical and preclinical

evidence for the neurotrophic effects of mood stabilizers:Implications for the pathophysiology and treatment of manic-depressive illness. Biol Psychiatry 48:740 754.

Martin SD, Martin E, Rai SS, Richardson MA, Royall R (2001):Brain blood flow changes in depressed patients treated withinterpersonal psychotherapy or venlafaxine hydrochloride.Arch Gen Psychiatry 58:641648.

Mayberg HS, Brannan SK, Mahurin RK, Jerabek PA, BrickmanJS, Tekell JL, et al (1997): Cingulate function in depression:A potential predictor of treatment response. Neuroreport8:iii.

Mayberg HS, Brannan SK, Tekell JL, Silva A, Mahurin RK,McGinnis S, et al (2000): Regional metabolic effects of

fluoxetine in major depression: Serial changes and relation-ship to clinical response. Biol Psychiatry 48:830 843.

Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK,Jarabek PA, et al (1999): Reciprocal limbic-cortical functionand negative mood: Converging PET findings in depressionand normal sadness. Am J Psychiatry 156:675682.

Medoff DR, Holcomb HH, Lahti AC, Tamminga CA (2001):Probing the human hippocampus using rCBF: Contrasts inschizophrenia. Hippocampus 11:543550.

Mueser KT, Penn DL, Blanchard JJ, Bellack AS (1997): Affectrecognition in schizophrenia: A synthesis of findings acrossthree studies. Psychiatry 60:301308.

Murphy FC, Rubinsztein JS, Michael A, Rogers RD, RobbinsTW, Paykel ES, Sahakian BJ (2001): Decision-making cog-nition in mania and depression. Psychol Med 31:679 693.

Murphy FC, Sahakian BJ, Rubinsztein JS, Michale A, RogersRD, Robbins TW, Paykel ES (1999): Emotional bias andinhibitory control processes in mania and depression. PsycholMed 29:13071321.

Nasrallah HA, Skinner TE, Schmalbrock P, Robitaille PM(1994): Proton magnetic resonance spectroscopy (iH MRS) ofthe hippocampal formation in schizophrenia: A pilot study.Br J Psychiatry 165:481485.

Nelson MD, Saykin AJ, Flashman LA, Riordan HJ (1998):Hippocampal volume reduction in schizophrenia as assessedby magnetic resonance imaging: A meta-analytic study. ArchGen Psychiatry 55:433440.

Nobler MS, Sackeim HA, Prohovnik I, Moeller JR, MukherjeeSSDB, Schnur DB, et al (1994): Regional cerebral blood flowin mood disorders, III. Tretament and clinical response. ArchGen Psychiatry 51:884 897.

OConnell RA, Van Heertum RL, Luck D, Yudd AP, Cueva JE,Billick SB, et al (1995): Single-photon emission computedtomography of the brain in acute mania and schizophrenia.J Neuroimaging 5:101104.

Ongur D, Drevets WC, Price JL (1998): Glial reduction in thesubgenual prefrontal cortex in mood disorders. Proc NatlAcad Sci U S A 95:1329013295.

Pantel J, Schroder J, Essig M, Popp D, Dech H, Knopp MV, etal (1997): Quantitative magnetic resonance imaging in geri-atric depression and primary degenerative dementia. J AffectDisord 42:69 83.

Paradiso S, Lamberty GJ, Garvey MJ, Robinson RG (1997):Cognitive impairment in the euthymic phase of chronicunipolar depression. J Nerv Ment Dis 185:748 754.

Pearlson GD, Marsh L (1999): Structural brain imaging in

schizophrenia: A selective review. Biol Psychiatry 46:627649.

Phillips ML, Drevets WC, Rauch SL, Lane R (2003): Neurobi-ology of emotion perception I: The neural basis of normalemotion perception. Biol Psychiatry 54:504 514.

Phillips ML, Senior C, David AS (2000): Perception of threat inschizophrenics with persecutory delusions: An investigationusing visual scan paths. Psychol Med 30:157167.

Phillips ML, Williams L, Senior C, Bullmore ET, Brammer MJ,Andrew C, et al (1999): A differential neural response tothreatening and non-threatening negative facial expressions inparanoid and non-paranoid schizophrenics. Psychiatry Res92:1131.



14/14

Premack D, Woodruff G (1978): Does the chimpanzee have atheory of mind? Behav Brain Sci 4:515526.

Rajarethinam R, DeQuardo JR, Miedler J, Arndt S, Kirbat R,Brunberg JA, et al (2002): Hippocampus and amygdala inschizophrenia: Assessment of the relationship of neuroanat-omy to psychopathology. Psychiatry Res 108:79 87.

Rajkowska G (2002): Cell pathology in bipolar disorder. BipolarDisord 4:105116.

Rajkowska G, Halaris A, Selemon LD (2001): Reductions inneuronal and glial density characterize the dorsolateral pre-frontal cortex in bipolar disorder. Biol Psychiatry 49:741752.

Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD,Meltzer H, et al (1999): Morphometric evidence for neuronaland glial prefrontal cell pathology in major depression. BiolPsychiatry 48:486 504.

Rajkowska G, Selemon LD, Goldman-Rakic PS (1998): Neuro-nal and glial somal size in the prefrontal cortex: A postmor-tem morphometric study of schizophrenia and Huntington

disease. Arch Gen Psychiatry 55:215224.Rubinow DR, Post RM (1992): Impaired recognition of affect in

facial expression in depressed patients. Biol Psychiatry31:947953.

Rubinsztein JS, Fletcher PC, Rogers RD, Ho LW, Aigbirhio FI,Paykel ES, et al (2001): Decision-making in mania: A PETstudy. Brain 124:25502563.

Sapin LR, Berrettini WH, Nurnberger JI, Rothblat L (1987):Mediational factors underlying cognitive changes and later-ality in affective illness. Biol Psychiatry 22:979 986.

Schneider F, Weiss U, Kessler C, Salloum JB, Posse S, GroddW, et al (1998): Differential amygdala activation in schizo-phrenia during sadness. Schizophr Res 34:133142.

Seidman LJ, Faraone SV, Goldstein JM, Goodman JM, KremenWS, Toomey R, et al (1999): Thalamic and amygdala-hippocampal volume reductions in first-degree relatives ofpatients with schizophrenia: An fMRI-based morphometricanalysis. Biol Psychiatry 46:941954.

Sheline YI (2000): 3D MRI studies of neuroanatomic changes inunipolar major depression: The role of stress and medicalcomorbidity. Biol Psychiatry 48:791800.

Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ,Mintun MA (2001): Increased amygdalar response to maskedemotional faces in depressed subjects resolves with antide-pressant treatment: An fMRI study. Biol Psychiatry 50:651659.

Sheline YI, Gado MH, Price JL (1998): Amygdala core nuclei

volumes are decreased in recurrent major depression. Neuro-report 9:20232028.

Sheline YI, Sanghavi M, Mintun MA, Gado MH (1999): De-pression duration but not age predicts hippocampal volumeloss in medically healthy women with recurrent major depres-sion. J Neurosci 19:5034 5043.

Shenton ME, Kikinis R, Jolesz FA, Pollak SD, LeMay M, WibleCG, et al (1992): Abnormalities in the left temporal lobe andthought disorder in schizophrenia. A quantitative magneticresonance imaging study. N Engl J Med 327:604 612.

Siegle G, Steinhauer SR, Thase ME, Stenger A, Carter CS(2002): Cant shake that feeling: Event-related fMRI assess-ment of sustained amygdala activity in response to emotional

information in depressed individuals. Biol Psychiatry51:693707.

Silfverskiold P, Risberg J (1989): Regional cerebral blood flowin depression and mania. Arch Gen Psychiatry 46:253259.

Smith GS, Reynolds CF, Pollock B, Derbyshire S, Nofzinger E,

Dew MA, et al (1999): Cerebral glucose metabolic responseto combined total sleep deprivation and antidepressant treat-

ment in geriatric depression. Am J Psychiatry 156:683689.

Smith MJ (1994): Experimental evidence for two dimensions ofcognitive disorders in depressives. J Psychiatr Res 28:401411.

Soares JC, Mann JJ (1997): The functional neuroanatomy ofmood disorders. J Psychiatr Res 31:393432.

Strakowski SM, DelBello MP, Sax KW, Zimmerman ME, ShearPK, Hawkins JM, et al (1999): Brain magnetic resonanceimaging of structural abnormalities in bipolar disorder. ArchGen Psychiatry 56:254 260.

Surguladze S, Senior C, Brebien G, Young AW, Travis MJ,Phillips ML (in press): Recognition accuracy and responsebias to happy and sad facial expressions in patients withmajor depression. Neuropsychology.

Sweeney JA, Kmiec JA, Kupfer DJ (2000): Neuropsychologicimpairments in bipolar and unipolar mood disorders on theCANTAB Neurocognitive Battery. Biol Psychiatry 48:674 685.

Taylor SF, Liberzon I, Decker LR, Koeppe RA (2002): Afunctional anatomic study of emotion in schizophrenia.Schizophr Res 5:159 172.

van Gorp WG, Altshuler L, Theberge DC, Wilkins J, Dixon W(1998): Cognitive impairment in euthymic bipolar patientswith and without prior alcohol dependence. A preliminarystudy. Arch Gen Psychiatry 55:4146.

Weinberger DR (1997): On localizing schizophrenic neuropa-thology. Schizophr Bull 23:537540.

Whittaker JF, Deakin JFW, Tomenson B (2001): Face processingin schizophrenia: Defining the deficit. Psychol Med 31:499 507.

Wilder-Willis KE, Sax KE, Rosenberg HL, Fleck DE, Shear PK,Strakowski SM (2001): Persistent attentional dysfunction inremitted bipolar disorder. Bipolar Disord3:58 62.

Williams JMG, Mathews A, Macleod C (1996): The emotionalStroop and psychopathology. Psychol Bull 120:324.

Wright IC, Rabe-Hesketh S, Woodruff PWR, David AS, MurrayRM, Bullmore ET (2000): Regional brain structure in schizo-phrenia: A meta-analysis of volumetric MRI studies. Am J

Psychiatry 157:16 25.Young HF, Bentall R (1995): Hypothesis testing in patients with

persecutory delusions: Comparison with depressed and nor-mal subjects. Br J Clin Psychol 34:353369.

Yurgelun-Todd DA, Gruber SA, Kanayama G, Killgore WD,Baird AA, Young AD (2000): FMRI during affect discrimi-nation in bipolar affective disorder. Bipolar Disord 2:237248.

Zuffante P, Leonard CM, Kuldau JM, Bauer RM, Doty EG,Bilder RM (2001): Working memory deficits in schizophre-nia are not necessarily specific or associated with MRI-based estimates of area 46 volumes. Psychiatry Res108:187209.


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