Self-conscious emotion deficits in frontotemporal lobar

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 Brain

 Volume 129, Number 9

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Brain Advance Access originally published online on July 14, 2006

Brain 2006 129(9):2508-2516; doi:10.1093/brain/awl145

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Self-conscious emotion deficits in frontotemporal

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lobar degeneration

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Virginia E. Sturm

1

, Howard J. Rosen

2

, Stephen

Allison

2

, Bruce L. Miller

2

and Robert W.

Levenson

1

1 Department of Psychology, University of California

Berkeley, CA, USA 2 Department of Neurology,

University of California San Francisco, CA, USA

Correspondence to: Robert W. Levenson, Department of

Psychology, 3210 Tolman Hall, #1650, University of

California, Berkeley, CA 94720-1650, USA E-mail: boblev@berkeley.edu

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Summary

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease associated with dramatic changes in emotion. The precise nature of these changes is not fully understood; however, we believe that the most salient losses relate to self-relevant processing. Thus, FTLD patients exhibit emotional changes that are consistent with a reduction in

Top

Summary

Introduction

Methods

Results

Discussion self-monitoring, self-awareness and the ability to place the self in a social context. In contrast, other more primitive aspects of the emotional system may remain relatively intact. The startle response is a useful way to

Conclusion

References examine the precise nature of emotional deficits in neurological patients.

In addition to a stereotyped defensive response (characterized by negative emotional facial behaviour and physiological activation), in many individuals it also evokes embarrassment, a selfconscious emotional response. Embarrassment seems to occur as the person becomes aware that the reaction to the startle was excessive and was observed by others. Because the self-conscious response depends on certain regions in frontal cortex, we expected that FTLD patients would have specific deficits in their self-conscious response. To test this notion, we examined the response of 30 FTLD patients and 23 cognitively normal controls to a loud, unexpected acoustic startle stimulus (115-dB burst of white noise).

Emotional behaviours were measured along with an assessment of somatic, electrodermal, cardiovascular and respiratory responses.

Results indicated that FTLD patients and controls were similar in terms of physiological responses and negative emotional facial behaviour to the startle, indicating that the defensive aspect of the startle was preserved. However, there were profound differences in the self-conscious response. FTLD patients showed significantly fewer facial signs of embarrassment than controls. This deficit in self-conscious response could not be explained by sex, cognitive status, age, education, medication, or differences in the negative emotional behaviour or physiological response. Thus, the emotional deficit in FTLD patients' response to the startle suggests a reduction in self-consciousness. These findings suggest that the emotional deficit in FTLD may be most profound in higher-order processes akin to those involved in the generation of embarrassment.

These deficits are consistent with neural loss in the medial prefrontal cortex, which may play an important role in the production of self-conscious emotions. Disrupted self-conscious emotions in FTLD patients may have clinical importance because these deficits may underlie some of the socially inappropriate behaviours that are common in these patients.

Key Words: FTLD; autonomic nervous system; emotion; frontal lobe; behaviour

Abbreviations: FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; MMSE, Mini-Mental State Examination; mPFC, medial prefrontal cortex

Received September 17, 2005.

Revised April 23, 2006.

Accepted May 9, 2006.

Introduction

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative

Top disease that selectively affects the anterior portions (i.e.

frontal lobes, temporal lobes and amygdala) of the brain (Neary et al ., 1998 ), regions

Summary

Introduction

Methods that are thought to be important for our navigation of the social and emotional world (Stuss and Levine, 2002 ). FTLD typically has its onset

Results

Discussion in mid-adulthood, is estimated to account for up to 20% of all cases of pre-senile dementia (Miller et al ., 1998 ) and has a prevalence similar to

Conclusion

References that of early-onset Alzheimer's disease (Ratnavalli et al ., 2002 ). The histological features of FTLD are varied (Stevens et al ., 1998 ; McKhann et al ., 2001 ;

Lipton et al ., 2004 ; Davies et al ., 2005 ; Johnson et al ., 2005 ). FTLD is a diagnostic category that includes three clinical subtypes: frontotemporal dementia (FTD), semantic dementia and progressive aphasia (Neary et al ., 1998 ). Although each subtype has a distinct pattern of cognitive, behavioural and emotional symptoms, there is also much overlap in the clinical presentation and neuroanatomical profile.

FTLD ravages social functioning. In other dementias, such as Alzheimer's disease, the initial symptoms involve primarily cognitive processes including memory and visuospatial abilities while social and emotional processes may remain relatively preserved (Swartz et al ., 1997 ; Mendez et al ., 1998 ). In FTLD, in contrast, memory and visuospatial abilities are often relatively spared until even quite late in the disease when patients require nursing home care (Gregory et al ., 1999 ); however, deficits in social behaviour typically are seen throughout the disease progression and can be quite profound (Gregory et al ., 1999 ; Williams et al ., 2005 ). FTLD patients often behave inappropriately and with disregard for social rules (Miller et al ., 1997 ) and have trouble comprehending other people's perspectives (Gregory et al ., 2002 ) and emotions

(Lavenu et al ., 1999 ; Rosen et al ., 2002 ; Rankin et al ., 2005 b ). FTLD patients also have difficulty with self-awareness, showing an inability to recognize even dramatic changes in their own personality (Rankin et al ., 2005 a ) and identity (Miller et al .,

2001 ).

Emotions can be reflex-like and require minimal cognitive processing (e.g. the fear one feels when awakened by an unfamiliar sound at night), or complex, requiring higherorder processing of context, self, others and social rules (e.g. the embarrassment one feels after greeting a colleague by the wrong name at a conference). Although it is well documented that FTLD disrupts emotional functioning, the precise nature of this disruption is not known. Most existing research on emotional functioning in FTLD has focused on a particular emotional process, the ability to identify another person's emotions from photographs (Lavenu et al ., 1999 ; Rosen et al ., 2002 ). Only one previous study from our laboratory by KHW Werner et al . (in review) evaluated the emotional responses of FTLD patients in vivo . This study confirmed that FTLD patients had trouble identifying the emotions being experienced by characters in films, but found that simple emotional reactivity (i.e. self-report, facial and autonomic nervous system responses) to the films remained intact. Thus, these findings suggest that there may be certain areas of emotional functioning that are disrupted in FTLD and others that are preserved.

Self-conscious emotion disruption?

Self-consciousness is thought to be unique to humans and certain great apes (Gallup,

1982 ). Self-conscious emotions (e.g. embarrassment, pride, guilt, shame) probably

evolved to preserve social networks (Parker, 1998 ) by facilitating the reparation of disrupted social bonds (Keltner and Buswell, 1997 ; Tangney, 1999 ). For example, embarrassment occurs as one reflects on the self through the eyes of others in the face of possible negative evaluation (Lewis, 1995 ) and promotes appeasement behaviour in other group members (Keltner and Buswell, 1997 ; Keltner and Anderson, 2000 ). Selfconscious emotions appear relatively late in ontogeny, not emerging until the requisite social cognitive abilities, such as the ability to form mental representations of self, others and social norms have developed (Lewis et al ., 1989 ).

Self-conscious emotions rely on complicated, distributed brain networks. Selfawareness, an integral component of self-conscious emotion, activates medial prefrontal cortex (mPFC) (Kircher et al ., 2000 ; Berthoz et al ., 2002 ; Johnson et al ., 2002 ;

Kelley et al ., 2002 ; Zysset et al ., 2002 ; Fossati et al ., 2004 ; Takahashi et al ., 2004 ;

Ochsner et al ., 2005 ). Self-awareness involves the mPFC during ‘active’ recollection of one's past (Fink et al ., 1996 ; Maddock et al ., 2001 ) as well as during ‘passive’ selfreflection that occurs when the mind is free to wander (Gusnard and Raichle, 2001 ;

Raichle et al ., 2001 ). The mPFC has many reciprocal connections with brain regions that are important for gauging physiological states (Allman et al ., 2001 ) and is thought to play a critical role in linking internal feeling states with environmental contexts

(Bechara et al ., 2000 ). Deficits in self-awareness have been reported in several psychopathological disorders that putatively involve frontal lobe dysfunction including autism (Frith and Frith, 1999 ; Carper and Courchesne, 2000 ; Toichi et al ., 2002 ) and schizophrenia (Pini et al ., 2001 ; Medalia and Lim, 2004 ; Suzuki et al ., 2005 ).

Therefore, neural loss in the frontal lobes caused by neurodegenerative disease may also have deleterious effects on self-awareness and, thus, self-conscious emotions.

Acoustic startle: elicitor of two types of emotional responses

In the present study, we used a single stimulus, the acoustic startle, to examine both negative and self-conscious emotional responding in FTLD patients. Early studies that utilized the acoustic startle administered it at a sufficiently aversive volume so as to produce a defensive, reflexive response (Sokolov, 1963 ). In more recent years, a less noxious version of the startle stimulus (a lower amplitude, repeatedly administered

‘probe’ stimulus) has gained popularity in studies of how emotional states modulate certain aspects of the startle reflex such as the eye-blink (Lang et al ., 1990 ). In the present study, we returned to the older tradition, using a 115-dB aversive acoustic stimulus that is 15 times louder than those typically used in startle probe studies. This enabled us to examine both (i) the negative emotional response, a fairly stereotypical defensive reaction (Ekman et al ., 1985 ) and (ii) the self-conscious response, a reaction that unfolds as one becomes aware of, appraises and reacts to one's defensive response

(Ekman et al ., 1985 ). This appraisal process is somewhat idiosyncratic; some individuals display anger or disgust, but most show self-conscious emotional behaviour

(e.g. embarrassed smiling, nervous laughter; see Fig. 1 for examples).

Fig. 1 Behavioural examples of a control participant's startle response. ( A ) Negative emotional behaviour (e.g. eyes widened, jaw

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[Download PowerPoint slide] dropped, shoulders raised). ( B ) Self-conscious emotional behaviour (e.g. smile suppression, as indexed by lip tightening). (Informed consent for the publication of these images was obtained from the participant.)

The defensive reaction to the startle stimulus is thought to have evolved to protect an organism's physical integrity when faced with a potential threat (Ekman et al ., 1985 ).

This response is phylogenetically old, as evidenced by its existence in quite simple organisms (Kandel, 1997 ), vertebrates (Cohen, 1974 ) and mammals (LeDoux and

Phelps, 2000 ). In humans, the startle response is typically elicited in the laboratory with a loud, aversive noise that occurs without warning. It is characterized by a behavioural display that includes lip stretches, eye closures, neck stretches, shoulder raises, forward lunges, head jerks and torso movements (Ekman et al ., 1985 ). Facial expressions and subjective experience of negative emotions such as fear and surprise are also typical (Roberts et al ., 2004 ). Although neurophysiologists often view the startle response as a reflex, detailed analysis of its timing, duration and behavioural displays reveal that it shares characteristics of emotions as well (Ekman et al ., 1985 ).

The basic startle response has been associated with subcortical brainstem networks. The origin of the startle response is thought to be in the nucleus reticularis pontis caudalis of the brainstem (Davis et al ., 1982 ), a region that relays signals both down the spinal cord via the reticulospinal tract and up to the cortex (Brown et al ., 1991 ; Kofler et al .,

2001 ). Bilateral lesions of this region abolish the reflexive startle response in animals

(Davis et al ., 1982 ). Humans with neurodegenerative diseases that affect the brainstem

(e.g. parkinsonian disorders such as progressive supranuclear palsy) have abnormal startle responses, which may result from interrupted cortical projections to the nuclei of the reticular formation in addition to disturbances in the brainstem (Valldeoriola et al .,

1997 ).

Differences between the brain regions associated with basic aspects of the startle response and the regions associated with self-consciousness (reviewed earlier) open the possibility that in diseases such as FTLD certain aspects of the startle could be disrupted while others could be preserved. Specifically, we predicted that the physiological and negative emotional aspects of the startle response would remain intact in FTLD patients, while the self-conscious aspects would be diminished. Previous startle research with patients has not distinguished between the different aspects of the startle response; however, our reading of these studies suggests that the basic aspects of the startle response remain intact in patients with brain damage in the orbitofrontal cortex (Roberts et al ., 2004 ) and amygdala (Tranel and Hyman, 1990 ; Bechara et al ., 1995 ; LaBar et al ., 1995 ), regions that are also affected in FTLD. In the realm of self-conscious emotional responding, there has been one study showing inappropriate self-conscious emotions in orbitofrontal patients (Beer et al ., 2003 ), but no studies of FTLD patients.

However, semi-structured interviews with informants (e.g. spouses, caregivers) have found a lack of self-conscious emotions (i.e.

embarrassment) to be ubiquitous in FTLD

(Snowden et al ., 2001 ).

These observations, combined with the vulnerability of brain regions thought to be important for self-awareness, led to our hypothesis that the selfconscious aspects of the startle response would be selectively disrupted in FTLD.

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Summary

Introduction

Methods

Results

Discussion

Conclusion

References

Methods

Participants

Thirty patients diagnosed with FTLD and 23 cognitively normal control participants were studied. Patients and controls were extensively evaluated (neurological testing, neuropsychological testing, blood, structural magnetic resonance imaging) at the

University of California, San Francisco Memory and Aging Center.

Brain imaging was done at the San Francisco Veterans' Administration Hospital. All patients met diagnostic criteria (Neary et al ., 1998 ) for FTLD [FTD ( N = 20) or semantic dementia ( N = 10) subtypes].

No controls had a previous history of neurological or psychiatric disorder.

The mean age of the patients was 61.5 years [standard deviation (SD) = 7.3 years], and the mean age of the controls was 66.0 years (SD = 7.9 years). The patient group consisted of 83.3% males, and the control group, 47.8% males. All participants were

European American except for one patient and one control who were Chinese American.

Mean education levels were 16.7 years (SD = 2.4) for the patient group and 17.1 (SD =

2.0) for the control group.

All participants were paid $30 for an 6-h laboratory session.

Clinical descriptions of the participants

Clinical evaluations and neuropsychological testing were completed for FTLD patients and controls in close proximity to the time of emotional assessment (within 3 months for patients, 1 year for controls).

Mini-Mental State Examination (MMSE) . Cognitive abilities were preliminarily assessed with the MMSE (Folstein et al ., 1975 ).

Patients' mean score was 25.4 (SD =

3.8), which places them in the mild range of impairment. Controls scored near ceiling with a mean of 29.7 (SD = 0.5).

Clinical Dementia Rating Scale (CDR) . Caregivers were interviewed in order to obtain a

CDR score for each participant. The CDR requires a semi-structured interview with an

informant to be conducted by a trained evaluator to rate the participant's day-to-day functioning. FTLD patients' scores placed them in the mild range of functional impairment ( M = 0.92, SD = 0.55). Controls were within the normal range ( M = 0.04,

SD = 0.14).

Neuropsychiatric Inventory (NPI) . The NPI is an informant-based scale that assesses the frequency and severity of psychopathological symptoms in dementia patients

(Cummings et al ., 1994 ). Controls were in the normal range on all measures; thus, only data for the FTLD patients ( n = 25) will be reported here. FTLD patients' mean total NPI score was 32.8 (SD = 18.9), which indicates a moderate level of psychopathological symptoms. Approximately half of FTLD patients were reported to exhibit emotional deficits and decreased social interest: 44% of patients were described as lacking affection and emotion, 48% were described as having lost interest in the activities and plans of others, 44% were described as having lost interest in family members or friends and 48% were described as losing their enthusiasm for their usual interests.

Medications . Medications that participants were taking on the day of emotional testing were determined. Those that were thought to have a possible effect on emotional responding [serotonin reuptake inhibitors (SSRIs), tricyclics, miscellaneous antidepressants, monoamine oxidase inhibitors, lithium, anti-psychotics, atypical antipsychotics, acetylcholinesterase inhibitors, glutamate agonists, benzodiazepines, dopamine agonists, barbituates, antiepileptics, psychostimulants, anticholinergics, beta blockers] were tallied.

This revealed that 13% of controls and 83% of patients were on one or more of these medications. The most common type for the FTLD patients was

SSRIs.

Bilateral lobar volumes . Volumes for the frontal, parietal, temporal and occipital lobes were obtained using the BRAINS2 software package (University of Iowa Image

Processing Lab).

BRAINS2 also provides a validated method for automated detection of lobar volumes based on registration of images in standardized space (Magnotta et al .,

2002 ). Lobar volumes were corrected for head size using the total intracranial volume

(brain plus CSF volumes). A comparison of these standardized lobar volumes between

FTLD patients ( N = 27) and controls ( N = 16) revealed that, as expected, FTLD patients had significantly less left frontal [ t (41) = –2.46, P < 0.05], right frontal [ t (41) = –1.87, P

= 0.07], left temporal [ t (40.7) = –1.99, P = 0.053] and right temporal [ t (39.1) = –1.80, P

= 0.08] lobe tissue than controls. There were no differences between FTLD patients and controls in bilateral parietal [right: t (41) = –0.26, ns; left: t (41) = –0.21, ns] or occipital

[right: t (41) = –0.63, ns; left: t (41) = 0.95, ns] tissue volumes. An analysis of FTLD subtypes (18 FTD, 8 semantic dementia) revealed that FTD patients had less right frontal lobe tissue than semantic dementia patients [ t (24) = –2.16, P < 0.05], and semantic dementia patients had less left temporal lobe tissue than FTD patients [ t (24) =

2.44, P < 0.05].

General procedure

Participants were assessed at the University of California, Berkeley. Upon arrival, participants signed consent forms (approved by the Committee for the Protection of

Human Subjects at the University of California, Berkeley) that delineated the experimental tasks (including ‘hearing a loud noise’). For FTLD participants, both patients and caregivers signed the consent forms. An additional consent form regarding the future use of the videotapes was also presented but was not signed until the end of

testing so that all participants would know exactly what had been recorded. Participants completed a health checklist regarding information about their medications, caffeine and alcohol intake, and recent sleep patterns to ensure that they had not taken substances or engaged in activities that would disrupt their normal physiological responses.

Participants were seated in a comfortable chair in a well-lit, 3 x 6 m experiment room where an experimenter attached physiological sensors and briefly oriented them to the procedures.

Experimental task: unanticipated acoustic startle

All stimuli were shown on a 21-in colour television monitor at a distance of 1.75 m from the participant. Participants were told to relax and watch the television screen but were not told what the task would consist of. An ‘X’ appeared on the television screen when the pre-trial baseline began and remained in view for 60 s. After 60 s, the startle stimulus (115-dB, 100-ms burst of white noise, akin to a gunshot) was presented without warning using hidden speakers located directly behind each participant's head.

Measures

Physiological responding

Physiological measures were monitored continuously using a Grass Model 7 polygraph, a computer with analogue-to-digital capability, and an online data acquisition software package written by one of the authors (R.W.L.). The software computed second-bysecond averages for each measure: (i) heart rate (Beckman miniature electrodes with

Redux paste were placed in a bipolar configuration on opposite sides of the participant's chest; the inter-beat interval was calculated as the interval, in milliseconds, between successive R waves), (ii) finger pulse amplitude (a UFI photoplethysmograph recorded the amplitude of blood volume in the finger using a photocell taped to the distal phalange of the index finger of the non-dominant hand), (iii) finger pulse transmission time (the time interval in milliseconds was measured between the R wave of the electrocardiogram (EKG) and the upstroke of the peripheral pulse at the finger site, recorded from the distal phalanx of the index finger of the non-dominant hand), (iv) ear pulse transmission time (a UFI photoplethysmograph attached to the right earlobe recorded the volume of blood in the ear, and the time interval in milliseconds was measured between the R wave of the EKG and the upstroke of peripheral pulse at the ear site), (v) systolic blood pressure (a blood pressure cuff was placed on the distal phalange of the non-dominant hand and continuously recorded the systolic blood pressure using an Ohmeda Finapress 2300), (vi) diastolic blood pressure (a blood pressure cuff was placed on the distal phalange of the non-dominant hand and continuously recorded the diastolic blood pressure), (vii) skin conductance [a constant-voltage device was used to pass a small voltage between Beckman regular electrodes (using an electrolyte of sodium chloride in unibase) attached to the palmar surface of the middle phalanges of the ring and index fingers of the non-dominant hand], (viii) general somatic activity (an electromechanical transducer attached to the platform under the participant's chair generated an electrical signal proportional to the amount of movement in any direction),

(ix) respiration period (a pneumatic bellows was stretched around the thoracic region, and the inter-cycle interval was measured in milliseconds between successive inspirations), (x) respiration depth (the point of the maximum inspiration minus the point of maximum expiration was determined from respiratory tracing), (xi) respiratory sinus arrhythmia (the rhythmic oscillation in heart period that accompanies breathing, which is an index of vagal control of the heart, was measured) and (xii) finger

temperature (a thermistor attached to the distal phalange of the little finger of the nondominant hand recorded temperature in degrees Fahrenheit).

These 12 measures were selected to provide a broad index of the activity of physiological systems important to emotional responding: cardiac, vascular, electrodermal, respiratory and striate muscle.

Facial behaviour

All participants were videotaped continuously with a remotely controlled, highresolution video camera that was partially concealed in the experiment room. Videotape timing was synchronized to the physiological measures using a system that inserted an invisible time-stamp on each video frame. Videotapes were later coded by a team of trained undergraduate coders with a modified version of the Expressive Emotional

Behavior Coding (Gross and Levenson, 1993 ), which is based on the Facial Action

Coding System (Ekman and Friesen, 1978 ). Coders, blind to participant diagnosis and to the nature of the trial, coded each second for nine emotional behaviours (anger, disgust, happiness, contempt, sadness, disgust, embarrassment, fear, surprise) on a 0–3 intensity scale. The code for embarrassment was based on Keltner and Buswell's

(1997) description (i.e. gaze aversion, smiling and laughter, smile suppression, blushing, face-touches). For each participant, a total of 41 s was coded, which included a

20-s pre-startle period, the second in which the startle occurred, and a 20-s post-startle period. Inter-coder reliability was high (intra-class correlation coefficient = 0.76). As noted below, only the coding of the 17-s period starting with the startle was used for the analyses in this paper. This enabled us to examine behaviour during the startle (which lasted 2 s) and immediately after (15 s).

Data reduction

Physiological and behavioural data were analysed during a 17-s period starting with the

1-s period in which the startle occurred and continuing for the next sixteen 1-s periods.

On the basis of our past experience, this time period is adequate to capture the entire startle response including any self-conscious reactions.

Physiological data during the 60 s before the startle were also analysed to enable correction for pre-startle baseline levels.


Physiological reactivity scores were computed for each measure by subtracting the average level for the 60-s pre-startle baseline period from the averaged level during the

17-s startle period.

To provide a single, more reliable measure of overall peripheral physiological responding, a composite score was calculated that comprised all physiological measures. To calculate this composite, standardized scores were computed for each physiological measure and reverse-scored as needed (i.e. cardiac inter-beat interval, finger pulse amplitude, finger pulse transmission time, ear pulse transmission time, respiration period) so that larger values reflected greater physiological arousal.

The standardized scores were then averaged, which resulted in a single physiological reactivity score for each participant.

Facial behaviour

For each emotional facial behaviour, the intensity scores for each occurrence during the

17-s startle period were summed.

A composite score for negative emotional behaviour was computed by summing the scores for fear, surprise, sadness, disgust and anger. The score for the embarrassment code was used to indicate self-conscious emotional responding. Thus, we ended up with two behavioural scores for each participant:

negative emotional behaviour and self-conscious behaviour. An analysis of outliers revealed that there were four instances (all FTLD patients) where scores were >3 SD from the group mean for that score.

These four data points were not included in further analyses.

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Summary

Introduction

Methods

Results

Discussion

Conclusion

References

Results

Because our patient and control groups had different proportions of males and females, we computed 2 (FTLD versus control) x 2 (men versus women) analyses of covariance

(ANCOVA), which enabled us to evaluate main effects of diagnosis and sex, and their interaction. Unless otherwise indicated, in all of our analyses the covariates were age,

MMSE scores and years of education.


We predicted that FTLD patients would have an intact physiological response to the startle. On using 2 (FTLD versus control) x 2 (men versus women) ANCOVA, we found that our results were consistent with this prediction. On using the physiological composite score, we found no differences between the physiological responses of FTLD patients and controls [ F (1, 43) = 0.62, ns].

Moreover, we found no indication of sex differences insofar as both the main effect for sex [ F (1, 43) = 0.87, ns] and the sex x diagnosis interaction [ F (1, 43) = 1.82, ns] were not significant.

Among the covariates, education [ F (1, 45) = 4.23, P < 0.05] and age [ F (1, 45) = 5.78, P < 0.05] both explained significant amounts of the variance in physiological responding with greater education and greater age associated with smaller physiological responses. Although the primary analysis focused on the physiological composite score, an analysis of the individual physiological measures also revealed no differences between FTLD patients and controls. In Table 1 non-standardized group means are presented for each physiological measure.

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Table 1 Group means of physiological responding in individual channels (corrected for pre-startle baseline levels)

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Negative emotional behaviour

We predicted that FTLD patients would show a negative behavioural response to the startle that was similar to that of controls.

On using a 2 (FTLD versus control) x 2 (men versus women) ANCOVA, we found that our results were consistent with this prediction.

On using the negative emotional behavioural composite, we found that there were no differences between FTLD patients and controls [ F (1, 43) = 0.49, ns].

Moreover, we found no significant sex differences; both the main effect of sex [ F (1, 43)

= 3.25, P = 0.08] and the sex x diagnosis interaction [ F (1, 43)= 1.27, ns] were not significant. Analysis of the specific emotion codes revealed no differences in sadness

[ F (1, 44) = 0.13, ns], surprise [ F (1, 44) = 0.00, ns] or disgust [ F (1, 44) = 0.01, ns].

However, controls showed more fear behaviour than FTLD patients [ F (1, 44) = 7.71, P

< 0.01], and FTLD patients showed more anger [ F (1, 44) = 4.29, P < 0.05] than controls.

Self-conscious emotional behaviour

We predicted that FTLD patients would show deficits in self-conscious behaviour compared with controls. On using a non-parametric test of proportions, we found that the 6.7% of FTLD patients who showed a self-conscious response was significantly smaller than the 34.8% of controls who showed this response ( z = 2.2, P < 0.05). Our 2

(FTLD versus control) x 2 (men versus women) ANCOVA was also consistent with this finding, revealing that FTLD patients showed significantly less self-conscious behaviour than controls [ F (1, 43) = 5.41 P < 0.05]. There was no indication of sex differences; both the main effect for sex [ F (1, 43) = 0.03, ns] and the sex x diagnosis interaction

[ F (1, 43) = 0.06, ns] were not significant.

Additional covariates: medications and negative emotions

We conducted several additional analyses to ensure that the deficit in self-conscious emotional behaviour we found in FTLD patients could not be accounted for by other factors.

Many FTLD patients and some of the controls in our sample were taking medications that might have affected their emotional responding; thus, we determined whether medication usage could have explained the found differences between FTLD patients and controls in self-conscious behaviour. We computed a one-way ANCOVA (FTLD versus control) in which the number of relevant medications that were being taken by each participant was used as a covariate. Even after controlling for number of medications, FTLD patients still showed less self-conscious behaviour than controls

[ F (1, 47) = 5.91, P < 0.05].

As noted earlier, there was a difference between FTLD patients and controls in their discrete negative emotional behaviour (FTLD showed less fear and more anger than controls). To ensure that deficits in self-conscious emotion did not result from differences in other aspects of their emotional response, we computed a one-way

ANCOVA (FTLD versus control) using negative emotional behaviour and physiological

response as covariates.

FTLD patients still showed less self-conscious behaviour than controls [ F (1, 45) = 13.43, P < 0.01].

Post hoc analyses of FTLD subtypes

We conducted post hoc analyses to explore whether there were subtype differences

(FTD versus semantic dementia) within our FTLD group. We computed a 2 (FTD versus semantic dementia) x 2 (men versus women) ANCOVA with our original covariates of age, MMSE and years of education. FTD and semantic dementia patients did not differ in their physiological responding [ F (1, 21) = 0.30, ns]; negative emotional behaviour [ F [1, 20] = 1.18, ns]; or self-conscious behaviour [ F (1, 20) = 1.69, ns].

Top

Summary

Introduction

Methods

Results

Discussion

Conclusion

References

Discussion

Emotion encompasses a spectrum of responses ranging from simple to complex.

Although it has been well documented that FTLD is a disease that disrupts emotional functioning, the precise nature of this disruption has not been well documented.

Previous studies of emotional functioning in FTLD patients have primarily assessed the ability to recognize emotions in photographs of facial expressions.

Deficits in selfconscious emotions, arguably an important contributor to the inappropriate social behaviour seen in the clinical syndrome, have not been assessed at all. Thus, the present study is unique in several ways including measuring multiple aspects of emotional responding in vivo in a controlled laboratory setting, assessing multiple indices of emotion (i.e. physiology and behaviour) and evaluating multiple types of emotion (i.e. negative and self-conscious emotions). This study reflects our view that the emotion system has multiple components that are differentially vulnerable to disease processes

(Levenson et al ., 2006 ). In the present study, we expected that the frontal neural loss in

FTLD would produce significant loss in the realm of self-conscious emotions while sparing simple emotional responding.

Our results confirmed these expectations. Using an acoustic startle stimulus that produces both negative emotional and self-conscious emotional response, we found preserved peripheral physiological response and negative emotional behaviour, but diminished self-conscious emotional behavioural in FTLD patients compared with controls.

These findings could not be explained by sex, cognitive status, age, education, medication or differences in the negative emotional behaviour or physiological response.

We believe that the deficit in self-conscious emotional behaviour results from loss of higher-order social cognitive processes that are involved in self-monitoring, viewing oneself from an observer's perspective and evaluating oneself in relation to social standards. Existing research suggests that FTLD patients do have impairments in related realms including (i) inability to self-reflect and to have insight into their personalities

(Eslinger et al ., 2005 ; Rankin et al ., 2005 a ), (ii) difficulty intuiting other people's perspectives (Gregory et al ., 2002 ) and (iii) difficulty recognizing other people's emotions (Lavenu et al ., 1999 ; Rosen et al ., 2002 ; Rankin et al ., 2005 b ).

The nature of the neural loss typically seen in FTLD provides clues for the likely basis of these deficits. The complex social and emotional processing involved in selfconscious emotions probably activates a network of brain regions that integrates relevant information including appraisals of the stimulus (which invoke memories, beliefs and feelings), evaluations of the surrounding environment and modifications of responding based on social rules. Critical to these processes are neural pathways linking higherorder cognitive processes (e.g. mPFC) with those that monitor internal physiological states (e.g. anterior cingulate cortex, anterior insula). Self-conscious emotions such as embarrassment require the ability to process representations of self, others and social rules, which probably engage extensive neural networks including the mPFC, an area that typically incurs significant loss in FTLD. The anterior cingulate (Critchley et al .,

2005 ) and anterior insula (Craig, 2002 ) cortices play important roles in the generation of subjective feeling states and in the integration of cognitive and affective information.

Our finding that FTLD patients' physiological responding to the startle stimulus was intact suggests that efferent brainstem pathways are intact.

However, input regarding this elevated physiological state, which would be critical to self-conscious behaviour, may not be available owing to disease-related losses in afferent pathways involving anterior cingulate and anterior insula.

Some indirect support for this speculation derives from recent findings concerning selfconscious emotional behaviour in patients with a different kind of frontal lobe damage—selective injury to the orbitofrontal cortex. In contrast to our findings with

FTLD patients, orbitofrontal patients express heightened self-conscious emotions (Beer et al ., 2003 ). Orbitofrontal patients typically have intact anterior cingulate and anterior insula cortices, and thus, in keeping with our model, should be able to produce selfconscious emotions. Moreover, the damage to orbitofrontal cortex may damage neural circuits necessary for emotion downregulation, thus resulting in inappropriate levels of self-conscious (and other) emotions.

Although we have been focusing on the loss of self-conscious emotional behaviour in

FTLD patients, our findings that the negative emotional behaviour and physiological aspects of the startle response are intact in these patients are also worthy of comment.

We recently found similar evidence for the preservation of behavioural and physiological responses to emotion-eliciting films in FTLD patients. Thus, it appears that despite significant amounts of neural loss, FTLD patients are still capable of generating emotional responses when confronted with stimuli such as unexpected loud noises and films with simple emotional themes. Thus, the emotional deficits in FTLD may be more specific than originally thought. Whereas some of the evolutionarily ‘older machinery’ of emotion is still functioning properly in FTLD, higher-order emotional processes such as those involved in generating self-conscious emotional behaviour or in detecting the emotions being experienced by others may be significantly impaired.

Clinical implications

Selective deficiency in self-conscious emotions may help elucidate some of the prominent clinical features of FTLD such as inappropriate social behaviour.

Embarrassment is an emotion that normally provides cues that socially unsuitable behaviour has occurred, behaviour should be modified and amends should be made.

Thus, lack of embarrassment in FTLD may be associated with the persistence of inappropriate behaviour, oblivion to social norms, and lack of social reparation. The patients in this study were in the mild-to-moderate range of impairment on most clinical ratings, which suggests that disruption of self-conscious emotion may occur even at early stages of disease progression. This finding is consistent with clinical observations that behavioural disturbances are typically an early marker of this disease.

These findings have implications for the paradoxical role of the self in FTLD. Whereas many FTLD patients become exceedingly self-centred over the course of their illness, their self-awareness decreases (e.g. they are unable to track changes in their personality and behaviour accurately). FTLD patients also have deficits in understanding other people and their emotional reactions.

Thus, they seem to lose acuity in their mental representations of self and others and in their ability to track the self, especially in dynamic social contexts.

Limitations

There were two characteristics of this study that need to be considered in interpreting findings. First, among the various kinds of emotional behaviours we coded, only embarrassment was considered as being self-conscious. Although we consider embarrassment to be the quintessential self-conscious emotion, it could be argued that other emotional behaviours such as happiness also grow out of self-consciousness. We chose not to treat happiness behaviours as self-conscious because of the difficulty of distinguishing between smiles of genuine amusement or relief (which probably would not be self-conscious) and ‘nervous’ smiles (which probably would be self-conscious).

Secondly, we speculated about particular brain areas where neural degeneration might have explained our findings, but could not confirm these with objective measures of tissue loss in these patients. Future work would benefit from quantifying loss in areas thought to be critical for self-conscious emotion such as mPFC, anterior insula and anterior cingulate cortex.

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Summary

Introduction

Methods

Results

Discussion

Conclusion

References

Conclusion

We studied the impact of FTLD on negative emotional behaviour, peripheral physiology and self-conscious emotional behaviour (embarrassment) in response to an aversive acoustic startle stimulus. Results indicated that the effects of FTLD on emotional responding may be more selective than commonly thought. Negative emotional behaviour and physiological responding to the startle stimulus were similar in FTLD patients and controls; however, FTLD patients showed much less self-conscious emotional behaviour.

These findings suggest that simple emotional responding is preserved in FTLD patients, probably reflecting the fact that the disease spares brainstem regions critical for generating these responses.

However, self-conscious emotions require higher-order social cognitive operations that utilize neural circuitry in regions of frontal cortex that are damaged in FTLD.

Acknowledgements

Grants were received from the National Institute on Aging AG107766 [GenBank] ,

AG19724, AG-03-006-01, AG019724 [GenBank] -02; National Institute of Mental

Health MH020006; and the State of California Alzheimer's Disease Research Center of

California 03-75271.

Top

Summary

Introduction

Methods

Results

Discussion

Conclusion

References

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Annals of the New York Academy of Sciences 935:107-117 (2001)

© 2001 New York Academy of Sciences

The Anterior Cingulate Cortex

The Evolution of an Interface between Emotion and Cognition

John M. Allman a , Atiya Hakeem a , Joseph M. Erwin b , Esther Nimchinsky c AND Patrick Hof d a

Division of Biology, California Institute of Technology, Pasadena, California 91125, USA b

Division of Neurobiology, Behavior, and Genetics, Bioqual, Rockville, Maryland 20850, USA c

Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA d

Neurobiology of Aging Laboratories, Mount Sinai School of Medicine, New York, New York 10029, USA

Address for correspondence: John M. Allman, Ph.D., Frank P. Hixon Professor of Neurobiology, California Institute of Technology, 1200 E. California Blvd., Pasadena, CA

91125. Voice: 626-395-6808; fax: 626-441-0679.

cebus@caltech.edu

ABSTRACT

We propose that the anterior cingulate cortex is a specialization of neocortex rather than a more primitive stage of cortical evolution. Functions central to intelligent behavior, that is, emotional self-control, focused problem solving, error recognition, and adaptive response to changing conditions, are juxtaposed

Evidence of an important with the emotions in this structure. role for the anterior cingulate cortex in these functions has accumulated through singleneuron recording, electrical stimulation, EEG, PET, fMRI, and lesion studies. The anterior cingulate cortex contains a class of spindle-shaped neurons that are found only in humans and the great apes, and thus are a recent evolutionary specialization probably related to these functions. The spindle cells appear to be widely connected with diverse parts of the brain and may have a role in the coordination that would be essential in developing the capacity to focus on difficult problems.

Furthermore, they emerge postnatally and their survival may be enhanced or reduced by environmental conditions of enrichment or stress, thus potentially influencing adult competence or dysfunction in emotional self-control and problem-solving capacity.

Key Words: Anteri or cingulate cortex • Cognition • Emotion • Problem solving • Self control • Spindle cells • Brain evolution

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ABSTRACT

SPINDLE CELLS

EVIDENCE FROM FUNCTIONAL

STUDIES

EVIDENCE FROM LESION STUDIES

ANTERIOR CINGULATE CORTEX AND...

SUMMARY AND SPECULATIONS

ACKNOWLEDGMENTS

REFERENCES

In 1878, Broca described le grand lobe limbique as a broad band of brain tissue wrapping around the corpus callosum and including parts of the ventral forebrain.

1

This is the source of the modern term limbic , which is used to describe this collection of brain structures; it is derived from the Latin word limbus , which means border, but which could also be taken to mean an interface.

Broca believed that the great limbic lobe was primarily involved in olfaction, which led to the term rhinencephalon 's being attached to this assortment of structures; however, modern studies indicate that olfactory functions are restricted to only a small portion of the ventral part of the limbic lobe.

The dorsal part of Broca's great limbic lobe is the cingulate cortex, so named because it forms a cingulum or collar around the corpus callosum. In 1937, Papez wrote: "The cortex of the cingular gyrus may be looked on as the receptive organ for the experiencing of emotion as the result of impulses coming from the hypothalamic region, in the same way as the area striata is considered the receptive cortex for photic excitations from the retina."

2

Papez also noted that tumors pressing on the cingulate cortex produced "loss of spontaneity in emotion, thought and activity." 2 Thus, Papez made an analogy between the neural pathway proceeding from the retina to the thalamus to the area striata (V1), and the pathway from the neuroendocrine centers of the hypothalamus to the thalamus to cingulate cortex. He believed that both circuits were phylogenetically ancient and evolved in parallel during the course of vertebrate evolution.

In 1945, Smith studied the cingulate cortex of macaque monkeys and found that electrical stimulation of the anterior portion corresponding to Brodmann's area 24 elicited changes in heart rate, blood pressure, and respiration as well as vocalizations and facial expressions.

3

He noted: "vocalization may occur alone, but in its fully developed form it is part of what appears to be a complex reaction characterized by opening of the eyes, dilatation of the pupils, and vocalization. Movements of the facial muscles, usually bilaterally, often accompany the vocalization, during which the lips may be protruded and rounded, or retracted, such as occurs in the ordinary life of the animal. The sounds emitted run nearly the whole gamut which the monkey is capable of producing. While the low-pitched guttural sound is the one most frequently obtained, it gives place at times to higher pitched cooing sounds, at other times to cries, soft and plaintive such as the animal makes at feeding time."

3

In a long series of publications beginning in 1949, MacLean devloped a concept of vertebrate brain evolution that he termed "the triune brain." 4 Central to his concept is the idea that the mammalian brain evolved in a series of concentric shells around an ancient reptilean core. The innermost of these shells he termed "paleomammalian," and it included the cingulate cortex.

He distinguished this from the outer shell, which he termed "neomammalian" and which comprised the neocortex. Sanides developed a related scheme for brain evolution in which he suggested that the cingulate cortex had a more primitive laminar structure than neocortex and preceded it in evolution.

5

Comparative studies of the genetic regulation of the development of the forebrain in amphibians, reptiles, birds, and mammals have done much to elucidate the evolution of this part of the brain.

6

These studies indicate that the mammalian cortex is homologous with the dorsal part of the forebrain in reptiles and amphibians and thus was a specialization derived from this area in the ancestors of mammals. This specialization involved the segregation of the cortex into layers with distinct inputs and outputs.

7

Anterior cingulate cortex is distinct from much of neocortex in lacking layer 4, which is one of several layers receiving thalamic input. It also has a particularly well-developed layer 5, which contains outputs to subcortical structures. However anterior cingulate is similar in these laminar specializations to the motor areas of the neocortex, which lie adjacent to anterior cingulate cortex. Thus, rather than being evidence that the cingulate cortex is more primitive than neocortex, these features indicate an affinity with the adjacent neocortical motor areas.

These data, together with the comparative and functional findings to be reviewed subsequently, suggest that the anterior cingulate cortex is a specialized area of neocortex devoted to the regulation of emotional and cognitive behavior.

SPINDLE CELLS

In humans, layer 5b of Brodmann's area 24 of the anterior cingulate cortex contains a distinctive class of large spindle-shaped neurons.

8 They differ from the ordinarily pyramidal neurons of layer 5 in lacking an array of basal dendrites radiating dendrite extending into layer 5 and instead have a single large basal dendrite (Fig. 1) . The presence of a single apical upward and a single basal dendrite extending downward creates the characteristic spindle shape.

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ABSTRACT

SPINDLE CELLS


The average volume of the cell body of a spindle cell is four times larger than that of the average pyramidal cell of layer 5.

9

Injections of retrograde tracers into the cingulum fiber bundle indicate that the spindle distance projections, but their exact connections neurons have longremain to be discovered. Recently, we have discovered that the spindle cells are present only in humans and our closest relatives, the great apes.

9 The concentration of spindle cells

STUDIES



is greatest in humans and declines with increasing taxonomic distance from more than gorillas, which humans.

9 , 10

Thus chimpanzees have have more than orangutans. We were unable to find any evidence of spindle cells after a careful search in 23 other species of primates and 30 nonprimate species.

9 Spindle cells probably originated in the


ACKNOWLEDGMENTS

REFERENCES common ancestor of humans and great apes, ago.

11 , 12 which would have been a dyropithecine ape living about 15 million

We have also found that the average volume of years the cell bodies of the spindle cells varies as a function of relative brain size (encephalization) across humans and great apes (Fig. 2) . This is not the case for the pyramidal neurons in layer 5 or the fusiform cells in layer 6 of anterior cingulate cortex. Because cell body size is probably related to the size encephalization.

of the axonal arborization, the axonal arborizations of the

This observation suggests that the spindle cells may have widespread spindle cells may be extensive and on a scale with connections with other parts of the brain. Recently, one of us (JMA) has studied the ontogenetic development of the spindle cells in humans by examining brains of different ages in the Yakovlev Brain Collection at the National

Museum of Health and Medicine. The spindle cells cannot be discerned at birth and first appear at four months of age. It is conceivable that the spindle cells are present at birth but have not yet differentiated into their characteristic bipolar shape. Some of the spindle cells in four- to eight-month-old infants bear the features of migratory neurons; they are elongated, densely staining, and have undulating leading and trailing processes (see Fig. 3 ).

13 15 The emergence of the spindle cells in four-month-old human infants coincides with the infant's capacity to hold its head steady, smile spontaneously, track an object visually, and reach

for that object.

16

The spindle cells may participate expression.

in the neural circuitry responsible for these functions, which are related to focused attention and emotional

FIGURE 1.

A pair of spindle cells in human anterior cingulate cortex.


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FIGURE 2. Whole brain volume residual versus cell volume from three different brain areas, for humans, bonobos, common chimpanzees, gorillas, and orangutans.

Brain volume residuals were computed by subtracting the average brain volume for a given species from the expected brain volume for that species given its body weight, as determined by a linear regression. Residual values were added to one, to make all values positive. ( A ) Brain volume residual is well correlated with spindle cell volume. Brain volume residual is not significantly correlated with the volume of either ( B ) fusiform cells or ( C ) pyramidal cells. Hs = Homo sapiens ; P. trog = Pan troglodytes , common chimpanzee; P. pan =

Pan paniscus , bonobo; Gorilla = Gorilla gorilla ; Pongo = Pongo pygmaeus , orangutan.


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FIGURE 3. Three possible migratory spindle cells in the anterior cingulate cortex of a 7month-old human infant.

The photomicrograph on the left depicts these cells in a single optical plane. In the photomicrograph on the right, the three spindle cells have been encoded in black on the basis of their appearance in multiple optical planes. Note the undulations in the apical and basal dendrites. This morphology persists into adulthood in some spindle cells and led von Economo 55 to describe these neurons as the "corkscrew cells." The scale bars in the upper left corners of each photomicrograph correspond to 15 µm.


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EVIDENCE FROM FUNCTIONAL STUDIES

The spindle cells are a hominoid specialization of the neural spindle circuitry of anterior cingulate cortex. How might the cells contribute to the functioning of anterior cingulate cortex in hominoids? In humans the anterior cingulate receives one of the richest dopaminergic innervations of any cortical area.

17 Although the spindle cells are not present in monkeys, data from monkeys are relevant to understanding the basic functions of anterior cingulate cortex in primates. These data show that the source of cortical dopaminergic input comes from cell bodies located in the ventral midbrain, which in behaving monkeys respond when the animal receives a reward or a reward-associated signal.

18

These dopaminergic neurons pause in their firing when an expected reward is not received. There is also direct evidence from humans that the dopaminergic projection to anterior cingulate cortex is reward-related. This finding comes from an ingenious experiment in which blood flow in anterior cingulate cortex was monitored with positron emission tomography (PET) in normal subjects and in patients with Parkinson's disease. Parkinson's disease destroys the dopaminergic neurons in the ventral midbrain. The subjects and patients performed delayed-response tasks under

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baseline conditions with and without monetary rewards. When the normal subjects received monetary rewards, the anterior cingulate cortex was activated, but this activation was completely absent in the Parkinson's patients, implying that the lack of dopaminergic input resulted in the loss of reward-related activity.

19 The anterior cingulate cortex also receives a strong projection from the amygdala, which probably relays negative, fear-related, information.

20 , 21

Some neurons in anterior cingulate cortex respond when the monkey receives a reward after performing a serial motor task.

21 About 8% respond when the monkey recognizes that it has made an error in the performance of the task.

22 Shima and Tanji trained monkeys to perform two tasks: pushing or turning a handle.

23 They then differentially varied the reward given for performing each of these tasks. The monkeys responded to decreasing reward by switching their activity to the other motor task, that is, from pushing to turning or vice versa, thus optimizing their receipt of reward. In about a third of their sample of cells recorded from anterior cingulate cortex, Shima and Tanji found neurons that responded to decreasing reward in which the monkeys failed to respond to the but not to continuous levels of reward. They also found, on the occasions reduced reward by changing their behavior, that this type of neuron also failed to respond. They then injected in anterior cingulate cortex small amounts of the powerful GABA agonist, muscimol, which temporarily silences cortical activity. The monkeys to fail to respond to changing reward. These elegant experiments indicate that anterior behavior so as to optimize payoff.

muscimol injections caused the cingulate cortex monitors performance and reward and adjusts

There is a remarkable counterpart to these monkey experiments in electroencephalographic (EEG) recordings made from scalp electrodes in humans. A large body of EEG data indicates that the anterior cingulate is the source of a 4- to 7-

Hertz signal present when the subject is performing a task requiring focused concentration.

24

The amplitude of this signal increases with task difficulty.

25

When the subject is restless and anxious, the signal is reduced or eliminated; when the anxiety is relieved with drugs, the signal is restored.

26 , 27

These findings suggest that one dimension in the functioning of anterior cingulate cortex varies between the poles of restless anxiety and focused problem solving. This is consistent with the common experience that focusing on a problem relieves anxiety. There is also evidence that, when the subject is aware of having made an error, there is a negative deflection in one cycle of this oscillation. This phenomenon has been referred to as "error-related negativity" and it arises from anterior cingulate cortex.

28 30

There is also a substantial body of data for anterior cingulate cortex from functional imaging studies in humans. In one of the earliest studies of cognitive function using positron emission tomography (PET), Petersen and his colleagues found that the anterior cingulate cortex was active when subjects generated word associations.

31

This activation is linked to focused mental effort. When the subjects are highly practiced and the performance of these word-generation tasks become nearly automatic, the anterior cingulate activation is no longer present.

32

A meta-analysis of over 100 PET investigations revealed that just as with the amplitude of the 4- to 7-Hertz signal, the activity of anterior cingulate cortex increased with task difficulty.

33

Strong evidence exists that the dorsal part of the anterior cingulate cortex is related to cognition, whereas the ventral part is more related to emotion.

34

This functional specialization is revealed by the sites activated during different Stroop tasks in functional magnetic resonance imaging (fMRI). Stroop tasks require the subject to respond in the presence of conflicting or confounding information. In the "counting

Stroop" the subject is asked to report the number of words present on a screen.

For example, in the cognitive version, the words are numbers such as "three" written four times; in the emotional version, the words are emotionally charged, such as "murder" written four times. The "counting Stroop" activates the dorsal part of the anterior cingulate cortex, whereas the "emotional Stroop" activates the ventral part. A large number of investigations are using different versions of the cognitive Stroop or other tasks involving conflicting information which activate the dorsal part of the anterior cingulate cortex. In PET studies, when normal subjects are asked to imagine angry or sad situations, the ventral part is activated.

35 , 36

When phobic, obsessive-compulsive and posttraumatic stress syndrome patients are presented with stimuli that trigger their symptoms, the ventral part is also activated.

37 40 In depressed patients with a parent or sibling who was also depressed, both the physical size and the metabolic activity of the ventral part of anterior cingulate cortex were reduced.

41

Although the centers of activation or deactivation are largely separated in the dorsal and ventral anterior

cingulate cortex, the total activity zones overlap, and the dorsal and ventral parts are probably anatomically interconnected. The functional distinction within anterior cingulate is also revealed by electrical stimulation in conscious patients. For example, stimulation of the ventral part produced intense fear or pleasure, whereas the more dorsal part produced a sense of anticipation of movement.

42 , 43

EVIDENCE FROM LESION STUDIES

Damasio and Van Hoesen have studied a series of stroke patients with large lesions of anterior cingulate cortex.

44

Immediately following the stroke, such patients lie in their hospital beds saying or doing little. Damasio and Van

Hoesen described one left anterior cingulate stroke patient one month after her stroke: recovered. She had considerable

"The patient was remarkably insight into the acute period of the illness and was able to give precious testimony as to her experiences then. Asked if she had ever experienced anguish for being apparently unable answered negatively. She didn't talk because to communicate she she had nothing to say. Her mind was empty. She apparently was able to follow our conversations even during the early period of the illness, but felt no will to reply to our questions." 44

Recently Cohen and his colleagues have studied a series of 18 patients who suffered from intractable pain and were treated with small bilateral lesions, 5 mm in diameter, in the anterior cingulate cortex.

45

More than a year after the surgery they studied the behavior of these patients in comparison with a control group of chronic pain patients who

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The lesioned patients showed reduced levels of spontaneous behavior.

They produced fewer verbal utterances during interviews than controls. In a written task, they also produced shorter statements.

When asked to make objects from Tinker Toys, they produced fewer and simpler objects. Thus, the spontaneity of their behavior was reduced over the long term by these small lesions of the anterior cingulate.

ANTERIOR CINGULATE CORTEX AND SELF-CONTROL

Posner and Rothbart have proposed that the anterior cingulate the individual progresses from infancy to childhood to adulthood.

cortex is involved in the maturation of self-control as

46

In the classic condition of lack of self-control, attention deficit hyperactivity disorder (ADHD), the normal response to anterior cingulate cortex.

47 the "counting Stroop" task is absent from

There is also evidence of increased functioning in anterior cingulate cortex in individuals

SUMMARY AND SPECULATIONS

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ABSTRACT with greater social insight and maturity. Lane and colleagues found that the activity of the anterior cingulate cortex was greater in subjects who had higher levels of social awareness based on objectively scored tests.

48 In these tests the subjects wrote about how they would perceive a particular social situation and how they would imagine one of the participants to perceive that same situation. The discrimination of affect in faces, which contributes to social awareness, also selectively activated anterior cingulate cortex.

49

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In conclusion, we propose that the anterior cingulate cortex is a specialization of neocortex rather than a more primitive stage of cortical evolution. The evidence from single-neuron well as focused recording, electrical stimulation, EEG, PET, fMRI, and lesion studies indicates that the anterior cingulate cortex has an important role in emotional self-control as problem-solving, error recognition, and adaptive response to changing conditions. These functions are central to intelligent behavior. They are juxtaposed in this structure and probably spindle cells are a novel specialization of the neural circuitry of anterior cingulate are intimately interconnected. The cortex that arose about 15 million years ago in an ancestor of great apes and humans.

9 This new circuitry probably augmented emotional self-control and focused problem-solving behavior in these animals and their descendants. Specifically, the spindle cells may possess widespread connections with other parts of the brain and may serve to coordinate the activity of these diverse parts to achieve self-control and the capacity to focus on difficult problems. The spindle cells appear to emerge postnatally and their development may be particularly influenced by environmental factors. This possibility is

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enrichment;

50 53

The survival of postnatally originating neurons in the dentate by contrast, stress diminishes the production of these neurons.

50 , 51 gyrus of the hippocampus is enhanced by environmental

The survival of postnatally originating neurons in the olfactory bulb is dependent on olfactory stimulation and the presence of brain-derived neurotrophic factor (BDNF), which is enhanced by maternal care in the hippocampus of rat pups.

52 54

Thus it is conceivable that environmental stimulation, stress, and the quality of parental care might also affect the survival and development of the spindle cells during infancy, thus influencing adult competence or dysfunction in emotional self-control and problem-solving capacity.

ACKNOWLEDGMENTS

This work was supported by National Intitues of Health Grants thank Karli Watson,

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AG14308 and EY11759 and the Hixon Fund. We comments on the manuscript assistance in using the Yakovlev Brain Collection at the National Museum of Health

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Self-conscious emotion deficits in frontotemporal lobar

Self-conscious emotion deficits in frontotemporal

lobar degeneration

Summary

Introduction

Methods

Results

Discussion

Conclusion

Acknowledgements

References

The Evolution of an Interface between Emotion and Cognition

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Self-conscious emotion deficits in frontotemporal lobar