Emotional Response in Patients With Frontal Brain Damage: Effects of Affective Valence and Information Content

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1 Behavioral Neuroscience Copyright 2005 by the American Psychological Association 2005, Vol. 119, No. 1, /05/$12.00 DOI: / Emotional Response in Patients With Frontal Brain Damage: Effects of Affective Valence and Information Content J. P. Sánchez-Navarro, J. M. Martínez-Selva, and F. Román Universidad de Murcia The authors investigated the role of the frontal lobes in the emotional response in 19 patients with brain damage and 23 control subjects. They studied the modulation of the startle blink reflex by affective pictures, and other autonomic responses. Patients showed a dissociation between the startle reflex and the affective valence ratings of the pictures, as a result of a low inhibition of the startle reflex by pleasant pictures. Pictures elicited lower skin conductance responses (SCRs) in patients than in controls, whereas the groups did not differ in the SCRs prompted by less significant acoustic stimuli. The findings point to the frontal lobe as a structure involved in the emotional response and in the physiological emotional arousal related to the complexity of the stimuli. J. P. Sánchez-Navarro, J. M. Martínez-Selva, and F. Román, Departamento de Anatomía Humana y Psicobiología, Facultad de Psicología, Universidad de Murcia, Murcia, Spain. J. P. Sánchez-Navarro was supported by a research fellowship of the Formación del Personal Investigador program granted by the Universidad de Murcia. Correspondence concerning this article should be addressed to J. P. Sánchez-Navarro, Departamento de Anatomía Humana y Psicobiología, Facultad de Psicología, Campus de Espinardo, Universidad de Murcia, 30100, Murcia, Spain. jpedro@um.es The aim of this research was to assess the role of the frontal lobe in the emotional response in patients with multifocal brain damage that included the frontal lobes. We used the affective modulation of the startle blink reflex developed by Lang and coworkers (e.g., Bradley, Cuthbert, & Lang, 1990; Vrana, Spence, & Lang, 1988) together with the recording of autonomic responses and the subjective assessment of affective stimuli. The frontal cortex is an important region of the circuitry related to emotion (Damasio, 1998; Damasio & Van Hoesen, 1984; Davidson, 2003; Davidson & Irwin, 1999; Davidson, Jackson, & Kalin, 2000; Phillips, Drevets, Rauch, & Lane, 2003). It seems that orbital and medial prefrontal structures are more involved in emotion than are dorsal lateral areas (Barbas, 2000; LeDoux, 1987; Phillips et al., 2003; Rolls, 1986; Yamasaki, LaBar, & McCarthy, 2002). Several studies that used functional neuroimaging techniques while subjects viewed emotional pictures have found that the prefrontal cortex is activated by emotional stimuli, but independently of their emotional valence (Lane, Reiman, Ahern, Schwartz, & Davidson, 1997; Lane, Reiman, Bradley, et al., 1997; Reiman et al., 1997; Teasdale et al., 1999). Other researchers have also suggested that the prefrontal cortex might be involved mainly in the processing of pleasant positive stimuli (Lane, Reiman, Bradley, et al., 1997; Paradiso et al., 1999). A direct association has also been established between frontal lobe and emotion from studies of brain-damaged subjects (Stuss & Benson, 1984; Stuss, Gow, & Hetherington, 1992). The lesion of the frontal lobe results in several emotional disturbances such as disinhibition, apathy, or akynetic behavior, depending on the localization of the lesion (Chow & Cummings, 1999; Cummings, 1985; Phillips et al., 2003). Damage to the orbitofrontal cortex results in a syndrome characterized by an inability to experience pleasant stimulation, especially when rewards are social or intellectual, and by disinhibition, impulsiveness, emotional incontinence, and irritability (Blumer & Benson, 1975; Chow & Cummings, 1999; Damasio, 1994; Damasio & Van Hoesen, 1984; Hecaen & Albert, 1978). In turn, damage to the dorsolateral areas of the frontal lobe gives rise to apathy and indifference symptoms; loss of impulse, interest, and motivation; a disrupting behavioral change; and poor organization and memory-searching strategies (Blumer & Benson, 1975; Chow & Cummings, 1999; Stuss et al., 1992). Several studies have also found that bilateral ventromedial lesions produce an alteration in the ability to anticipate future consequences, both positive and negative, of behavior (Bechara, Damasio, Damasio, & Anderson, 1994; Bechara, Damasio, Damasio, & Lee, 1999; Bechara, Damasio, Tranel, & Damasio, 1997; Bechara, Tranel, Damasio, & Damasio, 1996). Overall, Phillips et al. (2003) have pointed out that damage to the ventral, dorsal, or both regions of the frontal lobe leads to alterations of emotion. Different researchers have studied emotion in brain-damaged subjects by means of autonomic recordings and subjective assessments. Meadows and Kaplan (1994) studied the skin conductance response (SCR) and heart rate (HR) elicited by unpleasant and neutral pictures, as well as the subjective ratings of the pictures, in patients who showed either left or right brain damage and, in some cases, had lesions not located in the frontal lobes. Their results indicate that patients, particularly those with right brain damage, do not show larger SCRs to unpleasant pictures than to neutral ones, unlike those of the control group. However, patients and control subjects did not differ in the skin conductance orienting response elicited by loud tones, in the habituation level of the SCRs, basal level of skin conductance, basal HR, or HR deceleration elicited by the pictures where unpleasant pictures prompted a greater HR deceleration than neutral ones. Neither did the groups differ in their ratings of the affective valence and arousal of the pictures. These data point to a dissociation between the cognitive and the autonomic components of the emotional response. The 87

2 88 SÁNCHEZ-NAVARRO, MARTÍNEZ-SELVA, AND ROMÁN authors concluded that their data indicated an inability of the patients to show a normal physiological arousal elicited by emotional stimuli, which is cortically mediated and is different from the autonomic arousal associated with the orienting response. In this line, Zahn, Grafman, and Tranel (1999) also found that frontal lobe-damaged patients did not differ from a healthy control group in the magnitude and frequency of the skin conductance orienting responses elicited by pure tones or in skin conductance level (SCL) obtained during a rest period. However, they found that patients with right-sided and bilateral lesions in the cingulate gyrus showed low SCRs to all emotional pictures. In addition, each of the lesion subgroups (left, right, and bilateral) showed lower responses to gruesome pictures than to sexual pictures. These authors concluded that the lower SCRs shown by frontal patients are related to an impairment of the psychological response when patients have to carry out an effortful processing of stimuli with complex or significant content. However, these authors did not include the subjective ratings of the pictures made by the subjects, making it impossible to check whether the patients showed a dissociation between the SCRs and cognitive components of the emotion, as Meadows and Kaplan (1994) had found. In recent years, a considerable amount of research has shown that the startle blink reflex is a sensitive measure of emotion (Bradley, Codispoti, Cuthbert, & Lang, 2001; Lang, 1995; Lang, Bradley, & Cuthbert, 1990, 1992, 1997, 1998). Startle blinks are modulated by the affective state of the subject induced by foreground stimuli (i.e., emotional pictures) from which the startle is elicited (Bradley, 2000; Bradley, Cuthbert, & Lang, 1999). When a subject is aversively primed by viewing unpleasant pictures, the magnitude of the blink reflex elicited by an abrupt acoustic stimulus is enhanced in relation to startles elicited while viewing neutral pictures. In turn, when subjects are viewing pleasant pictures, the magnitude of the blinks is inhibited compared with startles appearing when viewing neutral ones (Bradley, Cuthbert, & Lang, 1990, Bradley et al., 2001; Cuthbert, Bradley, & Lang, 1996; Lang, 1995; Lang et al., 1997; Vrana et al., 1988). However, Cuthbert et al. (1996) have shown that this affect startle effect is also dependent on the arousal level elicited by the stimuli used to induce affective states in the subjects; hence, the emotional modulation of the startle reflex appears when the emotional stimuli (unpleasant and pleasant pictures) elicit high arousal levels. Other authors have pointed out that the aversive motivational system appears to depend on the cerebral amygdala (Lang et al., 1997). This statement comes from studies conducted on both nonhuman subjects (Campeau & Davis, 1995; Davis, 1998; Davis, Walker, & Lee, 1999; Hitchcock & Davis, 1986, 1987; LeDoux, 1998; LeDoux, Farb, & Ruggiero, 1990; Sananes & Davis, 1992) and human subjects (Angrilli et al., 1996; Buchanan, Tranel, & Adolphs, 2004). Angrilli et al. (1996) found that amygdala damage resulted in a lack of startle potentiation during unpleasant pictures compared with the startle elicited during neutral ones, whereas patients rated correctly the affective valence and arousal of the pictures. The authors interpreted the dissociation between the cognitive and the physiological components of the emotion as a cortical limbic dissociation caused by the amygdala damage. However, the absence of positive pleasant pictures does not allow assessment of whether the role of the amygdala is that of a common mediator of all emotions or only of a key region of an aversive defensive brain system. More recently, Buchanan et al. (2004) found this same effect of absence of startle modulation in a group of patients with amygdala damage. Particularly, their patients failed to show a potentiation of the startle reflex by unpleasant pictures, but they did show an attenuation of this response to the pleasant pictures, although this did not reach statistical significance. Their data also indicated a lack of correlation between the affective valence ratings of the pictures and the startle responses. The authors conclude that the amygdala is a necessary structure for the unpleasant-potentiation startle, but not for the pleasant-attenuation startle. Because the startle reflex modulation by emotional stimuli has been well established and is well supported, both experimentally and theoretically, we decided to use this technique in patients with brain damage that included the frontal lobe in order to further explore the relationship between emotion and the frontal lobe. According to previous research, patients would not be expected to differ from control subjects in the affective valence and arousal ratings of the pictures (Meadows & Kaplan, 1994). All subjects would rate pleasant pictures with the highest affective valence, followed by neutral and then unpleasant ones. In the case of arousal ratings, patients and controls would assign higher arousal ratings to pleasant and unpleasant pictures than to neutral ones. Because it has been proposed that the motivational appetitive system is more closely related to the frontal lobe (Lane, Reiman, Ahern, et al., 1997; Paradiso et al., 1999), patients were expected to show a potentiation of the startle reflex during unpleasant pictures, in comparison to neutral ones, whereas startle elicited during pleasant pictures would not be attenuated compared with startle elicited during neutral ones. In the case of startle blinks elicited by acoustic stimuli in the absence of pictures, no significant differences were expected between patients and controls. Following the results obtained in previous research on SCRs elicited by emotional pictures, we expected lower SCR magnitudes in patients than in control subjects (Meadows & Kaplan, 1994; Tranel & Damasio, 1994; Zahn et al., 1999). However, we also expected that acoustic stimuli in the absence of pictures would elicit similar SCR magnitudes in patients and control subjects (Zahn et al., 1999). From the results obtained by Meadows and Kaplan (1994), we expected patients and control subjects to show similar HR decelerations elicited by pictures. Two results could be expected in the deceleration prompted by the pictures: (a) larger decelerations elicited by unpleasant pictures than by pleasant and neutral ones (Greenwald, Cook, & Lang, 1989; Lang, Greenwald, Bradley, & Hamm, 1993), or (b) larger decelerations prompted by pleasant and unpleasant pictures than by neutral ones (Bradley, Lang, & Cuthbert, 1993; Cuthbert et al., 1996). Previous research in our laboratory gives support to the latter hypothesis (Sánchez-Navarro, Martínez-Selva, & Román, 2002, 2003). Thus, patients were not expected to differ from controls in the HR response prompted by acoustic stimuli in the absence of pictures. Subjects Method Brain-damaged group. Nineteen Spanish right-handed subjects with multifocal brain damage were recruited from the Neuropsychological Unit of the University of Murcia (see Table 1). Subjects had been referred to the Neuropsychological Unit from the Neurosurgery Service of the Hospital

3 FRONTAL LOBE DAMAGE AND EMOTIONAL RESPONSE 89 Table 1 Means (and Standard Deviations) of the Subject Demographic Characteristics Characteristic Patients Controls Age (years) (13.05) (2.45) Sex (male/female) 16/3 16/7 Education (years) 9.74 (2.33) 12 (0.00) Handedness a Right Right Lesion onset (months) (16.62) a As measured by the Edinburgh Handedness Inventory. Table 2 Lesion Localization in the Brain-Damaged Patients Patient Lesion type Hemisphere Localization 1 IS L F 2 IS L F/T 3 IS L F/T 4 IS L F/T 5 IS L F/T 6 TBI L F/T 7 TBI L F/BG 8 TBI L F/T 9 TBI R F/T 10 TBI R F/T 11 TBI R F/BG/IC 12 TBI R F/O 13 TBI R F/T 14 TBI R F 15 TBI B F/T 16 TBI B F 17 TBI B F 18 TBI B F 19 TBI B F Note. IS ischemic stroke; TBI traumatic brain injury; L left; R right; B bilateral; F frontal; T temporal; BG basal ganglia; IC internal capsule; O occipital. Clínico Universitario de Murcia. Inclusion criteria in the experimental sample were (a) a clinical diagnosis of brain insult, (b) a positive diagnostic of frontal brain damage obtained from the NMR or computed tomography (CT) scan carried out in the hospital exploration, and (c) a stable chronic lesion of at least 3 months duration after brain damage onset (Tranel, Bechara, & Denburg, 2002; Tranel & Damasio, 1994). Exclusion criteria for participation in the experiment were (a) the presence of a psychiatric or neurologic diagnosis before the brain damage; (b) the absence of frontal brain damage as shown by nuclear magnetic resonnance or CT scan; (c) substance abuse, including alcohol abuse; and (d) positive findings of deficits in orientation, sustained attention, comprehension, and visual agnosia shown in neuropsychological assessment. All of the patients showed multifocal brain lesions that included the frontal lobe. Eight patients had a left frontal lobe lesion, 6 had a right frontal lobe lesion, and 5 had a bilateral frontal lobe lesion. Causes of the brain illnesses were due to traumatic brain injury or ischemic strokes (vessel hemorrhage or occlusion). Table 2 summarizes the brain damage type and localization (as shown by the NMR and CT neuroimaging techniques). Subjects were assessed in order to establish the neuropsychological deficits in relation to their brain damage. The neuropsychological assessment included the following functions: attention, orienting, concentration, memory, visuospatial and visuoperceptive processing, language, and executive functions. All tests used for the assessment of each cognitive function are listed in Table 3. Neuropsychological tests showed that the patient group did not show deficits in their capabilities related to focused attention and concentration effectiveness; orientation to person, time, and place; speech comprehension; visuospatial and visuoperceptual functions; planning; abstract thinking; or shift of behavioral set. However, they did show a slowing of cognitive processing, deficits in organizing their thinking, mild problems in concept formation and delayed memory (verbal and visual domains), and small failures in naming. Because functions like orientation, sustained attention, concentration, comprehension, and visuoperceptual processing were not disordered, the deficits found in the patients did not handicap them for the experimental task. Because of technical problems in the recording session, some patients were excluded from analyses of some dependent measures: startle blink while viewing pictures and in the absence of pictures, n 19; SCR elicited by pictures, n 17; SCR elicited by acoustic stimuli in the absence of pictures, n 15, HR elicited by both pictures and acoustic stimuli in the absence of pictures, n 18; viewing time, affective valence, and arousal ratings, n 18. Control group. Twenty-three subjects were recruited through class advertisements from the School of Psychology of the University of Murcia Table 3 Means (and Standard Deviations) of the Neuropsychological Assessment Neuropsychological tests Patients Digit-Symbol Coding 4.06 (2.88) TMT-A* (93.34) TMT-B* 163 (55.42) Stroop (Interference) (10.31) WCST (Perseverative errors) (10.63) WCST (Categories completed)* 3.31 (2.06) Similarities subtest* 7.19 (2.34) Mazes subtest 9.36 (4.06) Orientation Intact Digits Forward 5 (1.33) Digits Backward 4.11 (1.28) Corsi Test 5.72 (1.23) Phonemic Verbal Fluency* (9.07) AVLT Delay* 6.47 (2.10) Visual Recall* 5.82 (3.49) Judgment of Line Orientation (5.59) Visual Form Discrimination (3.39) Boston Naming Test* (16.10) Token Test (7.82) Note. Digit-Symbol Coding subtest from the Wechsler Adult Intelligence Scale Third Edition (WAIS III; typical score); Trail Making Test Parts A and B (TMT-A and TMT-B; total time in seconds); Stroop Color Test (typical score of interference); Wisconsin Card Sorting Test (WCST; number of perseverative errors and number of categories achieved); Similarities and Picture Arrangement subtests from the WAIS III (typical scores); Mazes subtest from the Wechsler Intelligence Scale for Children Revised (typical score); Orientation (person, time, and place); Digits Forward and Backward from the WAIS III (number of digits achieved); Corsi Test (Corsi Block-Tapping Test; block span achieved); Phonemic Verbal Fluency (P/M/R letters; standard score); Auditive Verbal Learning Test (AVLT; 30-min delayed recall from the Wechsler Memory Scale Third Edition [WMS III]; typical score); Visual Recall 30-min delayed from the WMS III (typical score); Judgment of Line Orientation and Visual Form Discrimination from Benton (number of correct responses); Boston Naming Test (number of correct responses); Token Test (number of correct responses). Asterisks represent impaired performances.

4 90 SÁNCHEZ-NAVARRO, MARTÍNEZ-SELVA, AND ROMÁN (demographical data are summarized in Table 1). Inclusion criteria for participation in the experiment were (a) no history of neurologic or psychiatric disease, and (b) no substance or alcohol abuse. Because of technical problems, 1 subject was excluded from the SCR analyses (n 22). Materials and Design Fifty-four color pictures were selected from the International Affective Picture System 1 (IAPS; Center for the Study of Emotion and Attention, 1999). According to the normative data for the Spanish population (Moltó et al., 1999; Vila et al., 2001), 18 pictures were unpleasant (e.g., lesions, aggressions, etc.), 18 were pleasant (e.g., couples, sports, etc.), and 18 were neutral (e.g., household objects, etc.). Pleasant and unpleasant pictures did not differ in arousal level ( 6), and neutral pictures were low in their arousal level ( 3.5). The pictures were arranged in six blocks of nine pictures each, in such a way that three pictures of each affective valence type occurred in each block. Following the procedure of Bradley et al. (1990), we constructed three orders of picture presentation, and randomly assigned subjects to one of them. Each picture was presented for 6 s (with random intertrial intervals of s), and picture offset was a blank screen. Startle probes were presented during two out of three pictures of each affective category per block, at a random point between 3,500 and 4,500 ms after picture onset. To ensure unpredictability, we delivered two startle probes per block during the intertrial intervals. Pictures were generated on a PC and were presented to the subjects on a screen (maximum viewing area of 120 cm 90 cm) through a Mitsubishi LVP-S50UX picture projector, which, in order to avoid noise interference, was located in a room adjacent to the experimental chamber. The acoustic startle stimulus was a 50-ms, 105-dB(A) burst of white noise (20 Hz 20 KHz) with instantaneous rise- and fall-time, presented binaurally through headphones, and generated by a custom-made noise generator from the University of Murcia s facilities. This generator was connected to the PC, which presented all the pictures and facilitated the parameter programming of the acoustic and visual stimuli. The intensity of the acoustic startle stimulus was previously calibrated using a Brüel & Kjaer (Naerum, Denmark) artificial ear (Model 153) and sound level meter (Model 2231). Physiological Data Collection Apparatus. Acquisition, amplification, and filtering of the physiological signals were carried out by an A.D. Instruments (Charlotte, NC) PowerLab 8/sp data acquisition system, with a 10 V range, controlled by a 32-bit intern microprocessor to 16 MHz and a maximum speed acquisition of 100,000 samples per second, connected to a PC through a USB port (data transfer of 500 Kb per second). This system converted analog signals to digital by means of a 16-bit A/D converter. Acquisition system control, recording parameters, and data storage were performed with A.D. Instruments Chart v software. Startle blink reflex was measured by recording electromyographic activity from the orbicularis oculi muscle beneath the left eye, through bipolar placement of 4-mm Ag/AgCl surface electrodes (Fridlund & Cacioppo, 1986). The raw electromyograph signal was amplified, and frequencies below 60 Hz and above 500 Hz were filtered out with an A.D. Instruments BioAmp-ML132 bioamplifier. The raw signal was full-wave rectified and integrated offline with a time constant of 15 ms. SCLs and SCRs were obtained in two separate channels by the bipolar placement of 7-mm Ag/AgCl standard surface electrodes filled with isotonic electrolytic paste on the thenar (C6) and hypothenar (C8) eminences of the nondominant hand surface in control subjects and patients with bilateral brain damage (Fowles et al., 1981) and in the same hand as the side of the lesion in unilateral brain-damaged patients (Zoccolotti, Caltagirone, Pecchinenda, & Troisi, 1993). The raw signal was acquired with a Cibertec (Madrid, Spain) Biosig-CP1 module and calibrated to detect activity in the microsiemens range. Lead 1 electrocardiogram was recorded by means of 7-mm Ag/AgCl surface electrodes filled with hypertonic electrolyte. The signal was amplified with a 1-mV range, and filtered with cut-offs below 0.3 Hz and above 100 Hz, with a BioAmp-ML132 bioamplifier. All physiological signals were sampled continuously at 1000 Hz for the entire experimental session. Procedure. The study was conducted in the Laboratory of Human Psychophysiology of the University of Murcia, in a darkened, soundattenuating chamber (3.06 m long 2.02 m high 2.36 m wide). The data acquisition system, stimuli generator, and computers were located in an adjoining room. An intercom system allowed communication with subjects, who could be seen through a glass window (0.89 m 0.86 m) in one of the chamber walls. The environmental conditions of temperature and humidity were C ( 2.49) and 71.97% ( 8.86%) throughout the experiment. All sensors were attached once subjects were accommodated in a comfortable armchair, located 2minfront of the screen. After sensor attachment, subjects were instructed that a series of pictures would be displayed on the screen and that they should pay attention to each picture for the duration of its exposure. Subjects were also instructed that at times a brief noise would be heard over the headphones and that they should ignore it. After psychophysiological recording, electrodes were removed and subjects were asked to view the pictures again for as long as they liked, and to rate affective valence and arousal of each picture, using the Self- Assessment Manikin (pencil and paper version; Hodes, Cook, & Lang, 1985). This instrument is a 9-point rating scale for each dimension, such that 9 represents a high rating (i.e., high pleasure, high arousal), and 1 represents a low rating (i.e., low pleasure, low arousal). Participants were instructed that once they pushed a keyboard button, a picture would appear, and that when they pushed it again, the picture would disappear, leaving a blank screen. They should then rate the picture. For each subject, the presentation order of the pictures was the same as in the psychophysiological session. Data Reduction and Analysis All the signals were analyzed by means of the AD Instruments Chart v4.1.2 software for Windows. Startle data were reduced offline, and peak detection was performed with the peak parameters application developed by A.D. Instruments. Startle blink magnitude was scored as peak valley difference in microvolts within ms following startle probe onset. To decrease variability and to establish a common metric across subjects, the raw blink magnitudes elicited during the picture viewing trials were z-score standardized and expressed as T scores (M 50, SD 10) individually for each subject. Startle blinks elicited in the absence of pictures (intertrial probes) were analyzed without applying any transformation. For statistical analyses, magnitude was computed as zero in those trials with no response detected. SCR was scored as the greatest change above 0.02 Siemens occurring in a s time window following picture onset. All responses below 0.02 Siemens were computed as zero. A log transformation (log[scr 1]) was performed to normalize (Venables & Christie, 1980). SCRs elicited 1 Pictures selected from the International Affective Picture System: unpleasant (3100, 3102, 3150, 3170, 3350, 3400, 3500, 6230, 6242, 6260, 6313, 6350, 6360, 6530, 6570, 6821, 9050, 9920), neutral (7002, 7004, 7006, 7009, 7010, 7025, 7030, 7035, 7040, 7060, 7080, 7090, 7150, 7185, 7217, 7224, 7233, 7235), and pleasant (4652, 4658, 4659, 4664, 4669, 4670, 4672, 4800, 5621, 5623, 5626, 5628, 5629, 8030, 8180, 8370, 8490, 8496).

5 FRONTAL LOBE DAMAGE AND EMOTIONAL RESPONSE 91 by the acoustic stimuli in the absence of pictures were scored by the same methodology. SCL was obtained in the 3-min rest period before the trial onset in 15-s periods, and all the measurements obtained were averaged. HR was obtained by an offline transformation of the R-wave, providing a weighted mean of the beat-to-beat HR. This avoided overestimation and lag (Reyes del Paso & Vila, 1998). HR was averaged offline into halfsecond intervals in beats per minute, and then deviated from a 3-s baseline immediately preceding picture onset. The average of Seconds 2 to 4 (6.5-s values) was used in statistical analyses (Cuthbert et al., 1996). HR elicited by acoustic stimuli in the absence of pictures was obtained by the same methodology, but the average during the 6 s after stimuli onset was used in statistical analyses. Basal HR was obtained in 15-s intervals along the 3-min rest period before the trial onset, and all the measurements obtained were then averaged. A mixed model, repeated measures analysis of variance (ANOVA) was conducted on startle response obtained in picture trials, using a design with group (patient and control subjects), sex (male and female), and presentation order (1, 2 and 3) as between-subjects variables, and picture type (unpleasant, neutral, and pleasant) as a within-subject variable. In the case of SCR, HR, viewing time, affective valence ratings and arousal ratings, five mixed model, repeated measures ANOVAs were conducted, using a design with group (patient and control subjects), sex (male and female), and presentation order (1, 2, and 3) as between-subjects variables, and picture type (unpleasant, neutral, and pleasant) as a within-subject variable. In all cases, trend analyses were performed to assess the effect of the affective valence (linear trend) and the arousal (quadratic trend) on the psychophysiological, behavioral, and cognitive measures (Bradley et al., 1990). In the case of the intertrial acoustic probes delivered in the absence of pictures, separate (Group Sex Presentation Order) univariate ANOVAs were conducted on the average of the responses elicited by the intertrial probes on startle blink reflex, SCR, and HR change. Separate 2 2 (Group Sex) univariate ANOVAs were conducted to analyze the SCLs and basal HR in the initial 3-min rest period. Correlation analyses were also carried out to examine the relationship between the psychophysiological and behavioral responses elicited by the pictures and the subjective ratings. For this purpose, we followed the methodology used by Lang et al. (1993), with the individual pictures, instead of the subjects, forming the unit of analysis. All statistical analyses were performed with the SPSS program (Version 10; SPSS, Chicago, IL). When appropriate, a Greenhouse Geisser adjustment to the degrees of freedom was used in repeated measures tests in order to correct any potential inflation of the reported probability values (Bagiella, Sloan, & Heitjan, 2000). Comparisons were performed with a Bonferroni procedure to control the overall level of significance (Keselman, 1998). All statistical tests used the.05 level of significance. Subjective Measures Results Affective valence ratings showed only a significant main effect of picture type, F(2, 60) , p.001,.691. Trend analyses showed a linear trend, F(1, 30) , p.001, and pairwise comparisons showed significant differences between unpleasant and neutral, F(1, 30) , p.001, and pleasant versus neutral, F(1, 40) 75.34, p.001, indicating that subjects rated pleasant pictures with the highest affective valence, followed by neutral and unpleasant pictures. Arousal ratings also showed a significant main effect of picture type, F(2, 60) 77.64, p.001. Unpleasant and pleasant pictures were rated as more arousing than neutral ones: quadratic trend, F(1, 30) , p.001. Pairwise comparisons showed that subjects rated unpleasant and pleasant pictures as similar in arousal level, F(1, 30) 4.38, and rated both of them higher than neutral pictures, F(1, 30) , p.001, and F(1, 30) 77.56, p.001, respectively. In addition, a significant effect of group was found, F(1, 30) 5.15, p.05, indicating that patients rated the pictures as more arousing than did controls. Startle Reflex Analyses of blink magnitude showed a significant Group Picture Type interaction, F(2, 62) 5.45, p.01, showing significant differences between patient and control groups in the magnitude of the startle reflex, depending on the valence of the pictures (see Figure 1). We carried out statistical analyses in both groups separately to study the effects of the picture type variable. A main effect of picture type was found in the case of controls, F(2, 44) 40.86, p.001. A significant linear trend, F(1, 22) 77.44, p.001, indicated that larger startle blinks were elicited during unpleasant pictures than during pleasant pictures. When we compared unpleasant and pleasant pictures with neutral pictures, we found that startle blinks were potentiated during unpleasant pictures, F(1, 22) 11.50, p.01, and attenuated during pleasant ones, F(1, 22) 42.20, p.001. A main effect of picture type was also found in the patient group, F(2, 36) 44.83, p.005. As occurred in the control group, a significant linear trend F(1, 18) 9.80, p.01, showed larger startle blinks during unpleasant pictures than during pleasant pictures. However, when compared with neutral pictures, unpleasant pictures resulted in marginally potentiated startle blinks, although they did not reach statistical significance, F(1, 18) 6.86, p.052, and were not inhibited during pleasant pictures, F(1, 18) We carried out t test analyses to compare the responses between patient and control groups for each picture type. Results from the t test analyses showed significant differences between both groups in the startle blinks during unpleasant pictures, t(40) 2.44, p.05, and pleasant pictures, t(40) 3.56, p.001, but not in the case of neutral ones (t 1), indicating that patients showed lower startle blinks to unpleasant pictures and greater ones to pleasant pictures, compared with control subjects. Correlation analyses showed a significant negative correlation between startle blink and affective valence in the control group (r.584, p.001), whereas startle blink did not significantly correlate with arousal ratings. In the patient group, however, startle blink did not significantly correlate with affective valence ratings or arousal ratings. Skin Conductance SCR showed a significant effect of the Group Picture Type interaction, F(2, 56) 6.00, p.01,.814, indicating that both groups differed in the SCRs, depending on the picture type (see Figure 2). The group variable also showed a significant effect, F(1, 28) 4.82, p.05, with pictures eliciting larger SCRs in controls than in patients (see Table 4). In order to study the SCR pattern prompted by the pictures, we carried out separate statistical analyses in each group. In the

6 92 SÁNCHEZ-NAVARRO, MARTÍNEZ-SELVA, AND ROMÁN Figure 1. Startle reflex magnitude elicited during picture viewing in both control subjects and patients. Asterisks indicate significant group differences ( p.05). control group, we found a main effect of picture type, F(1, 42) 13.84, p.001,.70. Unpleasant and pleasant pictures elicited larger SCRs than neutral ones: quadratic trend, F(1, 21) 20.67, p.001. Single analyses confirmed this trend, showing that, compared with neutral pictures, unpleasant and pleasant pictures elicited larger SCRs, F(1, 21) 28.10, p.001, and F(1, 21) 13.23, p.01, respectively, but SCRs prompted by unpleasant and pleasant pictures did not differ (F 1). A main effect of picture type on SCRs was found in patients, F(2, 32) 4.96, p.05,.712; quadratic trend, F(1, 16) 6.78, p.05. Pleasant pictures elicited larger SCRs than neutral ones, F(1, 16) 8.07, p.05. In turn, SCRs to unpleasant Figure 2. Skin conductance response (SCR) elicited by pictures in both control subjects and patients. Asterisks indicate significant group differences ( p.05).

7 FRONTAL LOBE DAMAGE AND EMOTIONAL RESPONSE 93 Table 4 Response Means (and Standard Deviations) of the Dependent Variables Recorded in Both Groups in Relation to Pictures Patients Controls Measurements Unpleasant Neutral Pleasant Unpleasant Neutral Pleasant Blink magnitude (T score) (2.17) a (1.55) (2.37) b (2.59) a (2.15) (1.79) b SCR (log[scr 1]) (0.033) a (0.018) b (0.027) c (0.063) a (0.044) b (0.073) c Heart rate change (bpm) 2.18 (2.27) 0.85 (1.90) 1.77 (1.92) 2.85 (3.97) 0.90 (2.20) 2.33 (2.47) Picture viewing time (s) 7.33 (4.75) 6.29 (4.63) 6.83 (4.84) 5.69 (2.96) 4.49 (1.87) 5.32 (1.92) Affective valence ratings 2.01 (1.13) 5.48 (0.89) 7.49 (1.04) 2.48 (0.89) 5.14 (0.45) 7.40 (1.03) Arousal ratings a 6.49 (1.66) 2.07 (1.06) 6.36 (1.64) 5.79 (1.34) 1.82 (1.48) 5.40 (1.52) Note. For each measurement, shared subscripts indicate significant group differences ( p.05). SCR skin conductance response; bpm beats per minute. a Mean of arousal ratings was higher in patients (4.97) than in controls (4.34), p.05. pictures did not differ from those prompted by neutral ones, F(1, 16) SCRs in both groups showed a significant positive correlation with arousal ratings (r.650, p.001, and r.346, p.05, respectively), but did not significantly correlate with affective valence ratings. No significant differences were found in SCL between controls (29.05) and patients (24.95) in the 3-min rest period (F 1). HR We found a significant main effect of picture type, F(2, 60) 8.83, p.001,.802. Unpleasant and pleasant pictures prompted greater HR decelerations than neutral pictures: quadratic trend, F(1, 30) 13.08, p Pairwise analyses showed that unpleasant and pleasant pictures did not differ in the HR response elicited, F(1, 30) 1.05, but prompted greater HR decelerations than neutral pictures, F(1, 30) 10.67, p.005, and F(1, 30) 12.25, p.001, respectively. Change in HR showed a significant negative correlation with arousal ratings in both controls (r.327, p.05) and patients (r.568, p.001), and did not significantly correlate with affective valence ratings. Patients did not significantly differ from controls in the basal HR in the 3-min rest period, F(1, 37) Picture Viewing Time We did not find a significant effect of the Group Picture Type interaction (F 1), with picture type showing a significant main effect on picture viewing time, F(2, 60) 3.83, p.05,.807; quadratic trend, F(1, 30) 8.86, p.01. However, when we conducted correlation analyses, picture viewing time in the control group showed a significant positive correlation with arousal ratings (r.280, p.05) and SCR (r.333, p.05), and did not significantly correlate with affective valence ratings, while in the patient group picture viewing time did not correlate with either arousal ratings, affective valence ratings, or SCR. To study the absence of correlation of picture viewing time with the other variables in the patient group, we carried out post hoc analyses over the picture viewing time. Data showed a nearsignificant main effect of picture type, F(2, 34) 2.80, p.075; quadratic trend, F(1, 17) 5.07, p.05. Pairwise tests did not show significant differences between any picture type: unpleasant versus pleasant, F(1, 17) 1.12; unpleasant versus neutral, F(1, 17) 4.16; and pleasant versus neutral, F(1, 17) On the other hand, the control group showed a significant main effect of picture type, F(2, 44) 7.81, p.001; quadratic trend, F(1, 22) 17.36, p.001, and pairwise tests showed significant differences between unpleasant and neutral pictures, F(1, 22) 11.87, p.01, and between pleasant and neutral pictures, F(1, 22) 12.64, p.01, but not between pleasant and unpleasant ones, F(1, 22) Psychophysiological Response to Acoustic Stimuli in the Absence of Pictures Patients and controls differed in the magnitudes of the startle blinks elicited by the acoustic probes in the absence of pictures (see Table 5), as was revealed by the significant effect of group, 2 In order to assess whether this effect of the arousal on the heart rate change was due to the time interval selected to analyze this response, we carried out new analyses following the methodology used by Bradley et al. (2001). For each subject and each picture, we obtained the maximum deceleration from baseline in the first 3 s of picture viewing (Interval 1) and the maximum acceleration from baseline in the last 3 s of picture viewing (Interval 2). Analyses were carried out with picture type and interval (first 3 s and last 3 s) as within-subject variables, and group, sex, and picture order as between-subject variables. Analyses showed a significant Picture Type Interval interaction, F(2, 60) 5.57, p.01,.835, indicating differences in the HR change in function of the valence of the pictures between both intervals. In addition, an interval effect was also found, F(1, 30) , p.001, with subjects showing HR deceleration along the first 3sofpicture viewing ( 5.42), and acceleration along the last 3 s (2.55). Separate analyses for the effect of each interval on picture type were carried out. In the first 3 s of picture viewing, a significant effect was found, F(2, 80) 8.42, p.001, with both significant linear, F(1, 40) 5.14, p.05, and quadratic, F(1, 40) , p.005, trends. Unpleasant ( 6.07) and pleasant ( 5.43) pictures prompted a greater initial deceleration than neutral ones ( 4.81). In the last 3 s of picture viewing, a significant effect of picture type was also found, F(2, 80) 10.76, p.001,.860, with both unpleasant (2.15) and pleasant (1.73) pictures showing a lower HR acceleration than neutral ones (3.59): quadratic trend, F(1, 40) 15.17, p.001.

8 94 SÁNCHEZ-NAVARRO, MARTÍNEZ-SELVA, AND ROMÁN Table 5 Means (and Standard Deviations) of the Physiological Responses Elicited by Acoustic Stimuli in the Absence of Pictures Measurements Patients Controls Blink magnitude ( V) 0.53 (0.80) 1.33 (0.84)* SCR (log[scr 1]) 0.11 (0.096) 0.14 (0.099) Heart rate change (bpm) 0.09 (1.39) 1.09 (1.9) Note. SCR skin conductance response; bpm beats per minute. * p.05, significant difference between groups. F(1, 31) 7.63, p.05, with controls showing larger startle blinks than patients. Acoustic stimuli elicited similar SCRs in both patients and controls (F 1). The only significant effect was sex, F(1, 26) 4.31, p.05, with men (0.1430) showing larger SCRs than women (0.0687). Finally, patients and controls did not significantly differ in the HR change elicited by the acoustic stimuli in the absence of pictures: group, F(1, 30) Discussion This research was aimed at exploring further the role of the frontal lobe in emotion by using a paradigm based on the psychophysiological recording and subjective assessment of the emotional responses elicited by pictures. For this purpose, patients with multifocal brain damage that included the frontal lobe were selected, along with nondamaged control subjects. As expected, patients did not differ from controls in either affective valence or arousal ratings of the pictures. The data indicate that, like the control subjects, frontal lobe patients perceived the content depicted by the pictures and were able to rate them according to their valence and arousal components. Likewise, as predicted, patients did not show a real affective startle modulation, as compared with controls, though startle blinks during unpleasant pictures were greater than those elicited for pleasant ones. Startles elicited during pleasant pictures were not attenuated in comparison with those prompted during neutral ones. In this aspect, startle blinks did not differ during unpleasant and neutral pictures, but a trend was obtained that pointed to greater startles during unpleasant pictures than during neutral ones. An explanation of this result comes from the theoretical and experimental data on the role of other brain structures, such as the amygdala, on emotions. The biphasic theory of emotion developed by Lang and coworkers (Lang, 1995; Lang et al., 1990; Lang, Davis, & Öhman, 2000) proposes that two motivational systems in the brain subserve emotion the aversive defensive motivational system and the appetitive motivational system. Data coming from both animal studies and brain-damaged human studies point to the amygdala as the most important structure related to the aversive motivational system (Angrilli et al., 1996; Bradley et al., 2001; Buchanan et al., 2004; Davis, 1998; Lang et al., 1997, 1998, 2000; LeDoux, 1998). Nevertheless, the structures supporting the appetitive motivational system remain unknown. The data from our patients, and those from functional neuroimaging studies (e.g., Lane, Reiman, Ahern, et al., 1997; Paradiso et al., 1999), point to the frontal lobe as a key structure related to the appetitive motivational system. Our results, therefore, support the role of the frontal lobe in the initiation of the response to pleasant positive emotion, as several researchers have pointed out (Lane, Reiman, Bradley, et al., 1997; Paradiso et al., 1999). The greater startles elicited during unpleasant pictures could be due to the fact that the amygdala is a brain structure which is involved in the startle potentiation related to unpleasant negative stimuli, as animal and human research has shown (e.g., Buchanan et al., 2004; Campeau & Davis, 1995; Davis et al., 1999; LeDoux et al., 1990), and the lesions of our patients were not located within this structure. Angrilli et al. (1996) interpreted the lack of startle potentiation following amygdala damage as an effect of the low arousal elicited by the pictures in their patient. However, they did not record a psychophysiological arousal measurement (i.e., SCR), and their data are better explained by the lesion in the amygdala, which might affect the potentiation mechanism that this structure exerts on the startle response through its projections to the nucleus reticularis pontis caudalis (Davis et al., 1999). The absence of correlation between the startle blink magnitude and the affective valence ratings of the pictures indicates a dissociation between both indices in our patient group, in contrast to the data obtained in the control group. This dissociation would point to the implication of different brain regions in different aspects of the emotional response: posterior brain regions could be involved in the perception and cognitive processing of emotional stimuli (e.g., Bradley et al., 2003; Lang, Bradley, Fitzsimmons, et al., 1998), while anterior regions would be involved in the psychophysiological response elicited by complex stimuli (e.g., Zahn et al., 1999). Patients showed lower startle blink magnitudes than control subjects in those startles elicited by acoustic stimuli in the absence of pictures. It is difficult to give an explanation of this finding. This effect was also reported by Angrilli et al. (1996) in a patient with damage restricted to the amygdala. However, in a more recent study that used a larger sample of amygdala patients, Buchanan et al. (2004) did not find this attenuation. These unexpected data may point more to an inhibitory effect of the frontal cortex on either the amygdala or the nucleus reticularis pontis caudalis, or on both, leading to low startle magnitudes, rather than to an effect of a low autonomic arousal, because SCRs and HRs elicited by these stimuli were similar in both patients and control subjects. However, this effect requires further research. As expected, pictures elicited low SCRs in our patients, thus replicating previous research (e.g., Tranel & Damasio, 1994; Zahn et al., 1999). But contrary to predictions, we found that neutral pictures prompted lower SCRs than emotional ones in the patients, although the only effect was that of pleasant pictures eliciting higher SCRs than neutral ones. These low SCR magnitudes could not be explained by a deficit in the electrodermal system functioning because neither the SCLs during the rest period nor the SCRs elicited by acoustic stimuli in the absence of pictures differed from those of control subjects. This decrease of the autonomic arousal, as measured by SCR, in our patients could also explain the absence of startle blink modulation. Some researchers have found that in order to obtain the affective startle modulation startle potentiation to unpleasant pictures and inhibition to pleasant pictures in comparison to neutral ones it is necessary that both pleasant and unpleasant pictures prompt high arousal levels (Cuthbert et al., 1996). Our data on the low arousal level related to frontal brain

9 FRONTAL LOBE DAMAGE AND EMOTIONAL RESPONSE 95 damage, as shown by SCRs, reinforce this hypothesis and point to the importance of the emotional arousal (Bradley, 2000; Cuthbert et al., 1996). Taking all these findings together, we propose that the frontal lobe appears to be involved in the physiological emotional arousal related to the complexity of the stimuli. Data on the SCRs elicited by acoustic startles in the absence of pictures showed, as predicted, that patients and controls did not differ in the magnitude of this response. This result indicated, therefore, a difference between two types of arousal prompted by two kinds of stimuli: simple and complex psychological. Although SCRs elicited by pictures were lower in patients than in controls, acoustic startle stimuli in the absence of pictures elicited similar SCRs in both. This effect has been found previously by other researchers (e.g., Meadows & Kaplan, 1994; Zahn et al., 1999) and points to a dissociation in the physiological arousal elicited depending on the stimulus type: (a) Stimuli with a low level of significance or information content (e.g., white noise) prompt a physiological arousal that is not dependent on frontal brain structures, and (b) stimuli with a high level of significance (e.g., pictures) elicit a physiological arousal that seems to depend on the frontal cortex. As regards the arousal level prompted by simple acoustic stimuli, Tranel and Damasio (1989) have pointed out that the amygdala is not a necessary structure in generating SCRs, postulating that simple information can reach the autonomic hypothalamic station through either the thalamus or the prefrontal cortices. Our data and those reported by Tranel and Damasio (1994) and Zahn et al. (1999), however, have shown that frontal brain damage does not attenuate the SCRs to simple acoustic stimuli; therefore, the thalamus hypothalamus pathway might support the autonomic arousal prompted by simple stimuli. Regarding the arousal elicited by complex psychological stimuli, several authors (Tranel & Damasio, 1994; Zahn et al., 1999) have pointed to the ventromedial, cingulate, and dorsolateral frontal regions as key structures. In this line, prefrontal cortex appears to send robust projections to the autonomic centers of the hypothalamus, as animal research has shown (for a review, see Barbas, 2000). Therefore, prefrontal cortex seems to be anatomically and functionally involved in the electrodermal response to significant stimuli (Hugdahl, 1995). Our data did not show differences between patients and controls either in the HR elicited by acoustic stimuli in the absence of pictures or in the HR deceleration prompted by the pictures, as was expected. The same result had also been obtained in previous research (e.g., Meadows & Kaplan, 1994), and appears to indicate that HR responses elicited by simple and complex stimuli are not affected by frontal lobe damage, and that changes in this response prompted by complex stimuli would depend on other cortical or subcortical structures. The fact that simple acoustic stimuli elicited accelerative HR responses, plus the lack of differences between patients and controls, would seem to reflect a defense response (Bernston, Cacioppo, Quigley, & Fabro, 1994; Papillo & Shapiro, 1990; Quigley & Bernston, 1990), which does not seem to be mediated by the frontal cortex. In turn, HR deceleration elicited by pictures would reflect an orienting response (Bernston et al., 1994; Papillo & Shapiro, 1990; Quigley & Bernston, 1990), which is not mediated by the frontal cortex. In the patient group, we found a tendency to view the emotional pictures for longer times than neutral ones. However, pairwise comparisons did not show differences. This finding is supported by the lack of correlation between the picture viewing time and both arousal ratings of the pictures and the SCRs elicited by them in comparison to controls, and is in contrast to data from previous research (Lang et al., 1993). Several authors have pointed out that whereas orbital and ventromedial areas of the frontal lobe support emotional functions, dorsal and lateral regions in the frontal lobe may support the performance of executive functions and goaldirected behavior (Gray, Braver, & Raichle, 2002; Phillips et al., 2003). Hence, further research is necessary to establish the role of these structures in emotional behavior. Overall, our data show that in a group of patients with brain damage that includes the frontal lobe, a dissociation can be established between cognitive and psychophysiological components of the emotional response, particularly in the case of the affective valence ratings and the startle blink reflex. This dissociation could be explained by two factors: (a) the involvement of frontal lobe in pleasant-positive emotions (lesion results in an absence of startle inhibition during pleasant emotions), and (b) the involvement of frontal lobe in the physiological arousal elicited by emotionalsignificant stimuli (lesion results in a low autonomic arousal, as reflected by SCRs, elicited by emotional pictures). It can also be concluded that the frontal cortex appears to be involved in the mediation of the physiological arousal elicited by stimuli with psychological significance, but not in the autonomic arousal prompted by nonsignificant stimuli. In addition, the frontal lobe does not appear to mediate the HR decelerative changes elicited by pictures. Hence, our results indicate a more prominent role of the frontal lobe in the emotional response to complex stimuli, as shown by the data from the acoustic startle reflex modulation, autonomic recording, and subjective assessment. Further studies should be conducted to assess the differences in the startle response in subjects with focal lesions located in specific areas of the frontal lobe (e.g., frontal ventromedial) in order to confirm and extend our results. In addition, it would be desirable to study samples of subjects with amygdala damage using the startle procedure developed by Lang and colleagues (e.g., Bradley et al., 1990) together with other autonomic and behavior measures (e.g., SCR, HR, viewing time) in order to establish the role of the amygdala in both the startle modulation and the arousal response elicited by psychological emotional complex stimuli. Further research should also confirm the involvement of the frontal lobe in both pleasant emotions and the arousal elicited by complexemotional stimuli, as well as the brain structures and pathways involved. References Angrilli, A., Mauri, A., Palomba, D., Flor, H., Birbaumer, N., Sartori, G., & di Paola, F. (1996). Startle reflex and emotion modulation impairment after right amygdala lesion. Brain, 119, Bagiella, E., Sloan, R. P., & Heitjan, D. F. (2000). Mixed-effects models in psychophysiology. Psychophysiology, 37, Barbas, H. (2000). Connections underlying the synthesis of cognition, memory, and emotion in primate prefrontal cortices. Brain Research Bulletin, 52, Bechara, A., Damasio, A. R., Damasio, H., & Anderson, S. (1994). Insensitivity to future consequences following damage to human prefrontal cortex. Cognition, 50, Bechara, A., Damasio, H., Damasio, A. R., & Lee, G. P. (1999). 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