This section will present a brief overview of recent work from my laboratory that was designed to examine individual differences in measures of prefrontal activation and their relation to different aspects of emotion, affective style, and related biological constructs. These findings will be used to address the question of what underlying constituents of affective style such individual differences in prefrontal activation actually reflect.
In both infants (Davidson & Fox, 1989) and adults (Davidson & Tomarken, 1989) we noticed that there were large individual differences in baseline electrophysiological measures of prefrontal activation and that such individual variation was associated with differences in aspects of affective reactivity. In infants, Davidson and Fox (1989) reported that 10-month-old babies who cried in response to maternal separation were more likely to have less left-sided and greater right-sided prefrontal activation during a preceding resting baseline compared with those infants who did not cry in response to this challenge. In adults, we first noted that the phasic influence of positive and negative emotion elicitors (e.g., film clips) on measures of prefrontal activation asymmetry appeared to be superimposed upon more tonic individual differences in the direction and absolute magnitude of asymmetry (Davidson & Tomarken, 1989).
During our initial explorations of this phenomenon, we needed to determine if baseline electrophysiological measures of prefrontal asymmetry were reliable and stable over time and thus could be used as a trait-like measure. Tomarken, Davidson, Wheeler, and Doss (1992) recorded baseline brain electrical activity from 90 normal subjects on two occasions separately by approximately 3 weeks. At each testing session, brain activity was recorded during eight 1-min trials, four trials with eyes open and four with eyes closed, presented in counterbalanced order. The data were visually scored to remove artifact and then Fourier-transformed. Our focus was on power in the alpha band (8-13 Hz), although we extracted power in all frequency bands (see Davidson, Chapman, Chapman, & Henriques, 1990, for a discussion of power in different frequency bands and their relation to activation). We computed coefficient alpha as a measure of internal consistency reliability from the data for each session. The coefficient alphas were quite high, with all values exceeding .85, indicating that the electrophysiological measures of asymmetric activation indeed showed excellent internal consistency reliability. The test-retest reliability was adequate with intraclass correlations ranging from .65 to .75, depending upon the specific sites and methods of analysis. The major finding of import from this study was the demonstration that measures of activation asymmetry based upon power in the alpha band from prefrontal scalp electrodes showed both high internal consistency reliability and acceptable test-retest reliability to be considered a trait-like index.
The large sample size in this reliability study enabled us to select a small
group of extreme left and extreme right-frontally activated subjects for magnetic resonance (MR) scans to determine if there existed any gross morphometric differences in anatomical structure between these subgroups. None of our measures of regional volumetric asymmetry revealed any difference between the groups (unpublished observations). These findings suggest that whatever differences exist between subjects with extreme left versus right prefrontal activation, those differences are likely functional and not structural.
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group of extreme left and extreme right-frontally activated subjects for magnetic resonance (MR) scans to determine if there existed any gross morphometric differences in anatomical structure between these subgroups. None of our measures of regional volumetric asymmetry revealed any difference between the groups (unpublished observations). These findings suggest that whatever differences exist between subjects with extreme left versus right prefrontal activation, those differences are likely functional and not structural.
On the basis of our prior data and theory, we reasoned that extreme left and extreme right frontally activated subjects would show systematic differences in dispositional positive and negative affect. We administered the trait version of the Positive and Negative Affect Scales (PANAS; Watson, Clark, & Tellegen, 1988) to examine this question and found that the left-frontally activated subjects reported more positive and less negative affect than their right-frontally activated counterparts (Tomarken, Davidson, Wheeler, & Doss, 1992; see figure 5-1). More recently with Sutton (Sutton & Davidson, 1997), we showed that scores on a self-report measure designed to operationalize Gray's concepts of Behavioral Inhibition and Behavioral Activation (the BIS/BAS scales; Carver & White, 1994) were even more strongly predicted by electrophysiological measures of prefrontal asymmetry than were scores on the PANAS scales (see figure 5-2). Subjects with greater left-sided prefrontal activation reported more relative B AS to BIS activity compared with subjects exhibiting more right-sided prefrontal activation.
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We also hypothesized that our measures of prefrontal asymmetry would predict reactivity to experimental elicitors of emotion. The model we have developed over the past several years (see Davidson, 1992, 1994, 1995, for background) features individual differences in prefrontal activation asymmetry as a reflection of a diathesis that modulates reactivity to emotionally significant events. According to this model, individuals who differ in prefrontal asymmetry should respond differently to an elicitor of positive or negative emotion, even when baseline mood is partialed out. We (Wheeler, Davidson, & Tomarken, 1993) performed an experiment to examine this question. We presented short film clips designed to elicit positive or negative emotion. Brain electrical activity was recorded prior to the presentation of the film clips. Just after the clips
were presented, subjects were asked to rate their emotional experience during the preceding film clip. In addition, subjects completed scales that were designed to reflect their mood at baseline. We found that individual differences in prefrontal asymmetry predicted the emotional response to the films even after measures of baseline mood were statistically removed. Those individuals with more left-sided prefrontal activation at baseline reported more positive affect to the positive film clips, and those with more right-sided prefrontal activation reported more negative affect to the negative film clips. These findings support the idea that individual differences in electrophysiological measures of prefrontal activation asymmetry mark some aspect of vulnerability to positive and negative emotion elicitors. The fact that such relationships were obtained following the statistical removal of baseline mood indicates that any difference between left- and right-frontally activated in baseline mood cannot account for the prediction of film-elicited emotion effects that were observed.
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were presented, subjects were asked to rate their emotional experience during the preceding film clip. In addition, subjects completed scales that were designed to reflect their mood at baseline. We found that individual differences in prefrontal asymmetry predicted the emotional response to the films even after measures of baseline mood were statistically removed. Those individuals with more left-sided prefrontal activation at baseline reported more positive affect to the positive film clips, and those with more right-sided prefrontal activation reported more negative affect to the negative film clips. These findings support the idea that individual differences in electrophysiological measures of prefrontal activation asymmetry mark some aspect of vulnerability to positive and negative emotion elicitors. The fact that such relationships were obtained following the statistical removal of baseline mood indicates that any difference between left- and right-frontally activated in baseline mood cannot account for the prediction of film-elicited emotion effects that were observed.
In another study, we (Davidson, Dolski, et al., in preparation) examined relations between individual differences in prefrontal activation asymmetry and the emotion-modulated startle. In this study, we presented pictures from the International Affective Picture System (Lang et al., 1995) while acoustic startle probes were presented and the EMG-measured blink response from the orbicularis oculi muscle region was recorded (see Sutton, Davidson, Donzella, Irwin, & Dottl, 1997, for basic methods). Startle probes were presented both during the 6-s slide exposure as well as 500 ms following the offset of the pictures, on separate trials.1 We interpreted startle magnitude during picture exposure as providing an index related to the peak of emotional response, while startle magnitude following the offset of the pictures was taken to reflect the recovery from emotional challenge. Used in this way, startle probe methods can potentially provide new information on the time course of emotional responding. We expected that individual differences during actual picture presentation would be less pronounced than individual differences following picture presentation, because an acute emotional stimulus is likely to pull for a normative response across subjects, yet individuals are likely to differ dramatically in the time to recover. Similarly, we predicted that individual differences in prefrontal asymmetry would account for more variance in predicting magnitude of recovery (i.e., startle magnitude post-stimulus) than in predicting startle magnitude during the stimulus. Our findings were consistent with our predictions and indicated that subjects with greater right-sided prefrontal activation show a larger blink magnitude following the offset of the negative stimuli, after the variance in blink magnitude during the negative stimulus was partialed out. Measures of prefrontal asymmetry did not reliably predict startle magnitude during picture presentation. The findings from this study are consistent with our hypothesis and indicate that individual differences in prefrontal asymmetry are associated with the time-course of affective responding, particularly the recovery following emotional challenge.
In addition to the studies previously described using self-report and psychophysiological measures of emotion, we have also examined relations between individual differences in electrophysiological measures of prefrontal asymmetry and other biological indices, which in turn have been related to differential reactivity to stressful events. Two recent examples from our laboratory include measures of immune function and cortisol. In the case of the former, we examined differences between left- and right-prefrontally activated subjects in
natural killer (NK) cell activity, because declines in NK activity have been reported in response to stressful, negative events (Kiecolt-Glaser & Glaser, 1991). We predicted that subjects with right prefrontal would exhibit lower NK activity compared with their left-activated counterparts because the former type of subject has been found to report more dispositional negative affect, to show higher relative BIS activity and to respond more intensely to negative emotional stimuli. We found that right-frontally activated subjects indeed had lower levels of NK activity compared to their left-frontally activated counterparts (Kang, Davidson, Coe, Wheeler, Tomarken, & Ershler, 1991).
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natural killer (NK) cell activity, because declines in NK activity have been reported in response to stressful, negative events (Kiecolt-Glaser & Glaser, 1991). We predicted that subjects with right prefrontal would exhibit lower NK activity compared with their left-activated counterparts because the former type of subject has been found to report more dispositional negative affect, to show higher relative BIS activity and to respond more intensely to negative emotional stimuli. We found that right-frontally activated subjects indeed had lower levels of NK activity compared to their left-frontally activated counterparts (Kang, Davidson, Coe, Wheeler, Tomarken, & Ershler, 1991).
Recently, in collaboration with Kalin, our laboratory has been studying similar individual differences in scalp-recorded measures of prefrontal activation asymmetry in rhesus monkeys (Davidson, Kalin, & Shelton, 1992, 1993). We (Kalin, Larson, Shelton, & Davidson, 1998) acquired measures of brain electrical activity from a large sample of rhesus monkeys (n = 50). EEC measures were obtained during periods of manual restraint. A subsample of 15 of these monkeys were tested on two occasions 4 months apart. We found that the test-retest correlation for measures of prefrontal asymmetry was .62, suggesting similar stability of this metric in monkey and man. In the group of 50 animals, we also obtained measures of plasma cortisol during the early morning. We hypothesized that if individual differences in prefrontal asymmetry were associated with dispositional affective style, such differences should be correlated with cortisol, since individual differences in baseline cortisol have been related to various aspects of trait-related stressful behavior and psychopathology (see e.g., Gold, Goodwin, & Chrousos, 1988). We found that animals with right-sided prefrontal activation had higher levels of baseline cortisol than their left-frontally activated counterparts (see figure 5-3). Moreover, when blood samples were collected 2 years following our initial testing, animals classified as showing
extreme right-sided prefrontal activation at age 1 year had significantly higher baseline cortisol levels when they were 3 years of age compared with animals who were classified at age 1 year as displaying extreme left-sided prefrontal activation. These findings indicate that individual differences in prefrontal asymmetry are present in nonhuman primates and that such differences predict biological measures that are related to affective style.
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extreme right-sided prefrontal activation at age 1 year had significantly higher baseline cortisol levels when they were 3 years of age compared with animals who were classified at age 1 year as displaying extreme left-sided prefrontal activation. These findings indicate that individual differences in prefrontal asymmetry are present in nonhuman primates and that such differences predict biological measures that are related to affective style.
Affective Style and Psyche-pathology
Virtually all forms of psychopathology involve some abnormality in emotional processes, although the nature of these abnormalities is likely to differ among different disorders. The study of precisely what is abnormal in the emotional processing systems of individuals with different forms of psychopathology is very much in the earliest stages of investigation. We have used our findings in normal subjects as a foundation to probe the underlying neural substrates of affective and anxiety disorders with a major goal of understanding more precisely the nature of the abnormality in emotional processing in affective disorders.
One of the important sources of data on relations between brain function and emotion has come from studies of the affective styles of patients with localized brain lesions (see Robinson & Downhill, 1995, for a review). Robinson and his colleagues have reported that damage to the left frontal region is more likely to be associated with depression than damage to any other cortical region. Moreover, among patients with left hemisphere damage, more severe depressive symptomatology is present in those patients whose damage is closer to the frontal pole (Robinson, Kubos, Starr, Rao, & Price, 1984). Studies of regional brain function with neuroimaging of patients with psychiatric depressions have fairly consistently revealed a pattern of decreased blood flow or metabolism in left prefrontal regions at rest (Baxter et al., 1989; Bench, Friston, Brown, Scott, Frackowiak, & Dolan, 1992, 1993; Martinet et al., 1990; see George, Ketterer & Post, 1994, for review; see also Drevets et al., 1992, for a more complex pattern associated with pure familial depression).
We have conducted several studies examining regional brain electrical activity in depression. We hypothesized that most depression is fundamentally associated with a deficit in the approach/appetitive motivation system and should therefore be specifically accompanied by decreased activation in the left prefrontal region as measured by scalp electrophysiology. Henriques and Davidson (1991) obtained support for this hypothesis. Moreover, in another study, these authors demonstrated that the decrease in left prefrontal activation found among depressives was also present in recovered depressives who were currently euthymic, compared with never-depressed controls who were screened for lifetime history of psychopathology in both themselves as well as their first degree relatives (Henriques & Davidson, 1990). The findings from patients with localized unilateral brain damage, together with neuroimaging and electrophysiology studies in psychiatric patients without frank lesions, converge on the notion that depression is associated with a deficit in at least the prefrontal component of the approach system. We view this pattern of left prefrontal hypoactivation as a neural reflection of the decreased capacity for pleasure, loss of interest, and generalized decline in goal-related motivation and behavior.
Consistent with this notion are the data from another recent behavioral study
from my laboratory where we demonstrated using signal detection methods that depressed subjects were specifically hyporeactive to reward incentives (Henriques, Glowicki, & Davidson, 1994). In this study, we administered a verbal memory task under reward, punishment, and neutral incentive conditions. The rewards and punishments were monetary. Signal detection measures of sensitivity and response bias were computed. Nondepressed control subjects exhibited a more liberal response bias under both reward and punishment incentives. In other words, they were more likely to consider a stimulus as a signal if they were rewarded for correct hits or punished for misses. Depressed subjects showed a pattern quite similar to the controls in response to the punishment contingency. However, they failed to modify their response bias during the reward condition. In other words, the depressed subjects were less responsive to rewards compared with controls, while the groups showed no significant differences in response to punishment.
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from my laboratory where we demonstrated using signal detection methods that depressed subjects were specifically hyporeactive to reward incentives (Henriques, Glowicki, & Davidson, 1994). In this study, we administered a verbal memory task under reward, punishment, and neutral incentive conditions. The rewards and punishments were monetary. Signal detection measures of sensitivity and response bias were computed. Nondepressed control subjects exhibited a more liberal response bias under both reward and punishment incentives. In other words, they were more likely to consider a stimulus as a signal if they were rewarded for correct hits or punished for misses. Depressed subjects showed a pattern quite similar to the controls in response to the punishment contingency. However, they failed to modify their response bias during the reward condition. In other words, the depressed subjects were less responsive to rewards compared with controls, while the groups showed no significant differences in response to punishment.
Based upon the evidence reviewed earlier, we hypothesized that, in contrast to depression, anxiety disorders would be associated with an increase in right-sided rather than a decrease in left-sided prefrontal activation, particularly during an acute episode of anxiety. To test this hypothesis, we (Davidson, Marshall, Tomarken & Henriques, in press) exposed social phobics who were particularly fearful of making public speeches to the threat of having to make a public speech. We recorded brain electrical activity during an anticipation phase where subjects were presented with an audiotaped countdown that noted how much more time there was until they were to make their speech. The taped recorded message was presented every 30 s for a total of 3 min. We found that the phobics showed a large and highly significant increase over baseline in right-sided prefrontal and right-sided parietal activation. During the same anticipation period, the controls showed a very different pattern of regional changes. The only change to reach significance was in the left posterior temporal region. We interpret this latter change as likely a consequence of verbal rehearsal in anticipation of making the public speech. No region in the right hemisphere exceeded an even liberal statistical threshold for increased activation relative to a baseline condition. The change in prefrontal activation among the phobics is consistent with our hypothesis of increased right-sided activation associated with an increase in anxiety. The increase in right parietal activation is consistent with Heller's (1990) hypothesis of increased right-sided activation associated with the arousal component of anxiety. Indeed, simultaneous measures of heart rate in this study indicated that the phobics had higher heart rate compared with the controls, particularly during the anticipation phase.
Research using self-report measures of positive and negative affect as well as experienced increases in autonomic arousal indicate that decreased positive affect is uniquely associated with depression, while increased autonomic arousal is uniquely associated with anxiety. However, reported negative affect is something that has been found to be common to both anxiety and depression (Watson, Clark, Weber, Assenheimer, Strauss, & McCormick, 1995). We have hypothesized that the decrease in left prefrontal activation may be specific to depression, while the increase in right-sided prefrontal activation (as well as right parietal activation) may be specific to certain components of anxiety. Considerably more research is required to understand the contribution being made by the activated right prefrontal region to negative affect. Other work (see Posner & Petersen, 1990, for review) indicates that portions of the right
prefrontal region are activated during certain types of vigilance and attention (e.g., Knight, 1991; see Posner & Petersen, 1990, for review). Anxiety-related negative affect is accompanied by heightened vigilance (e.g., McNally, 1998), which may be reflected in the right prefrontal increase.
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prefrontal region are activated during certain types of vigilance and attention (e.g., Knight, 1991; see Posner & Petersen, 1990, for review). Anxiety-related negative affect is accompanied by heightened vigilance (e.g., McNally, 1998), which may be reflected in the right prefrontal increase.
One common region we believe to be associated with both anxiety and depression is the amygdala. While there is now a burgeoning literature on the anatomy and function of the amygdala (see Aggleton, 1993, for review), relatively little research has been conducted in intact humans, owing in large measure to the difficulty in imaging function in a structure that is relatively small (the adult human amygdala is not much more than 1 cm3 in volume). However, from what is known from both the animal and human studies, it appears that the amygdala plays an important role in assigning affective significance, particularly of negative valence, to both sensory as well as cognitive input (see LeDoux, 1992, for review). Using positron emission tomography (PET) to measure regional blood flow, several groups have reported increased blood flow in the amygdala in response to both behavioral (e.g., Schneider et al., 1995) and pharmacological (e.g., Ketterer et al., 1996) elicitors of negative affect. We have reported activation in the human amygdala using functional magnetic resonance imaging in response to aversive pictures (Irwin, Davidson, Lowe, Mock, Sorenson, & Turski, 1996). These studies suggest that activation in the human amygdala occurs in response to a broad range of elicitors of negative affect.
Both fMRI and O15 PET are ill-suited, for different reasons, for examining individual differences in resting or baseline levels of activation in the amygdala. As it is currently used, fMRI requires that at least two conditions be compared. What is measured is a relative difference in MR signal intensity between two or more conditions. Currently, fMRI is not calibrated in real physiological units. While O15 PET can be calibrated in real units, it reflects activity over a very short period of time (approximately 1 min) and thus, for psychometric reasons, is poorly suited to capture trait-like differences. It would be the equivalent of developing a single-item self-report instrument for assessing individual differences. PET used with flourodeoxyghicose (FDG) as a tracer, on the other hand, is well-suited to capture trait-like effects because the period of active uptake of tracer in the brain is approximately 30 min. Thus, it is inherently more reliable because the data reflect activity aggregated over this 30-min period. We have used resting FDG-PET to examine individual differences in glucose metabolic rate in the amygdala and its relation to dispositional negative affect in depressed subjects (Abercrombie, Larson, et al., 1998). We acquired a resting FDG PET scan as well as a structural MR scan for each subject. The structural MR scans are used for anatomical localization by coregistering the two image sets. Thus, for each subject, we used an automated algorithm to fit the MR scan to the PET image. Regions of interest (ROIs) were then drawn on each subject's MR scan to outline the amygdala in each hemisphere. These ROIs were drawn on coronal sections of subjects' MR images and the ROIs were then automatically transferred to the co-registered PET images. Glucose metabolism in the left and right amygdala ROIs were then extracted. The inter-rater reliability for the extracted glucose metabolic rate is highly significant with intraclass correlations between two independent raters ≥.97. We found that subjects with greater glucose metabolism in both the right and left amygdala report greater dispositional negative affect on the PAN AS scale (see figure 5-4). These findings indicate that individual differences in resting glucose metabolism in the amygdala are present
and that they predict dispositional negative affect among depressed subjects. Most nondepressed controls score so low on the PANAS trait negative scale that it is not possible to examine the same relation in this group because of the severe truncation of range for the PANAS scores.
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and that they predict dispositional negative affect among depressed subjects. Most nondepressed controls score so low on the PANAS trait negative scale that it is not possible to examine the same relation in this group because of the severe truncation of range for the PANAS scores.
The findings reviewed in this section indicate that the framework adopted for the study of individual differences in fundamental approach and with-drawal-related processes can be usefully applied in the study of psychopathology. A deficit in the approach system is viewed as a unique attribute of depressive disorders that is reflected in decreased left prefrontal activation. The acute symptoms of anxiety, as was described in our study with social phobics, was associated with a pronounced increase in both right-sided prefrontal and parietal activation. From research conducted in our laboratory as well as recent findings in the literature, it appears that amygdala activation may be a generic component of negative affect that is present in both anxiety and depression. Thus, differences between these disorders may be more pronounced for cortical systems that are critically involved in affect regulation and affect-cognition interaction, while subcortical contributions (in particular, the amygdala) may be common to both types of disorders and may in part be responsible for the substantial co-morbidity between these disorders (Watson et al., 1995).
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