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Psychological Well-being (Self-Acceptance)

Fig. 2. Scatterplot depicting the correlation between frontal EEG asymmetry (FC4 - FC3) and total psychological well-being. Relative left frontal asymmetry (denoted by positive values on the abscissa) is associatedwith higher levels ofwell-being. (Urryet al. 2004).

among individuals in their late 50s (Urry et al. 2004; see Fig. 2). Moreover, this association was present even when the association between prefrontal activation asymmetry and dispositional positive affect was statistically removed. These findings indicate that prefrontal activation asymmetry accounts for variance in well-being over and above that which is accounted for by positive affect.

In addition to the studies described above 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 that in turn have been related to differential reactivity to stressful events. Three recent examples from our laboratory include measures of immune function, Cortisol and corticotropin-releasing hormone (CRH). The latter two measures represent key molecules in the activation of a coordinated response to stressful events. Our strategy in each case was to examine relations between individual differences in measures of prefrontal activation asymmetry and these other biological indices. In two separate studies (Kang et al. 1991; Davidson et al. 1999), we examined relations between the prefrontal activation indices and natural killer (NK) activity, since declines in NK activity have been reported in response to stressful, negative events (Kiecolt-Glaser and Glaser 1981). We predicted that subjects with greater left-sided prefrontal activation would exhibit higher NK activity compared with their right-activated counterparts, because the former type of subject has been found to report more dispositional positive affect, to show higher relative BAS activity and to respond more intensely to positive emotional stimuli. In each of the two studies conducted with independent samples, we found that left-frontally activated subjects indeed had higher levels of NK activity compared to their right-frontally activated counterparts (Kang et al. 1991; Davidson et al. 1999). We also examined the magnitude of change in NK activity in response to stress and found that subjects with greater baseline levels of left prefrontal activation showed the smallest magnitude decline in NK activity in response to stress compared with other subjects (Davidson et al. 1999).

One of the concerns with the studies that examine NK function is the fact that this is an in vitro assay and its significance for immunocompetence is unclear. To address this concern, we recently completed a study examining relations between prefrontal activation asymmetry and antibody responses to influenza vaccine (Rosenkranz et al. 2003) in a middle-aged sample of 52 subjects with an average age of 58 years (evenly divided by sex). In this study, we recorded brain electrical measures in the same way as previously described. We compared individuals in the top and bottom quartile on measures of prefrontal activation asymmetry and found large differences between these extreme groups in antibody titers to influenza vaccine (see Fig. 3), with the left-prefrontally activated subjects showing significantly greater antibody titers compared with their right-prefrontally activated counterparts.

In collaboration with Kalin, our laboratory has been studying similar individual differences in scalp-recorded measures of prefrontal activation asymmetry in rhesus monkeys (Davidson et al. 1992,1993). We (Kalin et al. 1998) acquired measures of brain electrical activity from a large sample of rhesus monkeys (N=50). EEG measures were obtained during periods of manual restraint. A subsample of 15 of these monkeys was tested on two occasions four months apart. We found that the test-retest correlation for measures of prefrontal asymmetry was 0.62, 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 et al. 1988). We found that animals with left-sided prefrontal activation had lower levels of baseline Cortisol than their right-frontally activated counterparts (see Fig. 4). As can be seen from the figure, it is the left-activated animals that are particularly low compared with both middle and right-activated subjects. More-

right laterality group

Fig. 3. Bar graph of the mean antibody titer rise (log2) to influenza vaccine six months post-vaccine for extreme groups comprised of individuals (average age of 58 years) in the top and bottom 25th percentiles of activation asymmetry at the lateral frontal (F7/8) site. Error bars denote standard error of the mean. The difference between groups was highly significant (f(22) =3.81, p<.001). (Rosenkranz et al. 2003).

right laterality group

Fig. 3. Bar graph of the mean antibody titer rise (log2) to influenza vaccine six months post-vaccine for extreme groups comprised of individuals (average age of 58 years) in the top and bottom 25th percentiles of activation asymmetry at the lateral frontal (F7/8) site. Error bars denote standard error of the mean. The difference between groups was highly significant (f(22) =3.81, p<.001). (Rosenkranz et al. 2003).

Fig. 4. Basal morning plasma Cortisol from one-year-old rhesus monkeys classified as left-(N=12), middle- (N=16) or right- (N=ll) frontally activated based upon electrophysiological measurements. Error bars denote standard error ofthe mean. (Kalin et al.1998).

Frontal Asymmetry Groups

Fig. 4. Basal morning plasma Cortisol from one-year-old rhesus monkeys classified as left-(N=12), middle- (N=16) or right- (N=ll) frontally activated based upon electrophysiological measurements. Error bars denote standard error ofthe mean. (Kalin et al.1998).

Left Right

Asymmetry Group

Left Right

Asymmetry Group

Fig. 5. Differences between right- (N=9) and left-prefrontally (N=10) activated animals in cerebrospinal fluid measures of corticotropin releasing hormone at five different ages. Units are in pg/ml and error bars denote standard error of the mean. The original classification of the animals as extreme right or left activated was performed on the basis ofbrain electrical activity data collected when the animals were 13 months of age. (Kalin et al. 2000).

over, when blood samples were collected two years following our initial testing, animals classified as showing extreme left-sided prefrontal activation at age one year had significantly lower baseline Cortisol levels when they were three years of age compared with animals who were classified at age one year as displaying extreme right-sided prefrontal activation. Similar findings were obtained with cerebrospinal fluid levels of CRH. Those animals with greater left-sided prefrontal activation showed lower levels of CRH (Kalin et al. 2000; see Fig. 5). These findings indicate that individual differences in prefrontal asymmetry are present in non-human primates and that such differences predict biological measures that are related to affective style.

With the advent of neuroimaging, it has become possible to investigate the relation between individual differences in aspects of amygdala function and measures of affective style. We have used PET with flourodeoxyglucose (FDG) as a tracer to investigate relations between individual differences in glucose metabo lism in the amygdala and dispositional negative affect. FDG-PET is well-suited to capture trait-like effects, since the period of active uptake of tracer in the brain is approximately 30 minutes. Thus, it is inherently more reliable than 0— blood flow measures, since the FDG data reflect activity aggregated over a 30-minute 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 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 ROI's were then extracted. The inter-rater reliability for the extracted glucose metabolic rate is highly significant, with intra-class correlations between two independent raters being >_0.97. We found that subjects with lower levels of glucose metabolism in the right amygdala report less dispositional negative affect on the PANAS scale (r's= 0.41 and 0.56 in separate samples). 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.

In a small sample of 12 normal subjects, we (Irwin et al. 1996) have been able to examine the relation between the magnitude of MR signal change in the amygdala in response to aversive compared with neutral pictures and dispositional negative affect on the PANAS scale. We correlated the average value of the voxels with the maximum Student's t from the left and right amygdala with dispositional negative affect. There was a robust correlation, such that subjects showing the least increase in signal intensity in the right amygdala reported the lowest levels of dispositional negative affect. The findings from the fMRI and PET studies of amygdala function indicate that individual differences in both tonic activation and phasic activation in response to aversive stimuli predict the intensity of dispositional negative affect.

Emotion regulation: A key component ofaffective style

One of the key components of affective style is the capacity to regulate negative emotion and specifically to decrease the duration of negative affect once it arises. We have suggested in several articles that the connections between the PFC and amygdala play an important role in this regulatory process (Davidson 1998a; Davidson and Irwin 1999; Davidson et al. 2000b). In two recent studies, we (Jackson et al. 2003; Larson et al. 1998) examined relations between individual differences in prefrontal activation asymmetry and the emotion-modulated startle. In both studies, we presented pictures from the International Affective Picture System (Lang et al. 1995) while acoustic startle probes were presented and the EMG-mea-sured blink response from the orbicularis oculi muscle region was recorded (see Sutton et al. 1997a for basic methods). Startle probes were presented both during the slide exposure and at various latencies following the offset of the pictures, on separate trials. We interpreted startle magnitude during picture exposure as providing an index related to the peak of emotional response, whereas startle magnitude following the offset of the pictures was taken to reflect the automatic 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, since an acute emotional stimulus is likely to pull for a normative response across subjects whereas individuals are more likely to differ once the stimulus has terminated. 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 in each study were consistent with our predictions and indicated that subjects with greater right-sided prefrontal activation showed a larger blink magnitude following the offset of the negative stimuli, after the variance in blink magnitude during the negative stimulus was partialled out. Measures of prefrontal asymmetry did not reliably predict startle magnitude during picture presentation. The findings from these studies 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 a related study, we found that subjects with greater baseline levels of left prefrontal activation are better able to voluntarily suppress negative affect (see Jackson et al. 2000a,b). Moreover, using functional MRI, we have demonstrated that, when subjects are instructed to voluntarily regulate their negative emotion, reliable bilateral changes in amygdala MR signal intensity are found (Schaefer et al. 2000) and that the magnitude of MR signal decrease in the amygdala during instructions to down-regulate negative affect are predicted by increased MR signal in the ventromedial prefrontal cortex (Urry et al. 2003).

The findings from these studies indicate that individual differences in prefrontal activation may play an important role in emotion regulation. Individuals who report less dispositional negative affect and more dispositional positive affect may be those individuals who have increased facility at regulating negative affect and, specifically, in modulating the intensity of negative affect once it has been activated.

Plasticityin the central circuitryofemotion

The circuitries that underlie emotion regulation, in particular, the amygdala and prefrontal cortex, have been targets of intensive study of plasticity (see Davidson et al. 2000a for extensive discussion). In a series of elegant studies in rats, Meaney and his colleagues (Francis and Meaney 1999) have demonstrated that an early environmental manipulation in rats - frequency of maternal licking/grooming and arched-back nursing - produces a cascade of biological changes in the offspring that shape the central circuitry of emotion and, consequently, alter the animal's behavioral and biological responsivity to stress. For example, the offspring of mothers high in licking and grooming show increased central benzodi-

azepine receptor densities in various subnuclei of the amygdala as well as in the locus ceruleus (LC), increased a2 adrenoreceptor density in the LC and decreased CRH receptor density in the LC (Caldji et al. 1998). In other research, Meaney and co-workers have reported that rats exposed to high licking/grooming mothers exhibited a permanent increase in concentrations of receptors for glucocorticoids in both the hippocampus and the prefrontal cortex (Liu et al. 1997; Meaney et al. 1988,1996). All of these changes induced by early maternal licking/grooming and related behavior involve alterations in the central circuitry of emotion that results in decreased responsiveness to stress later in life.

These findings in animals raise the possibility that similar effects may transpire in humans. There are clearly short-term changes in brain activation that are observed during voluntary emotion regulation, as noted above. Whether repeated practice in techniques of emotion regulation lead to more enduring changes in patterns of brain activation is a question that has not yet been answered in extant research. There are limited data available that indicate that cognitive behavioral therapy for certain disorders (e.g., obsessive compulsive disorder; simple phobia) produces changes in regional brain activity that are comparable to those produced by medication (Baxter et al. 1992; Paquette et al. 2003; Goldapple et al. 2004).

What is largely absent are data on plastic changes in the brain that might be produced by the practice of methods specifically designed to increase positive affect, such as meditation. In a recent study, we examined changes in brain electrical activity and immune function following an eight-week training program in mindfulness meditation (Davidson et al. 2003). In this study, subjects were randomly assigned to a meditation group or a wait-list control group and each of these groups was tested before and after the eight-week training program, as well as four months following the end of the program. We found that subjects in the meditation group showed significantly larger increases in left-sided anterior activation compared with their counterparts in the control group. Subjects received an influenza vaccine just after the eight-week program was completed and we found that influenza antibody titers were significantly higher in the meditators compared with the controls. Most remarkably, we observed that those subjects who showed the largest magnitude change in brain activity also showed the largest increase in antibody titers (see Fig. 6). In a very recent study, we (Lutz et al. 2004) tested long-term meditation practitioners and studied changes in brain electrical signals induced by the practice of specific forms of meditation. The adepts were compared with a control group who were interested in learning to meditate and were taught the practices and had one week to practice prior to the laboratory assessment. We found remarkably large increases in gamma band activity and synchrony across large-scale cortical regions in the gamma band in the adepts when they were meditating compared with the novices. These findings suggest that training procedures designed explicitly to facilitate well-being result in demonstrable and predictable changes in brain and immune function.

The Dalai Lama himself has raised this question in his recent book, The Art of Happiness (Dalai Lama and Cutler 1998), where he explains that "The systematic training of the mind - the cultivation of happiness, the genuine inner transformation by deliberately selecting and focusing on positive mental states and challenging negative mental states -is possible because of the very structure and function

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