Psychoneuroimmunology describes how psychological processes affect health and immunity. Next week we will discuss this topic in more detail. However, this week you will write a review of theDavidsonan

We focus on emotion-related brain activity because medi- tation has been found in numerous studies to reduce anxiety and increase positive affect (4 – 8). In an extensive corpus of work on the functional neuroanatomical substrates of emotion and affective style, we have established that the frontal regions of the brain exhibit a specialization for certain forms of positive and negative emotion (9, 10). Left-sided activation in several anterior regions is observed during certain forms of positive emotion and in subjects with more dispositional pos- itive affect (10, 11). We therefore hypothesized that because meditation decreases anxiety and increases positive affect, subjects who were practicing meditation should show in- creased left-sided activation in these territories compared with those in a wait-list control group.

Recent studies have established that greater relative left- sided anterior activation at baseline is associated with en- hanced immune function using measures of NK activity (12, 13). There has been a paucity of serious research attention to possible immune alterations that might be produced by med- itation (14). This is somewhat surprising in light of the fact that negative psychosocial influences on immunity have now been well established (15–17). Recent research indicates that relaxation and stress management procedures increase T-cy- totoxic/suppressor (CD3 CD) lymphocytes in HIV-infected men (18). On the basis of recent research demonstrating the negative impact of stressful life events on antibody titers in response to influenza vaccine (19), we vaccinated all subjects at the end of the 8-week meditation program (in mid Novem- ber), along with the subjects in wait-list control group at the same time. We hypothesized that the meditators would show greater antibody titers in response to the vaccine compared with the subjects in the wait-list control group. On the basis of From Laboratory for Affective Neuroscience (R.J.D., J.S., M.R.), Depart- ment of Psychology, University of Wisconsin, Madison, Wisconsin; Stress Reduction Clinic, Division of Preventive and Behavioral Medicine (J.K.-Z., S.F.S., F.U.), Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; Departments of Medicine and Microbiol- ogy (D.M.), University of Wisconsin Medical School; Department of the History of Science (A.H.), Harvard University, Cambridge, Massachusetts; Departments of Preventive Cardiology and Sports Medicine (K.B.), Univer- sity of Wisconsin-Madison Hospitals and Clinics Center for Mindfulness, Madison, Wisconsin; and Department of Oral Biology (J.F.S.), College of Dentistry, Ohio State University, Columbus, Ohio.

Address reprint requests to: Richard J. Davidson, PhD, Laboratory for Affective Neuroscience, University of Wisconsin, 1202 W. Johnson St., Madison, WI 53706. Email: [email protected] Received for publication April 4, 2002; revision received December 27, 2002.

DOI: 10.1097/01.PSY.0000077505.67574.E3 564Psychosomatic Medicine 65:564 –570 (2003) 0033-3174/03/6504-0564 Copyright © 2003 by the American Psychosomatic Society the association we have previously reported between anterior activation asymmetry and NK activity, we also predicted that the magnitude of change toward greater relative left-sided activation would be associated with a larger increase in anti- body titers in response to the vaccine.

METHODS Measures of brain electrical activity were recorded before random assign- ment to each of the two groups (Time 1) and then again immediately after (Time 2) and four months after (Time 3) the training period ended. Brain electrical activity, or EEG, and EOG (for correcting EEG for eye movements) was recorded during both baseline conditions and in response to a positive and negative emotion induction using methods that have been extensively de- scribed in previous research (20, 21). EEG was recorded from 27 sites distributed across the scalp and referenced to linked ears during 8 1-minute baseline trials, four with eyes open and four with eyes closed, presented in counterbalanced order according to our established procedures (22). EEG was also recorded during a 1-minute period before and a 3-minute period after subjects wrote about one of three of the most positive and negative experi- ences in their life. These events were listed on a questionnaire administered to subjects before the start of the entire protocol. For this task, the EEG was aggregated across the 1-minute period before and the 3-minute period after the writing itself. Data were not collected during writing because of movement artifact. The EEG was parsed into 1.024-second epochs, overlapped by 50% and then processed with the use of a fast Hartley transform method to derive measures of spectral power density in the -band (8 –13 Hz), which is inversely related to activation (20, 22). Asymmetric activation was indexed using an asymmetry score that is computed by subtracting log-transformed left hemisphere -power densities from the comparable measure derived from homologous right-sided electrodes.

After each of the writing periods, subjects were given the PANAS (23) in state form. In addition, at each assessment, they were administered the PANAS in trait form, along with the Spielberger State-Trait Anxiety Inven- tory (24) in trait form. In addition, subjects in the meditation group were asked to provide daily reports of the frequency and number of minutes and tech- niques of formal meditation practice.

Blood draws were then obtained at 3 to 5 weeks and then again at 8 to 9 weeks after vaccination to examine antibody titers in response to the vaccine using the hemagglutination inhibition assay (19).

A total of 48 right-handed subjects who were employees of a biotechnol- ogy corporation in Madison, Wisconsin, were recruited to participate. Of these, 41 subjects completed some of the measures for at least two of the assessments. The initial laboratory evaluation was conducted before random group assignment. Subjects were then randomly assigned to the meditation group (N 25; 19 female) and the wait-list control group (N 16; 10 female) at a ratio of approximately 3:2. There were no differences between groups in the number of subjects who failed to complete the study. Average age of subjects was 36 years and did not differ between group (range 23 to 56 years). All but two subjects were white (one Asian-American in the treatment group; one South Asian Indian in the control group). Subjects in the wait-list control group were evaluated at each assessment period along with subjects in the meditation group. After completion of the last assessment, the wait-list control subjects were provided with an 8-week training program comparable to that provided to the subjects in the meditation group.

The meditation training (known as MBSR) was delivered by J.K.-Z., and was directly modeled on the MBSR intervention originally developed at the University of Massachusetts Medical Center (25, 26). The effects of MBSR have been reported in numerous clinical studies with diverse populations, as well as in medical students (27, 28). One study demonstrated significant effects of mindfulness on the rate of skin clearing in patients with moderate to severe psoriasis (29) Two recent reviews of MBSR research called for studies to elucidate potential mechanisms of action (30, 31).

The training consisted of a class that met weekly for 2.5 to 3 hours per class, along with a silent seven-hour retreat that was held during week 6 of the course. In addition, subjects were assigned home practice that consisted offormal and informal meditative practices that they were instructed to perform for 1 hour per day, 6 days per week, with the aid of guided audiotapes.

The statistical analysis of the data focused on the interactions between group (Meditation/Wait-list control) and time (Times 1–3, with the first assessment occurring before the intervention, Time 2 occurring immediately after the 8-week intervention and Time 3 occurring four months after the training period ended. MANOVAs were computed for each of the four anterior asymmetry measures. In addition to examining main effects and the interaction, linear trends were also tested. Follow-up ANOVAs on the sepa- rate time periods were performed. RESULTS Affect and Anxiety Measures We evaluated self-report measures of positive and negative affect and anxiety before and after the training. There was a significant Group Time interaction [F(1,31) 5.45,p .05] on a measure of trait anxiety, the Spielberger State-Trait Anxiety Inventory (24), accounted for by a reduction in anx- iety for subjects in the meditation group from Time 1 to Time 2[t(20) 2.86,p .01; see Figure 1). There was no significant Group Time interaction on the Positive and Negative Affect Scale (23). However, in light of the clear a priori predictions for the meditators to show significant de- creases in negative affect with treatment, we tested change over time within each group. There was a significant decrease in trait negative affect with the mediators showing less nega- tive affect at Times 2 and 3 compared with their negative affect at Time 1 [t(20) 2.27 andt(21) 2.45, respectively, p .05 for both; not shown]. Subjects in the control group showed no change over time in negative affect (t 1).

Brain Electrical Activity Measures Based on previous findings linking asymmetric anterior activation to positive affect, we specifically examined changes in four anterior electrode sites (F3/4, FC7/8, T3/4, and C3/4 in the International 10/20 system) during both base-line periods and in response to the emotion inductions. We computed MANOVAs with Group and Time (Times 1–3) as factors and examined main effects and interactions, as well as linear Fig. 1. Mean trait anxiety from the Spielberger State-Trait Anxiety Inven- tory (24) measured separately by group and time. Error bars reflect means SE. BRAIN AND IMMUNE FUNCTION IN MEDITATION 565 Psychosomatic Medicine 65:564 –570 (2003) trends. For the baseline period assessments, there was a mar- ginally significant Group Time linear trend (F(1,33) 3.73,p .06) and a significant main effect for Group (across time periods;F(1,33) 4.57,p .04). When the comparison of change from baseline for each time period was examined, there was a significant Group Time interaction [F(1,37) 5.14,p .05] for the Time 1–3 comparison and a marginally significant Group Time interaction [F(1,33) 2.82,p .10] for the Time 1-Time 2 comparison for the central leads (C3/4). At Time 1, no group differences were present at baseline for any region. At both Time 2 and Time 3, medita- tors showed significantly greater relative left-sided activation at the central sites (C3/4) compared with the wait-list control group (p .05 for each; see Figure 2).

The omnibus MANOVA performed on the positive emo- tion induction condition revealed a marginally significant overall Group Time interaction [F(2,26) 2.52,p .10] for the anterior temporal (T3/4) electrode leads. When the comparison of change from baseline for each time period was examined, there was a significant Group Time interaction [F(1,30) 4.82,p .05] for the Time 1-Time 2 comparison.

This same interaction for the Time 1-Time 3 comparison was marginally significant and in the same direction [F(1,29) 3.46,p .07]. In response to the positive emotion induction at Time 1, no group differences were present in any region.

However, meditators showed a significant increase in left- sided anterior temporal activation from Time 1 to Time 2 (p .05), whereas controls showed no change (Figure 3). There were no other significant Group Time interactions for any other electrode site for the positive emotion induction.

In response to the negative affect induction, the omnibus MANOVA revealed a marginally significant linear trendfor the Group Time interaction [F(1,27) 2.94,p .10] for the anterior temporal leads. The Group Time inter- action for the Time 1-Time 2 comparison for the anterior temporal region (T3/4) was again in the same direction as the other interactions, but not significant [F(1,31) 3.16, p .08].

In response to the negative emotion induction for the cen- tral leads, an omnibus MANOVA revealed a marginally sig- nificant Group Time interaction [F(2,32) 2.78,p .08], along with a marginally significant linear trend for this inter- action [F(1,33) 3.45,p .07]. In addition, there was a significant main effect for Group [F(1,33) 6.78,p .01].

For the central leads, the Group Time interaction for the Time 1-Time 2 comparison wasF(1,33) 3.62,p .07, and for the Time 1-Time 3 comparison it wasF(1,37) 5.41,p .05. Again, there were no group differences in any region at Time 1. At Times 2 and 3, subjects in the meditation group showed significantly greater left-sided activation (C3/C4) compared with subjects in the control group (for Time 2:p .05; for Time 3:p .01). The meditators evinced a significant increase in left-sided activation in this region from Time 1 to Time 2 (p .05; not shown) and Time 3 (p .05: Figure 4).

There were no group differences present for any of the posterior electrodes sites for any of the conditions.

Influenza Vaccine Antibody Titers In response to the influenza vaccine, the meditators dis- played a significantly greater rise in antibody titers from the 4 to the 8 week blood draw compared with the controls [t(33) 2.05,p .05; Figure 5].

Fig. 2. Means SE of asymmetric activation during baseline for subjects in the Meditation group and Control group during Time 1 (before random assignment, before treatment began) and Time 3. The ordinate is an asymmetric metric that represents right minus left log-transformed power density from the C4/C3 electrode sites. This is a standard index of asymmetric activation (20). Higher numbers on this indicate greater left-sided activation. R. J. DAVIDSON et al. 566Psychosomatic Medicine 65:564 –570 (2003) Relations Among Measures To examine the relation between the magnitude of increase in left anterior activation and the magnitude of antibody titer rise in response to the influenza vaccine from the 4- to 8-week blood draw, we computed a change score for each subject toexpress the change in activation asymmetry from Time 1 to Times 2 and 3 and correlated the change in activation asym- metry with the rise in antibody titers, separately for each group. Among subjects in the meditation group, those who showed a greater increase in left-sided activation from Time 1 Fig. 3. Means SE asymmetric activation (in the T3/T4 electrode sites) in response to the positive emotion induction in the Meditation group and Control group during Times 1 and 2. The ordinate is the same metric of asymmetric activation displayed in Figure 2.

Fig. 4. Means SE asymmetric activation in response to the negative emotion induction in the Meditation group and Control group during Times 1 and 3.

The ordinate is the same metric of asymmetric activation displayed in Figure 2 (C3/C4).

BRAIN AND IMMUNE FUNCTION IN MEDITATION 567 Psychosomatic Medicine 65:564 –570 (2003) to Time 2 displayed a larger rise in antibody titers (r .53,p .05; see Figure 6) while there was no significant relation between these variables for subjects in the control group (r .26). These correlations were not significantly different.

We also examined correlations between the frequency and duration of reported practice and changes in the self-reportand EEG measures that showed significant Group Time interactions, as well as antibody titers to influenza vaccine.

There were no significant associations between the measures of practice and any of the biological or self-report measures.

Descriptive statistics on these measures of daily practice are provided in Table 1.

Fig. 5. Means SE antibody rise from the 3- to 5-week to the 8- to 9-week blood draw in the Meditation and Control groups. The ordinate displays the difference in the log-transformed antibody rise between the 3- to 5- and the 8- to 9-week blood draws derived from the hemagglutination inhibition assay.

Fig. 6. Scatter plot for the meditation group only showing the relation between the change in asymmetric anterior activation at baseline from Time 1 toTime 2 in C3/C4 and the magnitude of rise in antibody titers to the influenza vaccine from the week 3 to 5 to the week 8 to 9 blood draw. The meditators that showed the largest magnitude increase in left-sided anterior activation from Time 1 to Time 2 also showed the largest rise in antibody titers from the 3- to 5- to 8- to 9-week blood draws. There was no significant relation between these variables in the control group. R. J. DAVIDSON et al. 568Psychosomatic Medicine 65:564 –570 (2003) DISCUSSION These findings are the first to document significant changes in anterior activation asymmetry as a function of meditation training. A variety of previous research has established that activation asymmetries in anterior scalp regions are related to dispositional affect. Moreover, such asymmetries reflect both state and trait components (32, 33) with both phasic positive mood as well as dispositional positive affect associated with greater relative left-sided anterior activation. On the basis of an extensive corpus of both animal and human data, Davidson and colleagues recently suggested (33) that prefrontal activa- tion asymmetries are plastic and could be shaped by training.

The findings from this study are the first to suggest that meditation can produce increases in relative left-sided anterior activation that are associated with reductions in anxiety and negative affect and increases in positive affect.

We predicted that we would find significant changes in prefrontal as well as central electrode locations. It is unclear why our most consistent findings were observed at the central leads (C3/C4), although this is a region where we have ob- served reliable affect-related asymmetries in the past (11).

Moreover, we have found robust asymmetric increases in left premotor activation in response to positive emotional pictures in a study that measured regional glucose metabolism with positron emission tomography (34). The fact that there was no significant increase in dispositional positive affect in the med- itation group may be related to the failure to detect increases in left prefrontal activation. It may well be that if the duration and/or intensity of the intervention were increased, the in- creases would be observed in both positive affect and left prefrontal activation.

It is of interest that we observed reliable increases in left-sided activation with training in the meditation group in response to both the positiveandnegative affect induction.

We have suggested on the basis of a growing literature on the neural bases of emotion regulation that left-sided anterior activation is associated with more adaptive responding to negative and/or stressful events. Specifically, individuals with greater left-sided anterior activation have been found to show faster recovery after a negative provocation (see Refs. 32 and 33 for reviews).

To our knowledge, this is the first demonstration of a reliable effect of meditation on an in vivo measure of immune function. The finding may reflect a relatively more rapid peak rise in antibody titers among the meditators compared with the controls. The observation that the magnitude of change in immune function was greater for those subjects showing thelarger shift toward left-sided activation further supports earlier associations between these indices (12, 13).

There are several limitations of our study that are important to note. First, there was a relatively small number of subjects who participated and this limited our statistical power. A number of our hypothesized effects were in the predicted direction, but failed to reach significance. Second, the study examined the impact of a relatively brief intervention deliv- ered in a demanding work environment during regular busi- ness hours. It will be of interest in the future to examine the changes in brain and immune function produced by MBSR or more intensive training in a more conducive learning environ- ment. And, finally, the measures of brain function we obtained are relatively crude (see Ref. 20 for a discussion of their limitations). Future studies should examine the impact of meditation using more neuroanatomically informative mea- sures of brain function such as functional magnetic resonance imaging.

Our findings indicate that a short training program in mindfulness meditation (MBSR) has demonstrable effects on brain and immune function and underscores the need for additional research on the biological consequences of this intervention. The authors thank the John D. and Catherine T. MacArthur Foundation’s Research Network on Mind-Body interaction, The Fetzer Institute, and National Institutes for Mental Health (Grant P50 MH61083), and Anne Skillings for technical support during the intervention phase of the study.

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