Tokiko Isowa

Association of neural and physiological responses during voluntary emotion suppression.

Recent neuroimaging studies have shown that several prefrontal regions play critical roles in inhibiting activation of limbic regions during voluntary emotion regulation. The present study aimed to confirm prior findings and to extend them by identifying the frontal neural circuitry associated with regulation of peripheral physiological responses during voluntary emotion suppression. Ten healthy female subjects were presented with affectively positive, neutral, and negative pictures in each of an Attending and Suppression task. Regional cerebral blood-flow changes were measured using 15O-water positron emission tomography, and autonomic (heart rate: HR, skin conductance response: SCR) and endocrine (adrenocorticotropic hormone: ACTH) indices were measured during both tasks. The left amygdala and the right anterior temporal pole were activated during the Attending task, whereas activation was observed in the left lateral prefrontal cortex (LPFC), including the adjacent medial prefrontal cortex (MPFC), and medial orbitofrontal cortex (MOFC) during the Suppression task. In the Attending task, activation in the amygdala and MOFC positively correlated with magnitudes of the SCR and ACTH responses. Emotion suppression elicited enhancement of SCR and the strength of the effect positively correlated with activation in the MOFC. These results suggest that the MOFC plays a pivotal role in top-down regulation of peripheral physiological responses accompanying emotional experiences.

Reactivity of immune, endocrine and cardiovascular parameters to active and passive acute stress

This study clarified associations among immune, autonomic, and endocrine activities during mental arithmetic and cold pressor stress tasks in 26 women in the follicular phase. Both tasks decreased CD3+ T cells, CD4+ T cells, and CD19+ B cells, whereas they increased lymphocytes, granulocytes, NK cells, and NK cell activity (NKCA). The mental arithmetic task had a greater impact than the cold pressor task on changes in CD3+ T cells and in NK cells. Cardiovascular reactivity to active stress was associated with increased NK cells and decreased CD3+ T cells. Reduced cortisol levels during passive stress were associated with decreased CD19+ B cells and with increased NK cells. The merits of this study are that it controlled the following factors. Perceived stress during the two tasks was matched; both tasks lasted long enough to elicit high-magnitude responses; and the length of the intervening rest period minimized probable carryover effects between tasks.

Transient responses of inflammatory cytokines in acute stress

It has been demonstrated that concentrations of pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are elevated by acute stress. Although several studies confirmed robust changes in IL-6, how acute stress affects other cytokines was less clear. Therefore, the present study simultaneously examined the effects of acute stress on several pro-inflammatory cytokines. Sixteen male participants were given the Trier Social Stress Test (TSST). Blood samples were collected at baseline, immediately after, and 30, 60, and 90min after the TSST. IL-1beta significantly increased immediately after the TSST and returned to the baseline level after 30min. Additionally, this elevation of IL-1beta was correlated with the perceived intensity of stress. These results showed that the concentration of IL-1beta is rapidly regulated, and that elevation of the IL-1beta level could possibly be attributed to transient mobilization of monocytes caused by sympathetic nervous activation. Moreover, a transient increase of IL-1beta might be conveyed to the brain and play a role in forming negative emotional states.

Temporal variation of acute stress responses in sympathetic nervous and immune systems

Sympathetic nervous activity plays a prominent role in acute stress responses in the immune system, enhancement of innate immunity and suppression of specific immunity. The present study was conducted to examine the temporal characteristics of such immune responses to acute stress and to determine their association with sympathetic activity in detail. For this purpose, 15 female undergraduates engaged in a continuous mental arithmetic task for 14 min, and we collected their blood samples for immune indices (CD3+ T cells, CD4+ T cells, NK cells) each 3 min during the task and saliva samples before and after the task. Our results showed that the proportion of Natural Killer cells (NK cells) increased even 2 min after initiation of the task, whereas proportions of CD3+ and CD4+ lymphocytes decreased 8 min after initiation of the task. Moreover, we found significant correlations between cardiovascular activity and the variations of immune indices.

Associations among positive mood, brain, and cardiovascular activities in an affectively positive situation.

It is hypothesized that experiencing positive emotions such as pleasure leads to a perception of the body being in a positive state. This study demonstrated associations among positive mood, brain, and cardiovascular activities by simultaneously recording these activities when positive emotions were evoked in participants watching films revolving around a love story. Heart rate variability analysis revealed increased parasympathetic nervous activity while watching the film. The following brain regions were significantly activated in the positive condition relative to the control condition: medial prefrontal cortex, thalamus, superior temporal gyrus, inferior frontal gyrus, and cerebellum. Further, covariate analyses indicated that these brain regions were temporally associated with subjective positive mood. Activities of brain regions considered to be related to interoceptive awareness, such as the insular cortex, anterior cingulate cortex, amygdala, and orbitofrontal cortex, were also temporally associated with the cardiovascular change. These results suggest that while an individual experiences positive emotions, activities of the central nervous system and cardiovascular system may be interrelated, and the brain may perceive the body to be in a positive state.

Imaging brain and immune association accompanying cognitive appraisal of an acute stressor.

Acute stress elicits multiple responses in autonomic, endocrine, and immune systems. Cognitive appraisal is believed to be one important modulator of such stress responses. To investigate brain substrates of crosstalks between the homeostasis-maintaining systems accompanying appraisal of stressor controllability, we simultaneously recorded regional cerebral blood flow (rCBF) using 15O-water positron emission tomography, cardiovascular indices (heart rate (HR) and blood pressure (BP)), neuroendocrine indices (concentrations of epinephrine, norepinephrine, and adrenocorticotropic hormone (ACTH) in blood), and immune indices (proportions of subsets of lymphocytes (NK cells, helper T cells, cytotoxic T cells, and B cells) in blood), in 11 male subjects who performed a mental arithmetic task with either high controllability (HC) and low controllability (LC). The LC task resulted in less sense of control in subjects than the HC task. Significant increases of rCBF in the medial and lateral orbitofrontal cortices (OFC), and in the medial and lateral prefrontal cortices (MPFC, LPFC) were observed by subtracting the HC task from the LC task. More importantly, significant positive correlations between rCBF and HR, BP, and NK cells were commonly found in the OFC and MPFC during the LC tasks, but not during the HC tasks. The present results showed for the first time that the prefrontal neural network including the OFC and MPFC might be one pivotal region for bi-directional functional association between the brain and peripheral autonomic and immune activities accompanying appraisal of an acute stressor.

Immune, endocrine and cardiovascular responses to controllable and uncontrollable acute stress.

This study, using a triadic-yoked design, clarified the effects of controllability of acute stress on responses of immune, cardiovascular (heart rate and blood pressure), and cortisol activities. Forty-three women in their follicular phase completed a mental arithmetic task as a stressor in which controllability was manipulated by correct or yoked-bogus feedback. The task decreased proportions of CD3+ T cells, CD4+ T cells, and CD19+ B cells, whereas it increased the numbers of white blood cells, lymphocytes, natural killer (NK) cells, and NK cell activity (NKCA). Our main hypothesis that greater immune and cardiovascular responses to the task would be obtained under the uncontrollable condition than under the controllable condition was not supported. However, the uncontrollable stress condition, but not the controllable situation, led to higher correlations between heart rate or blood pressure, and various immune parameters. On the other hand, parameters of heart rate variability reflecting sympathetic and parasympathetic activities showed significant correlations only with NKCA. These results suggest that immune responses were most directly associated with cardiovascular activities under the uncontrollable condition.

Brain and autonomic association accompanying stochastic decision-making

To examine the functional association between brain and autonomic activities accompanying decision-making, we simultaneously recorded regional cerebral blood flow using (15)O-water positron emission tomography and event-related brain potentials (ERPs) time-locked to feedback of reward and punishment, as well as cardiovascular parameters, during a stochastic decision-making task. We manipulated the uncertainty of outcomes in the task; specifically, we compared a condition with high predictability of reward/punishment (contingent-reward condition) and a condition with low predictability of reward/punishment (random-reward condition). The anterior cingulate cortex (ACC) was commonly activated in both conditions. Compared with the contingent-reward condition, the orbitofrontal and right dorsolateral prefrontal cortices and dorsal striatum were activated in the random-reward condition, where subjects had to continue to seek contingency between stimuli and reward/punishment. Activation of these brain regions correlated with a positive component of ERPs locked to feedback signals (feedback-related positivity), which showed an association with behavioral decision-making in the contingent-reward condition. Furthermore, cardiovascular responses were attenuated in the random-reward condition, where continuous attention and contingency monitoring were needed, and such attenuation of cardiovascular responses was mediated by vagal activity that was governed by the rostral ACC. These findings suggest that the prefrontal-striatal network provides a neural basis for decision-making and modulation over the peripheral autonomic activity accompanying decision-making.

Regulation of natural killer cell redistribution by prefrontal cortex during stochastic learning.

Acute stress elicits redistribution of lymphocyte subsets, especially natural killer (NK) cells, probably for preparatory defense against potential invasion of antigens in fight-flight situations. We previously reported that regulation of lymphocyte redistribution is based on the evaluation of the controllability of a stressor (Kimura, K., Ohira, H., Isowa, T., Matsunaga, M., Murashima, S. 2007. Regulation of lymphocytes redistribution via autonomic nervous activity during stochastic learning. Brain Behav. Immun. 21, 921-934; Ohira, H., Isowa, T., Nomura, M., Ichikawa, N., Kimura, K., Miyakoshi, M., Iidaka, T., Fukuyama, S., Nakajima, T., Yamada, J. 2008. Imaging brain and immune association accompanying cognitive appraisal of an acute stressor. Neuroimage 39, 500-514). Specifially, lymphocyte redistribution is somewhat attenuated when a stressor is uncontrollable, probably to save biological energy in a situation where appropriate coping is unclear. We infer that this phenomenon might reflect top-down regulation over peripheral immune function by higher-ordered brain regions. To investigate the neural basis of such a phenomenon, we simultaneously recorded regional cerebral blood flow using (15)O-water positron emission tomography and cardiovascular (blood pressure and heart rate), neuroendocrine (epinephrine, norepinephrine, and adrenocorticotropic hormone), and immune (proportions of NK cells and helper T cells in blood) indices in 16 male subjects who performed a stochastic learning task with manipulation of controllability (controllable vs. uncontrollable). Consistent with previous studies, the proportion of peripheral NK cells was attenuated in an uncontrollable stress condition. The dorsolateral prefrontal and orbitofrontal cortices were activated in the uncontrollable situation but not in the controllable condition, and additionally, these prefrontal brain regions significantly correlated with the degree of redistribution of NK cells in the uncontrollable condition. The results of the study suggest these brain regions are involved in both evaluation of the controllability of a stressor and regulation of immune function.

Chronic stress modulates neural and cardiovascular responses during reversal learning

Animal studies have revealed that chronic stress shifts cognitive strategies from the flexible goal-directed action to the simple and rigid habit action. In addition, stress-induced atrophy in the prefrontal cortex and dorsomedial striatum which are involved in the goal-directed action and hypertrophy of the dorsolateral striatum which is critical for the habit action were parallel with the effects of chronic stress on behaviors. The present study tested whether these previous findings in animal studies are compatible in humans by analyzing effects of chronic stress on neural and cardiovascular responses, which are likely important for performing appropriate actions. Twenty healthy men exposed to low or high chronic job stress performed a stochastic reversal learning task, which required cognitive flexibility and the goal-directed action. Regional cerebral blood flow was evaluated during the task using (15)O-water positron emission tomography, and cardiovascular parameters such as blood pressure and heart rate were also measured. During the reversal learning task, whereas participants with low chronic job stress exhibited activity in the anterior caudate, as well as orbitofrontal cortex, ventrolateral prefrontal cortex, insula, and midbrain, which might be related to the goal-directed action, participants with high chronic job stress exhibited no activity in such brain regions. Furthermore, participants with high chronic job stress exhibited less reactivity in diastolic blood pressure, which might be mediated by anterior cingulate cortical activity. These findings, in line with previous studies, suggested that chronic job stress correlates with less activity in brain regions related to the goal-directed action, and insensitive physiological responses in humans.