Cleveland Clinic Journal of Medicine

The traditional paradigm for cardiac care has emphasized the use of technology to treat disease. Our focus on technologies such as echocardiography, advanced imaging instrumentation, and cardiac catheterization mirrors the preoccupation of society as a whole with technologic advances.

Attention has only recently been given to the patient’s emotional experience and how this might relate to outcomes, recovery, and healing. An expanded paradigm of cardiac care incorporates pain relief, emotional support, spiritual healing, and a caring environment. These elements of patient-centered care aim to relieve stress and anxiety in order to achieve a better clinical outcome.

PATIENT-CENTERED CARE

The importance of patient-centered care is illustrated by the results of a 2007 survey in which 41% of patients cited elements of the patient experience as factors that most influenced their choice of hospital.¹ Accepted wisdom on patient choice has historically centered on medical factors such as clinical reputation, physician recommendations, and hospital location, each of which was cited by 18% to 21% of the patients surveyed. Elements of the patient experience cited in the study include stress-reducing factors such as the appearance of the room, ease of scheduling, an environment that supports family needs, convenience and comfort of common areas, on-time performance, and simple registration procedures.

Székely et al² found in a 4-year followup study that high levels of preoperative anxiety predicted greater mortality and cardiovascular morbidity following cardiac surgery. In a study by Tully et al,³ preoperative anxiety was also predictive of hospital readmission following cardiac surgery. Preoperative stress and anxiety are reliable predictors of postoperative distress.⁴

The variety and relative efficacy of interventions to reduce stress and anxiety are not well studied. Voss et al⁵ showed that cardiac surgery patients who were played soothing music experienced significantly reduced anxiety, pain, pain distress, and length of hospital stay. One Cleveland Clinic study of massage therapy, however, was unable to demonstrate a statistically significant therapeutic benefit, despite patient satisfaction with the therapy.⁶

THE ADVENT OF HEALING SERVICES

Identifying patients who exhibit significant preoperative stress and providing, as part of an expanded cardiac care paradigm, emotional care both pre- and postoperatively may ameliorate clinical outcomes. As such, the Heart and Vascular Institute at the Cleveland Clinic formed a healing services division, based on the concept that healing is more than simply physical recovery from a particular procedure. The division’s mission statement is: “To enhance the patient experience by promoting healing through a comprehensive set of coordinated services addressing the holistic needs of the patient.”

At the Cleveland Clinic, healing services are now integrated with standard services to enhance the cardiac care paradigm. Our standard medical services focus on areas of communication and pain control, both of which affect anxiety and stress. The need for enhanced communication is significant: 75% of patients admitted to a Chicago hospital were unable to name a single doctor assigned to their care, and of the remaining 25%, only 40% of responders were correct.⁷

It is worth noting that communicating more information to a patient is not necessarily better. Patients given detailed preoperative information about their disease and the potential complications of their cardiac surgery had levels of preoperative, perioperative, and postoperative stress, anxiety, and depression similar to those who received routine medical information.^8,9 On the other hand, patients desire information about their postoperative plan of care while they are experiencing it, and value communication with physicians, nurses, healing services personnel, and other caregivers when it is presented in a calm and forthright manner. Communications should emphasize that the entire clinical team is there to help the patient get better.

THE FIFTH VITAL SIGN

Pain control is an aspect of care that was long ignored. The goal of the pain control task force at the Cleveland Clinic is the development of effective, efficient, and compassionate pain management.

The fifth vital sign, one that escapes the electronic medical record, can be addressed by this question: “How are you feeling?” Treating pain will reduce stress and anxiety. Before surgery, pain management priorities are discussed with patients, and at each daily encounter the goal is to set, refine, and exceed expectations for pain control through discussion and frequent pain assessments.

Reducing anxiety and stress is the goal of both standard care services and healing services, resulting in more satisfied patients with better clinical outcomes.

CASE: “YOU AND THE TEAM MADE ME GET OUTOF BED AND MOVE FORWARD”

Bobbi is a 78-year-old woman who was initially recovering well following cardiac surgery, including valve surgery, but had to return to the intensive care unit, which is difficult for patients. She was subsequently returned to the floor but was reluctant to walk and progressed slowly, despite normal electrocardiogram, radiographs, and blood panel results. We discovered that her husband was in hospice care in another state, causing Bobbi anxiety as she expressed concern over being her husband’s caregiver while being weakened physically herself. She was fearful of moving forward and her recovery stalled.

The primary care nurse referred her to the healing services team. The healing services team provided support for her anxiety and stress, and reviewed options for managing her husband’s care. She participated in Reiki, spiritual support, and social work services. During her admission her husband died, so the team provided appropriate support.

When asked about her experience upon leavingthe hospital, Bobbi did not mention her surgeon or the success of her heart valve procedure, but commented instead on the healing services team that enabled her to get through the experience.

The traditional paradigm for cardiac care has emphasized the use of technology to treat disease. Our focus on technologies such as echocardiography, advanced imaging instrumentation, and cardiac catheterization mirrors the preoccupation of society as a whole with technologic advances.

Attention has only recently been given to the patient’s emotional experience and how this might relate to outcomes, recovery, and healing. An expanded paradigm of cardiac care incorporates pain relief, emotional support, spiritual healing, and a caring environment. These elements of patient-centered care aim to relieve stress and anxiety in order to achieve a better clinical outcome.

PATIENT-CENTERED CARE

The importance of patient-centered care is illustrated by the results of a 2007 survey in which 41% of patients cited elements of the patient experience as factors that most influenced their choice of hospital.¹ Accepted wisdom on patient choice has historically centered on medical factors such as clinical reputation, physician recommendations, and hospital location, each of which was cited by 18% to 21% of the patients surveyed. Elements of the patient experience cited in the study include stress-reducing factors such as the appearance of the room, ease of scheduling, an environment that supports family needs, convenience and comfort of common areas, on-time performance, and simple registration procedures.

Székely et al² found in a 4-year followup study that high levels of preoperative anxiety predicted greater mortality and cardiovascular morbidity following cardiac surgery. In a study by Tully et al,³ preoperative anxiety was also predictive of hospital readmission following cardiac surgery. Preoperative stress and anxiety are reliable predictors of postoperative distress.⁴

The variety and relative efficacy of interventions to reduce stress and anxiety are not well studied. Voss et al⁵ showed that cardiac surgery patients who were played soothing music experienced significantly reduced anxiety, pain, pain distress, and length of hospital stay. One Cleveland Clinic study of massage therapy, however, was unable to demonstrate a statistically significant therapeutic benefit, despite patient satisfaction with the therapy.⁶

THE ADVENT OF HEALING SERVICES

Identifying patients who exhibit significant preoperative stress and providing, as part of an expanded cardiac care paradigm, emotional care both pre- and postoperatively may ameliorate clinical outcomes. As such, the Heart and Vascular Institute at the Cleveland Clinic formed a healing services division, based on the concept that healing is more than simply physical recovery from a particular procedure. The division’s mission statement is: “To enhance the patient experience by promoting healing through a comprehensive set of coordinated services addressing the holistic needs of the patient.”

At the Cleveland Clinic, healing services are now integrated with standard services to enhance the cardiac care paradigm. Our standard medical services focus on areas of communication and pain control, both of which affect anxiety and stress. The need for enhanced communication is significant: 75% of patients admitted to a Chicago hospital were unable to name a single doctor assigned to their care, and of the remaining 25%, only 40% of responders were correct.⁷

It is worth noting that communicating more information to a patient is not necessarily better. Patients given detailed preoperative information about their disease and the potential complications of their cardiac surgery had levels of preoperative, perioperative, and postoperative stress, anxiety, and depression similar to those who received routine medical information.^8,9 On the other hand, patients desire information about their postoperative plan of care while they are experiencing it, and value communication with physicians, nurses, healing services personnel, and other caregivers when it is presented in a calm and forthright manner. Communications should emphasize that the entire clinical team is there to help the patient get better.

THE FIFTH VITAL SIGN

Pain control is an aspect of care that was long ignored. The goal of the pain control task force at the Cleveland Clinic is the development of effective, efficient, and compassionate pain management.

The fifth vital sign, one that escapes the electronic medical record, can be addressed by this question: “How are you feeling?” Treating pain will reduce stress and anxiety. Before surgery, pain management priorities are discussed with patients, and at each daily encounter the goal is to set, refine, and exceed expectations for pain control through discussion and frequent pain assessments.

Reducing anxiety and stress is the goal of both standard care services and healing services, resulting in more satisfied patients with better clinical outcomes.

CASE: “YOU AND THE TEAM MADE ME GET OUTOF BED AND MOVE FORWARD”

Bobbi is a 78-year-old woman who was initially recovering well following cardiac surgery, including valve surgery, but had to return to the intensive care unit, which is difficult for patients. She was subsequently returned to the floor but was reluctant to walk and progressed slowly, despite normal electrocardiogram, radiographs, and blood panel results. We discovered that her husband was in hospice care in another state, causing Bobbi anxiety as she expressed concern over being her husband’s caregiver while being weakened physically herself. She was fearful of moving forward and her recovery stalled.

The primary care nurse referred her to the healing services team. The healing services team provided support for her anxiety and stress, and reviewed options for managing her husband’s care. She participated in Reiki, spiritual support, and social work services. During her admission her husband died, so the team provided appropriate support.

When asked about her experience upon leavingthe hospital, Bobbi did not mention her surgeon or the success of her heart valve procedure, but commented instead on the healing services team that enabled her to get through the experience.

The traditional paradigm for cardiac care has emphasized the use of technology to treat disease. Our focus on technologies such as echocardiography, advanced imaging instrumentation, and cardiac catheterization mirrors the preoccupation of society as a whole with technologic advances.

Attention has only recently been given to the patient’s emotional experience and how this might relate to outcomes, recovery, and healing. An expanded paradigm of cardiac care incorporates pain relief, emotional support, spiritual healing, and a caring environment. These elements of patient-centered care aim to relieve stress and anxiety in order to achieve a better clinical outcome.

PATIENT-CENTERED CARE

The importance of patient-centered care is illustrated by the results of a 2007 survey in which 41% of patients cited elements of the patient experience as factors that most influenced their choice of hospital.¹ Accepted wisdom on patient choice has historically centered on medical factors such as clinical reputation, physician recommendations, and hospital location, each of which was cited by 18% to 21% of the patients surveyed. Elements of the patient experience cited in the study include stress-reducing factors such as the appearance of the room, ease of scheduling, an environment that supports family needs, convenience and comfort of common areas, on-time performance, and simple registration procedures.

Székely et al² found in a 4-year followup study that high levels of preoperative anxiety predicted greater mortality and cardiovascular morbidity following cardiac surgery. In a study by Tully et al,³ preoperative anxiety was also predictive of hospital readmission following cardiac surgery. Preoperative stress and anxiety are reliable predictors of postoperative distress.⁴

The variety and relative efficacy of interventions to reduce stress and anxiety are not well studied. Voss et al⁵ showed that cardiac surgery patients who were played soothing music experienced significantly reduced anxiety, pain, pain distress, and length of hospital stay. One Cleveland Clinic study of massage therapy, however, was unable to demonstrate a statistically significant therapeutic benefit, despite patient satisfaction with the therapy.⁶

THE ADVENT OF HEALING SERVICES

Identifying patients who exhibit significant preoperative stress and providing, as part of an expanded cardiac care paradigm, emotional care both pre- and postoperatively may ameliorate clinical outcomes. As such, the Heart and Vascular Institute at the Cleveland Clinic formed a healing services division, based on the concept that healing is more than simply physical recovery from a particular procedure. The division’s mission statement is: “To enhance the patient experience by promoting healing through a comprehensive set of coordinated services addressing the holistic needs of the patient.”

At the Cleveland Clinic, healing services are now integrated with standard services to enhance the cardiac care paradigm. Our standard medical services focus on areas of communication and pain control, both of which affect anxiety and stress. The need for enhanced communication is significant: 75% of patients admitted to a Chicago hospital were unable to name a single doctor assigned to their care, and of the remaining 25%, only 40% of responders were correct.⁷

It is worth noting that communicating more information to a patient is not necessarily better. Patients given detailed preoperative information about their disease and the potential complications of their cardiac surgery had levels of preoperative, perioperative, and postoperative stress, anxiety, and depression similar to those who received routine medical information.^8,9 On the other hand, patients desire information about their postoperative plan of care while they are experiencing it, and value communication with physicians, nurses, healing services personnel, and other caregivers when it is presented in a calm and forthright manner. Communications should emphasize that the entire clinical team is there to help the patient get better.

THE FIFTH VITAL SIGN

Pain control is an aspect of care that was long ignored. The goal of the pain control task force at the Cleveland Clinic is the development of effective, efficient, and compassionate pain management.

The fifth vital sign, one that escapes the electronic medical record, can be addressed by this question: “How are you feeling?” Treating pain will reduce stress and anxiety. Before surgery, pain management priorities are discussed with patients, and at each daily encounter the goal is to set, refine, and exceed expectations for pain control through discussion and frequent pain assessments.

Reducing anxiety and stress is the goal of both standard care services and healing services, resulting in more satisfied patients with better clinical outcomes.

CASE: “YOU AND THE TEAM MADE ME GET OUTOF BED AND MOVE FORWARD”

Bobbi is a 78-year-old woman who was initially recovering well following cardiac surgery, including valve surgery, but had to return to the intensive care unit, which is difficult for patients. She was subsequently returned to the floor but was reluctant to walk and progressed slowly, despite normal electrocardiogram, radiographs, and blood panel results. We discovered that her husband was in hospice care in another state, causing Bobbi anxiety as she expressed concern over being her husband’s caregiver while being weakened physically herself. She was fearful of moving forward and her recovery stalled.

The primary care nurse referred her to the healing services team. The healing services team provided support for her anxiety and stress, and reviewed options for managing her husband’s care. She participated in Reiki, spiritual support, and social work services. During her admission her husband died, so the team provided appropriate support.

When asked about her experience upon leavingthe hospital, Bobbi did not mention her surgeon or the success of her heart valve procedure, but commented instead on the healing services team that enabled her to get through the experience.

The impact of clinician stress on the health care system is significant. It can adversely affect the patient experience, compromise patient safety, hinder the delivery of care in a manner that is inconsistent with producing quality outcomes, and increase the overall cost of care.

CLINICIAN STRESS IS PREVALENT

Models of health care that restore human interaction are desperately needed. Clinicians today are overwhelmed by performance assessments that are based on length of stay, use of evidence-based medication regimens, and morbidity and mortality outcomes. Yet clinicians have few opportunities to establish more than cursory relationships with their patients—relationships that would permit better understanding of patients’ emotional well-being and that would optimize the overall healing experience.

Shanafelt et al¹ surveyed 7,905 surgeons and found that clinician stress is pervasive: 64% indicated that their work schedule left inadequate time for their personal or family life, 40% reported burnout, and 30% screened positive for symptoms of depression. Another survey of 763 practicing physicians in California found that 53% reported moderate to severe levels of stress.² Nonphysician clinicians have significant levels of stress as well, with one survey of nurses finding that, of those who quit the profession, 26% cited stress as the cause.³

THE EFFECT OF CLINICIAN STRESSON QUALITY OF CARE

In the Shanafelt et al study, high levels of emotional exhaustion correlated positively with major medical errors over the previous 3 months.¹ Nearly 9% of the surgeons surveyed reported making a stress-related major medical mistake in the past 3 months; among those surgeons with high levels of emotional exhaustion, that figure was nearly 15%. This study also found that every 1-point increase in the emotional exhaustion scale (range, 0 to 54) was associated with a 5% increase in the likelihood of reporting a medical error.¹

In a study of internal medicine residents, fatigue and distress were associated with medical errors, which were reported by 39% of respondents.⁴

STRESS AND COMMUNICATION

Stress can damage the physician-nurse relationship, with a significant impact not only on clinicians, but also on delivery of care. The associated breakdowns in communication can negatively affect several areas, including critical care transitions and timely delivery of care. Stress also affects morale, job satisfaction, and job retention.⁵

ADDRESSING THE IMPACT OF CLINICIAN STRESS

The traditional response to complaints registered by patients has been behavioral coaching, disruptive-behavior programs, and the punitive use of satisfaction metrics, which are incorporated into the physician’s annual evaluation. These approaches do little to address the cause of the stress and can inculcate cynicism instead.

A more useful approach is to define and strive for an optimal working environment for clinicians, thereby promoting an enhanced patient experience. This approach attempts to restore balance to both the business and art of medicine and may incorporate biofeedback and other healing services to clinicians as tools to minimize and manage stress.

The business of medicine may be restored by enhancing the culture and climate of the hospital, improving communication and collaboration, reducing administrative tasks, restoring authority and autonomy, and eliminating punitive practices. The art of medicine may be restored by valuing the sacred relationship between clinician and patient, learning to listen more carefully to the patient, creating better healing environments, providing emotional support, and supporting caregivers.

The impact of clinician stress on the health care system is significant. It can adversely affect the patient experience, compromise patient safety, hinder the delivery of care in a manner that is inconsistent with producing quality outcomes, and increase the overall cost of care.

CLINICIAN STRESS IS PREVALENT

Models of health care that restore human interaction are desperately needed. Clinicians today are overwhelmed by performance assessments that are based on length of stay, use of evidence-based medication regimens, and morbidity and mortality outcomes. Yet clinicians have few opportunities to establish more than cursory relationships with their patients—relationships that would permit better understanding of patients’ emotional well-being and that would optimize the overall healing experience.

Shanafelt et al¹ surveyed 7,905 surgeons and found that clinician stress is pervasive: 64% indicated that their work schedule left inadequate time for their personal or family life, 40% reported burnout, and 30% screened positive for symptoms of depression. Another survey of 763 practicing physicians in California found that 53% reported moderate to severe levels of stress.² Nonphysician clinicians have significant levels of stress as well, with one survey of nurses finding that, of those who quit the profession, 26% cited stress as the cause.³

THE EFFECT OF CLINICIAN STRESSON QUALITY OF CARE

In the Shanafelt et al study, high levels of emotional exhaustion correlated positively with major medical errors over the previous 3 months.¹ Nearly 9% of the surgeons surveyed reported making a stress-related major medical mistake in the past 3 months; among those surgeons with high levels of emotional exhaustion, that figure was nearly 15%. This study also found that every 1-point increase in the emotional exhaustion scale (range, 0 to 54) was associated with a 5% increase in the likelihood of reporting a medical error.¹

In a study of internal medicine residents, fatigue and distress were associated with medical errors, which were reported by 39% of respondents.⁴

STRESS AND COMMUNICATION

Stress can damage the physician-nurse relationship, with a significant impact not only on clinicians, but also on delivery of care. The associated breakdowns in communication can negatively affect several areas, including critical care transitions and timely delivery of care. Stress also affects morale, job satisfaction, and job retention.⁵

ADDRESSING THE IMPACT OF CLINICIAN STRESS

The traditional response to complaints registered by patients has been behavioral coaching, disruptive-behavior programs, and the punitive use of satisfaction metrics, which are incorporated into the physician’s annual evaluation. These approaches do little to address the cause of the stress and can inculcate cynicism instead.

A more useful approach is to define and strive for an optimal working environment for clinicians, thereby promoting an enhanced patient experience. This approach attempts to restore balance to both the business and art of medicine and may incorporate biofeedback and other healing services to clinicians as tools to minimize and manage stress.

The business of medicine may be restored by enhancing the culture and climate of the hospital, improving communication and collaboration, reducing administrative tasks, restoring authority and autonomy, and eliminating punitive practices. The art of medicine may be restored by valuing the sacred relationship between clinician and patient, learning to listen more carefully to the patient, creating better healing environments, providing emotional support, and supporting caregivers.

The impact of clinician stress on the health care system is significant. It can adversely affect the patient experience, compromise patient safety, hinder the delivery of care in a manner that is inconsistent with producing quality outcomes, and increase the overall cost of care.

CLINICIAN STRESS IS PREVALENT

Models of health care that restore human interaction are desperately needed. Clinicians today are overwhelmed by performance assessments that are based on length of stay, use of evidence-based medication regimens, and morbidity and mortality outcomes. Yet clinicians have few opportunities to establish more than cursory relationships with their patients—relationships that would permit better understanding of patients’ emotional well-being and that would optimize the overall healing experience.

Shanafelt et al¹ surveyed 7,905 surgeons and found that clinician stress is pervasive: 64% indicated that their work schedule left inadequate time for their personal or family life, 40% reported burnout, and 30% screened positive for symptoms of depression. Another survey of 763 practicing physicians in California found that 53% reported moderate to severe levels of stress.² Nonphysician clinicians have significant levels of stress as well, with one survey of nurses finding that, of those who quit the profession, 26% cited stress as the cause.³

THE EFFECT OF CLINICIAN STRESSON QUALITY OF CARE

In the Shanafelt et al study, high levels of emotional exhaustion correlated positively with major medical errors over the previous 3 months.¹ Nearly 9% of the surgeons surveyed reported making a stress-related major medical mistake in the past 3 months; among those surgeons with high levels of emotional exhaustion, that figure was nearly 15%. This study also found that every 1-point increase in the emotional exhaustion scale (range, 0 to 54) was associated with a 5% increase in the likelihood of reporting a medical error.¹

In a study of internal medicine residents, fatigue and distress were associated with medical errors, which were reported by 39% of respondents.⁴

STRESS AND COMMUNICATION

Stress can damage the physician-nurse relationship, with a significant impact not only on clinicians, but also on delivery of care. The associated breakdowns in communication can negatively affect several areas, including critical care transitions and timely delivery of care. Stress also affects morale, job satisfaction, and job retention.⁵

ADDRESSING THE IMPACT OF CLINICIAN STRESS

The traditional response to complaints registered by patients has been behavioral coaching, disruptive-behavior programs, and the punitive use of satisfaction metrics, which are incorporated into the physician’s annual evaluation. These approaches do little to address the cause of the stress and can inculcate cynicism instead.

A more useful approach is to define and strive for an optimal working environment for clinicians, thereby promoting an enhanced patient experience. This approach attempts to restore balance to both the business and art of medicine and may incorporate biofeedback and other healing services to clinicians as tools to minimize and manage stress.

The business of medicine may be restored by enhancing the culture and climate of the hospital, improving communication and collaboration, reducing administrative tasks, restoring authority and autonomy, and eliminating punitive practices. The art of medicine may be restored by valuing the sacred relationship between clinician and patient, learning to listen more carefully to the patient, creating better healing environments, providing emotional support, and supporting caregivers.

Traditionally, biofeedback was considered to be a stress management technique that targeted sympathetic nervous system (SNS) overdrive with an adrenal medullary system backup. Recent advances in autonomic physiology, however, have clarified that except in extreme situations, the SNS is not the key factor in day-to-day stress. Rather, the parasympathetic branch of the autonomic nervous system appears to be a more likely candidate for mediating routine stress because, unlike the SNS, which has slow-acting neurotransmitters (ie, catecholamines), the parasympathetic nervous system has the fast-acting transmitter acetylcholine.

VAGAL WITHDRAWAL: AN ALTERNATIVE TO SYMPATHETIC ACTIVATION

Porges¹ first proposed the concept of vagal withdrawal as an indicator of stress and stress vulnerability; this contrasts with the idea that the stress response is a consequence of sympathetic activation and the hypothalamic-pituitary-adrenal axis response. In the vagal withdrawal model, the response to stress is stabilization of the sympathetic system followed by termination of parasympathetic activity, manifested as cardiac acceleration.

Respiratory sinus arrhythmia (RSA), or the variability in heart rate as it synchronizes with breathing, is considered an index of parasympathetic tone. In the laboratory, slow atropine infusion produces a transient paradoxical vagomimetic effect characterized by an initial increase in RSA, followed by a flattening and then a rise in the heart rate.² This phenomenon has been measured in people during times of routine stress, such as when worrying about being late for an appointment. In such individuals, biofeedback training can result in recovery of normal RSA shortly after an episode of anxiety.

Historically, the focus of biofeedback was to cultivate low arousal, presumably reducing SNS activity, through the use of finger temperature, skin conductance training, and profound muscle relaxation. More sophisticated ways to look at both branches of the autonomic nervous system have since emerged that allow for sampling of the beat-by-beat changes in heart rate.

HEART RATE VARIABILITY BIOFEEDBACK

The concept of modifying the respiration rate (paced breathing) originated some 2,500 years ago as a component of meditation. It is being revisited today in the form of heart rate variability (HRV) biofeedback training, which is being used as a stress-management tool and a method to correct disorders in which autonomic regulation is thought to be important. HRV biofeedback involves training to increase the amplitude of HRV rhythms and thus improve autonomic homeostasis.

Normal HRV has a pattern of overlapping oscillatory frequency components, including:

• a high-frequency rhythm, 0.15 to 0.4 Hz, which is the RSA;
• a low-frequency rhythm, 0.05 to 0.15 Hz, associated with blood pressure oscillations; and
• a very-low-frequency rhythm, 0.005 to 0.05 Hz, which may regulate vascular tone and body temperature.

The goal of HRV biofeedback is to achieve respiratory rates at which resonance occurs between cardiac rhythms associated with respiration (RSA, or high-frequency oscillations) and those caused by baroreflex activity (low-frequency oscillations).

Spectral analysis has demonstrated that nearly all of the activity with HRV biofeedback occurs at a low-frequency band. The reason is that activity in the low-frequency band is related more to baroreflex activity than to HRV compared with other ranges of frequency. Breathing rates that correspond to baroreflex effects, called resonance frequency breathing, represent resonance in the cardiovascular system. Several devices are available whose mechanisms are based on the concept of achieving resonance frequency breathing. One such device is a slow-breathing monitor (Resp-e-rate) that has been approved by the US Food and Drug Administration for the adjunctive treatment of hypertension.

Improved HRV may suggest an improved risk status: Kleiger et al⁴ found that the relative risk of mortality was 5.3 times greater for people with SDNN of less than 50 msec compared with those whose SDNN was greater than 100 msec. In Del Pozo’s study, eight of 30 patients in the intervention group achieved an SDNN of greater than 50 msec (vs 0 at pretreatment) compared with three of 31 controls (vs two at pretreatment).³ As an additional benefit of HRV biofeedback, patients in the intervention group who entered the study with hypertension all became normotensive.

In a meta-analysis, van Dixhoorn and White⁵ found fewer cardiac events, fewer episodes of angina, and less occurrence of arrhythmia and exercise-induced ischemia from intensive supervised relaxation therapy in patients with ischemic heart disease. Improvements in scales of depression and anxiety were also observed with relaxation therapy.

Other studies have shown biofeedback to have beneficial effects based on the Posttraumatic Stress Disorder Checklist, the Hamilton Depression Rating Scale, and, in patients with mild to moderate heartfailure, the 6-minute walk test.^6–8

The proposed mechanism for the beneficial effects of biofeedback found in clinical trials is improvement in baroreflex function, producing greater reflex efficiency and improved modulation of autonomic activity.

CONCLUSION

A shift in emphasis to vagal withdrawal has led to new forms of biofeedback that probably potentiate many of the same mechanisms thought to be present in Eastern practices such as yoga and tai chi. Results from small-scale trials have been promising for HRV biofeedback as a means of modifying responses to stress and promoting homeostatic processes that reduce the intensity of symptoms and improve surrogate markers associated with a number of disorders.

Traditionally, biofeedback was considered to be a stress management technique that targeted sympathetic nervous system (SNS) overdrive with an adrenal medullary system backup. Recent advances in autonomic physiology, however, have clarified that except in extreme situations, the SNS is not the key factor in day-to-day stress. Rather, the parasympathetic branch of the autonomic nervous system appears to be a more likely candidate for mediating routine stress because, unlike the SNS, which has slow-acting neurotransmitters (ie, catecholamines), the parasympathetic nervous system has the fast-acting transmitter acetylcholine.

VAGAL WITHDRAWAL: AN ALTERNATIVE TO SYMPATHETIC ACTIVATION

Porges¹ first proposed the concept of vagal withdrawal as an indicator of stress and stress vulnerability; this contrasts with the idea that the stress response is a consequence of sympathetic activation and the hypothalamic-pituitary-adrenal axis response. In the vagal withdrawal model, the response to stress is stabilization of the sympathetic system followed by termination of parasympathetic activity, manifested as cardiac acceleration.

Respiratory sinus arrhythmia (RSA), or the variability in heart rate as it synchronizes with breathing, is considered an index of parasympathetic tone. In the laboratory, slow atropine infusion produces a transient paradoxical vagomimetic effect characterized by an initial increase in RSA, followed by a flattening and then a rise in the heart rate.² This phenomenon has been measured in people during times of routine stress, such as when worrying about being late for an appointment. In such individuals, biofeedback training can result in recovery of normal RSA shortly after an episode of anxiety.

Historically, the focus of biofeedback was to cultivate low arousal, presumably reducing SNS activity, through the use of finger temperature, skin conductance training, and profound muscle relaxation. More sophisticated ways to look at both branches of the autonomic nervous system have since emerged that allow for sampling of the beat-by-beat changes in heart rate.

HEART RATE VARIABILITY BIOFEEDBACK

The concept of modifying the respiration rate (paced breathing) originated some 2,500 years ago as a component of meditation. It is being revisited today in the form of heart rate variability (HRV) biofeedback training, which is being used as a stress-management tool and a method to correct disorders in which autonomic regulation is thought to be important. HRV biofeedback involves training to increase the amplitude of HRV rhythms and thus improve autonomic homeostasis.

Normal HRV has a pattern of overlapping oscillatory frequency components, including:

• a high-frequency rhythm, 0.15 to 0.4 Hz, which is the RSA;
• a low-frequency rhythm, 0.05 to 0.15 Hz, associated with blood pressure oscillations; and
• a very-low-frequency rhythm, 0.005 to 0.05 Hz, which may regulate vascular tone and body temperature.

The goal of HRV biofeedback is to achieve respiratory rates at which resonance occurs between cardiac rhythms associated with respiration (RSA, or high-frequency oscillations) and those caused by baroreflex activity (low-frequency oscillations).

Spectral analysis has demonstrated that nearly all of the activity with HRV biofeedback occurs at a low-frequency band. The reason is that activity in the low-frequency band is related more to baroreflex activity than to HRV compared with other ranges of frequency. Breathing rates that correspond to baroreflex effects, called resonance frequency breathing, represent resonance in the cardiovascular system. Several devices are available whose mechanisms are based on the concept of achieving resonance frequency breathing. One such device is a slow-breathing monitor (Resp-e-rate) that has been approved by the US Food and Drug Administration for the adjunctive treatment of hypertension.

Improved HRV may suggest an improved risk status: Kleiger et al⁴ found that the relative risk of mortality was 5.3 times greater for people with SDNN of less than 50 msec compared with those whose SDNN was greater than 100 msec. In Del Pozo’s study, eight of 30 patients in the intervention group achieved an SDNN of greater than 50 msec (vs 0 at pretreatment) compared with three of 31 controls (vs two at pretreatment).³ As an additional benefit of HRV biofeedback, patients in the intervention group who entered the study with hypertension all became normotensive.

In a meta-analysis, van Dixhoorn and White⁵ found fewer cardiac events, fewer episodes of angina, and less occurrence of arrhythmia and exercise-induced ischemia from intensive supervised relaxation therapy in patients with ischemic heart disease. Improvements in scales of depression and anxiety were also observed with relaxation therapy.

Other studies have shown biofeedback to have beneficial effects based on the Posttraumatic Stress Disorder Checklist, the Hamilton Depression Rating Scale, and, in patients with mild to moderate heartfailure, the 6-minute walk test.^6–8

The proposed mechanism for the beneficial effects of biofeedback found in clinical trials is improvement in baroreflex function, producing greater reflex efficiency and improved modulation of autonomic activity.

CONCLUSION

A shift in emphasis to vagal withdrawal has led to new forms of biofeedback that probably potentiate many of the same mechanisms thought to be present in Eastern practices such as yoga and tai chi. Results from small-scale trials have been promising for HRV biofeedback as a means of modifying responses to stress and promoting homeostatic processes that reduce the intensity of symptoms and improve surrogate markers associated with a number of disorders.

Traditionally, biofeedback was considered to be a stress management technique that targeted sympathetic nervous system (SNS) overdrive with an adrenal medullary system backup. Recent advances in autonomic physiology, however, have clarified that except in extreme situations, the SNS is not the key factor in day-to-day stress. Rather, the parasympathetic branch of the autonomic nervous system appears to be a more likely candidate for mediating routine stress because, unlike the SNS, which has slow-acting neurotransmitters (ie, catecholamines), the parasympathetic nervous system has the fast-acting transmitter acetylcholine.

VAGAL WITHDRAWAL: AN ALTERNATIVE TO SYMPATHETIC ACTIVATION

Porges¹ first proposed the concept of vagal withdrawal as an indicator of stress and stress vulnerability; this contrasts with the idea that the stress response is a consequence of sympathetic activation and the hypothalamic-pituitary-adrenal axis response. In the vagal withdrawal model, the response to stress is stabilization of the sympathetic system followed by termination of parasympathetic activity, manifested as cardiac acceleration.

Respiratory sinus arrhythmia (RSA), or the variability in heart rate as it synchronizes with breathing, is considered an index of parasympathetic tone. In the laboratory, slow atropine infusion produces a transient paradoxical vagomimetic effect characterized by an initial increase in RSA, followed by a flattening and then a rise in the heart rate.² This phenomenon has been measured in people during times of routine stress, such as when worrying about being late for an appointment. In such individuals, biofeedback training can result in recovery of normal RSA shortly after an episode of anxiety.

Historically, the focus of biofeedback was to cultivate low arousal, presumably reducing SNS activity, through the use of finger temperature, skin conductance training, and profound muscle relaxation. More sophisticated ways to look at both branches of the autonomic nervous system have since emerged that allow for sampling of the beat-by-beat changes in heart rate.

HEART RATE VARIABILITY BIOFEEDBACK

The concept of modifying the respiration rate (paced breathing) originated some 2,500 years ago as a component of meditation. It is being revisited today in the form of heart rate variability (HRV) biofeedback training, which is being used as a stress-management tool and a method to correct disorders in which autonomic regulation is thought to be important. HRV biofeedback involves training to increase the amplitude of HRV rhythms and thus improve autonomic homeostasis.

Normal HRV has a pattern of overlapping oscillatory frequency components, including:

• a high-frequency rhythm, 0.15 to 0.4 Hz, which is the RSA;
• a low-frequency rhythm, 0.05 to 0.15 Hz, associated with blood pressure oscillations; and
• a very-low-frequency rhythm, 0.005 to 0.05 Hz, which may regulate vascular tone and body temperature.

The goal of HRV biofeedback is to achieve respiratory rates at which resonance occurs between cardiac rhythms associated with respiration (RSA, or high-frequency oscillations) and those caused by baroreflex activity (low-frequency oscillations).

Spectral analysis has demonstrated that nearly all of the activity with HRV biofeedback occurs at a low-frequency band. The reason is that activity in the low-frequency band is related more to baroreflex activity than to HRV compared with other ranges of frequency. Breathing rates that correspond to baroreflex effects, called resonance frequency breathing, represent resonance in the cardiovascular system. Several devices are available whose mechanisms are based on the concept of achieving resonance frequency breathing. One such device is a slow-breathing monitor (Resp-e-rate) that has been approved by the US Food and Drug Administration for the adjunctive treatment of hypertension.

Improved HRV may suggest an improved risk status: Kleiger et al⁴ found that the relative risk of mortality was 5.3 times greater for people with SDNN of less than 50 msec compared with those whose SDNN was greater than 100 msec. In Del Pozo’s study, eight of 30 patients in the intervention group achieved an SDNN of greater than 50 msec (vs 0 at pretreatment) compared with three of 31 controls (vs two at pretreatment).³ As an additional benefit of HRV biofeedback, patients in the intervention group who entered the study with hypertension all became normotensive.

In a meta-analysis, van Dixhoorn and White⁵ found fewer cardiac events, fewer episodes of angina, and less occurrence of arrhythmia and exercise-induced ischemia from intensive supervised relaxation therapy in patients with ischemic heart disease. Improvements in scales of depression and anxiety were also observed with relaxation therapy.

Other studies have shown biofeedback to have beneficial effects based on the Posttraumatic Stress Disorder Checklist, the Hamilton Depression Rating Scale, and, in patients with mild to moderate heartfailure, the 6-minute walk test.^6–8

The proposed mechanism for the beneficial effects of biofeedback found in clinical trials is improvement in baroreflex function, producing greater reflex efficiency and improved modulation of autonomic activity.

CONCLUSION

A shift in emphasis to vagal withdrawal has led to new forms of biofeedback that probably potentiate many of the same mechanisms thought to be present in Eastern practices such as yoga and tai chi. Results from small-scale trials have been promising for HRV biofeedback as a means of modifying responses to stress and promoting homeostatic processes that reduce the intensity of symptoms and improve surrogate markers associated with a number of disorders.

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder whose symptoms emerge following exposure to extreme stress, such as those encountered in the battlefield or as a result of sexual abuse or natural disasters. The ability to employ coping mechanisms affects the disorder’s presentation as well as the frequency, intensity, and duration of the symptoms. The “Wounded Warrior” program at East Carolina University (Greenville, NC) was developed to promote the functional independence of US Marines, including those with PTSD.

STRESS RESPONSE: INTERACTION OF THE BRAIN AND IMMUNE SYSTEM

Walter Cannon coined the “flight or fight” response to stress in the early 20th century, in which he emphasized the importance of the parasympathetic system.¹ In 1988, Folkow clarified the description as an immune response to stress.² The stress response is now understood to be a neuroendocrine function that includes a feedback loop between the hypothalamus and the pituitary and adrenal glands; stimulation of the hypothalamus promotes secretion of corticotropin-releasing hormone (CRH) into the hypophyseal portal system, which supplies the anterior pituitarywith blood. CRH stimulates the secretion of adrenocorticotropic hormone into the bloodstream by the pituitary, prompting the adrenal glands to release the stress hormone cortisol.

Cortisol mobilizes the body’s defenses to meet the challenge of an adverse situation. It modulates the stress response by inhibiting the further release of CRH by the hypothalamus. Cortisol thus protects healthy cells and tissues by inhibiting an overreaction from the immune system. Without this protective effect, the interaction between the brain and the immune system can become dysregulated, increasing the risk of immune disorders.

THE CENTRAL AUTONOMIC NETWORK

The central nervous system that regulates the overall balance of the autonomic nervous system (ANS) has been called the central autonomic network (CAN).³ The CAN helps control executive, social, affective, attentional, and motivational functions. Therefore, the old paradigm of simply decreasing hyperarousal of the ANS to treat negative affective states and dispositions is inadequate. Instead, restoring the appropriate relationship between the ANS and the central nervous system is the aim behind interventions to treat PTSD.

Autonomic, cognitive, and affective functions assist humans in maintaining balance when confronted with external challenges. The CAN controls inhibitory or negative processes that permit specific behavior and redeploy resources needed elsewhere. When negative circuits are compromised, positive circuits develop, resulting in hypervigilance, the symptoms of which can be devastating and, if not ameliorated, can develop into permanent conditions. In one study,Vietnam veterans with PTSD had an 8% reduction in the volume of their right hippocampus compared with veterans without PTSD. Another study calculated a 26% reduction in the left hippocampus and a 22% reduction in the right in veterans with the most severe PTSD compared with veterans who were in combat but had no PTSD symptoms.⁴

A common subcortical neural system regulates defensive behavior, including autonomic, emotional, and cognitive behavior. When the prefrontal cortex is taken “off line” for whatever reason, parasympathetic inhibitory action is withdrawn, and relative sympathetic dominance, associated with defense, occurs.

CONFRONTING HYPERAROUSAL

The question then arises of how to train the ANS to avoid hypervigilance. Growing evidence supports the use of heart rate variability as a predictor of hypervigilance and inefficient allocation of attentional and cognitive resources.

The overall objective of heart rate variability training is to decrease ANS hyperarousal and to improve its balance. “Wounded warriors” learn to control ANS responses to stress-producing stimuli (eg, thoughts, memories, and images associated with combat). The goal of training is to decrease arousal and maintain ANS balance for increasing lengths of time.

Once it was observed that alpha waves were dysfunctional in vulnerable populations, protocols were developed to train alpha and theta waves as a method of improving function. Peniston and colleagues^5–9 showed that increased alpha and theta brain wave production resulted in normalized personality measures and prolonged the period of time before relapse in alcoholics. This protocol has also shown efficacy as an intervention in depression and PTSD.

BIOFEEDBACK TRAINING PROGRAM

The US Department of Defense is studying a combination of central nervous system biofeedback with ANS biofeedback, with the goal of restoring and maintaining tone between the systems.

The training program used in the study lasts 1 month, and starts with a session for preassessment, 16 biofeedback sessions (four per week), a postprogram evaluation, and a 3-month followup. Each week, participants are exposed to stress-producing stimuli that increase in intensity:

• Week 1: Stroop Color Word Test, math stressor, talk stressor/everyday events
• Week 2: Talk stressor, combat experiences
• Week 3: Images and sounds of combat
• Week 4: Virtual Baghdad or Afghanistan (virtual reality exposure)

Each biofeedback session consists of 5 minutes of baseline evaluation; 5 minutes in which the veteran is subjected to the weekly stressor; 20 minutes of heart rate variability and neurofeedback training; 5 more minutes of training with the weekly stressor; 20 more minutes of heart rate variability and neurofeedback training; and finally 5 minutes of recovery.

SUMMARY

Dysfunction in the balance of both the ANS and central nervous system is associated with symptoms of PTSD in combat veterans. Methods that are designed to restore balance in these systems are needed to ameliorate these symptoms. Biofeedback and neurofeedback are safe methods with which to achieve these goals.

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder whose symptoms emerge following exposure to extreme stress, such as those encountered in the battlefield or as a result of sexual abuse or natural disasters. The ability to employ coping mechanisms affects the disorder’s presentation as well as the frequency, intensity, and duration of the symptoms. The “Wounded Warrior” program at East Carolina University (Greenville, NC) was developed to promote the functional independence of US Marines, including those with PTSD.

STRESS RESPONSE: INTERACTION OF THE BRAIN AND IMMUNE SYSTEM

Walter Cannon coined the “flight or fight” response to stress in the early 20th century, in which he emphasized the importance of the parasympathetic system.¹ In 1988, Folkow clarified the description as an immune response to stress.² The stress response is now understood to be a neuroendocrine function that includes a feedback loop between the hypothalamus and the pituitary and adrenal glands; stimulation of the hypothalamus promotes secretion of corticotropin-releasing hormone (CRH) into the hypophyseal portal system, which supplies the anterior pituitarywith blood. CRH stimulates the secretion of adrenocorticotropic hormone into the bloodstream by the pituitary, prompting the adrenal glands to release the stress hormone cortisol.

Cortisol mobilizes the body’s defenses to meet the challenge of an adverse situation. It modulates the stress response by inhibiting the further release of CRH by the hypothalamus. Cortisol thus protects healthy cells and tissues by inhibiting an overreaction from the immune system. Without this protective effect, the interaction between the brain and the immune system can become dysregulated, increasing the risk of immune disorders.

THE CENTRAL AUTONOMIC NETWORK

The central nervous system that regulates the overall balance of the autonomic nervous system (ANS) has been called the central autonomic network (CAN).³ The CAN helps control executive, social, affective, attentional, and motivational functions. Therefore, the old paradigm of simply decreasing hyperarousal of the ANS to treat negative affective states and dispositions is inadequate. Instead, restoring the appropriate relationship between the ANS and the central nervous system is the aim behind interventions to treat PTSD.

Autonomic, cognitive, and affective functions assist humans in maintaining balance when confronted with external challenges. The CAN controls inhibitory or negative processes that permit specific behavior and redeploy resources needed elsewhere. When negative circuits are compromised, positive circuits develop, resulting in hypervigilance, the symptoms of which can be devastating and, if not ameliorated, can develop into permanent conditions. In one study,Vietnam veterans with PTSD had an 8% reduction in the volume of their right hippocampus compared with veterans without PTSD. Another study calculated a 26% reduction in the left hippocampus and a 22% reduction in the right in veterans with the most severe PTSD compared with veterans who were in combat but had no PTSD symptoms.⁴

A common subcortical neural system regulates defensive behavior, including autonomic, emotional, and cognitive behavior. When the prefrontal cortex is taken “off line” for whatever reason, parasympathetic inhibitory action is withdrawn, and relative sympathetic dominance, associated with defense, occurs.

CONFRONTING HYPERAROUSAL

The question then arises of how to train the ANS to avoid hypervigilance. Growing evidence supports the use of heart rate variability as a predictor of hypervigilance and inefficient allocation of attentional and cognitive resources.

The overall objective of heart rate variability training is to decrease ANS hyperarousal and to improve its balance. “Wounded warriors” learn to control ANS responses to stress-producing stimuli (eg, thoughts, memories, and images associated with combat). The goal of training is to decrease arousal and maintain ANS balance for increasing lengths of time.

Once it was observed that alpha waves were dysfunctional in vulnerable populations, protocols were developed to train alpha and theta waves as a method of improving function. Peniston and colleagues^5–9 showed that increased alpha and theta brain wave production resulted in normalized personality measures and prolonged the period of time before relapse in alcoholics. This protocol has also shown efficacy as an intervention in depression and PTSD.

BIOFEEDBACK TRAINING PROGRAM

The US Department of Defense is studying a combination of central nervous system biofeedback with ANS biofeedback, with the goal of restoring and maintaining tone between the systems.

The training program used in the study lasts 1 month, and starts with a session for preassessment, 16 biofeedback sessions (four per week), a postprogram evaluation, and a 3-month followup. Each week, participants are exposed to stress-producing stimuli that increase in intensity:

• Week 1: Stroop Color Word Test, math stressor, talk stressor/everyday events
• Week 2: Talk stressor, combat experiences
• Week 3: Images and sounds of combat
• Week 4: Virtual Baghdad or Afghanistan (virtual reality exposure)

Each biofeedback session consists of 5 minutes of baseline evaluation; 5 minutes in which the veteran is subjected to the weekly stressor; 20 minutes of heart rate variability and neurofeedback training; 5 more minutes of training with the weekly stressor; 20 more minutes of heart rate variability and neurofeedback training; and finally 5 minutes of recovery.

SUMMARY

Dysfunction in the balance of both the ANS and central nervous system is associated with symptoms of PTSD in combat veterans. Methods that are designed to restore balance in these systems are needed to ameliorate these symptoms. Biofeedback and neurofeedback are safe methods with which to achieve these goals.

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder whose symptoms emerge following exposure to extreme stress, such as those encountered in the battlefield or as a result of sexual abuse or natural disasters. The ability to employ coping mechanisms affects the disorder’s presentation as well as the frequency, intensity, and duration of the symptoms. The “Wounded Warrior” program at East Carolina University (Greenville, NC) was developed to promote the functional independence of US Marines, including those with PTSD.

STRESS RESPONSE: INTERACTION OF THE BRAIN AND IMMUNE SYSTEM

Walter Cannon coined the “flight or fight” response to stress in the early 20th century, in which he emphasized the importance of the parasympathetic system.¹ In 1988, Folkow clarified the description as an immune response to stress.² The stress response is now understood to be a neuroendocrine function that includes a feedback loop between the hypothalamus and the pituitary and adrenal glands; stimulation of the hypothalamus promotes secretion of corticotropin-releasing hormone (CRH) into the hypophyseal portal system, which supplies the anterior pituitarywith blood. CRH stimulates the secretion of adrenocorticotropic hormone into the bloodstream by the pituitary, prompting the adrenal glands to release the stress hormone cortisol.

Cortisol mobilizes the body’s defenses to meet the challenge of an adverse situation. It modulates the stress response by inhibiting the further release of CRH by the hypothalamus. Cortisol thus protects healthy cells and tissues by inhibiting an overreaction from the immune system. Without this protective effect, the interaction between the brain and the immune system can become dysregulated, increasing the risk of immune disorders.

THE CENTRAL AUTONOMIC NETWORK

The central nervous system that regulates the overall balance of the autonomic nervous system (ANS) has been called the central autonomic network (CAN).³ The CAN helps control executive, social, affective, attentional, and motivational functions. Therefore, the old paradigm of simply decreasing hyperarousal of the ANS to treat negative affective states and dispositions is inadequate. Instead, restoring the appropriate relationship between the ANS and the central nervous system is the aim behind interventions to treat PTSD.

Autonomic, cognitive, and affective functions assist humans in maintaining balance when confronted with external challenges. The CAN controls inhibitory or negative processes that permit specific behavior and redeploy resources needed elsewhere. When negative circuits are compromised, positive circuits develop, resulting in hypervigilance, the symptoms of which can be devastating and, if not ameliorated, can develop into permanent conditions. In one study,Vietnam veterans with PTSD had an 8% reduction in the volume of their right hippocampus compared with veterans without PTSD. Another study calculated a 26% reduction in the left hippocampus and a 22% reduction in the right in veterans with the most severe PTSD compared with veterans who were in combat but had no PTSD symptoms.⁴

A common subcortical neural system regulates defensive behavior, including autonomic, emotional, and cognitive behavior. When the prefrontal cortex is taken “off line” for whatever reason, parasympathetic inhibitory action is withdrawn, and relative sympathetic dominance, associated with defense, occurs.

CONFRONTING HYPERAROUSAL

The question then arises of how to train the ANS to avoid hypervigilance. Growing evidence supports the use of heart rate variability as a predictor of hypervigilance and inefficient allocation of attentional and cognitive resources.

The overall objective of heart rate variability training is to decrease ANS hyperarousal and to improve its balance. “Wounded warriors” learn to control ANS responses to stress-producing stimuli (eg, thoughts, memories, and images associated with combat). The goal of training is to decrease arousal and maintain ANS balance for increasing lengths of time.

Once it was observed that alpha waves were dysfunctional in vulnerable populations, protocols were developed to train alpha and theta waves as a method of improving function. Peniston and colleagues^5–9 showed that increased alpha and theta brain wave production resulted in normalized personality measures and prolonged the period of time before relapse in alcoholics. This protocol has also shown efficacy as an intervention in depression and PTSD.

BIOFEEDBACK TRAINING PROGRAM

The US Department of Defense is studying a combination of central nervous system biofeedback with ANS biofeedback, with the goal of restoring and maintaining tone between the systems.

The training program used in the study lasts 1 month, and starts with a session for preassessment, 16 biofeedback sessions (four per week), a postprogram evaluation, and a 3-month followup. Each week, participants are exposed to stress-producing stimuli that increase in intensity:

• Week 1: Stroop Color Word Test, math stressor, talk stressor/everyday events
• Week 2: Talk stressor, combat experiences
• Week 3: Images and sounds of combat
• Week 4: Virtual Baghdad or Afghanistan (virtual reality exposure)

Each biofeedback session consists of 5 minutes of baseline evaluation; 5 minutes in which the veteran is subjected to the weekly stressor; 20 minutes of heart rate variability and neurofeedback training; 5 more minutes of training with the weekly stressor; 20 more minutes of heart rate variability and neurofeedback training; and finally 5 minutes of recovery.

SUMMARY

Dysfunction in the balance of both the ANS and central nervous system is associated with symptoms of PTSD in combat veterans. Methods that are designed to restore balance in these systems are needed to ameliorate these symptoms. Biofeedback and neurofeedback are safe methods with which to achieve these goals.

Question from audience: Why does the Cleveland Clinic start its healing services program preoperatively rather than postoperatively?

Dr. Gillinov: We have a fairly well defined preoperative set of medical tests, and during this process nurses present patients with materials that explain the experience, and nurses and doctors make themselves available in special classes to answer patients’ questions. In doing so, we have increasingly identified patients preoperatively who have stress or problems.

Last week I saw a woman who had a leaking mitral valve, but her symptoms were out of proportion to her disease. She had loss of energy and appetite, and she wasn’t eating much. She was depressed and our team picked that up. She actually never had to undergo surgery. We referred her to a psychologist and, according to her son, she started to feel better. By starting preoperatively, we’re sometimes able to pick out things that we should treat instead of heart disease.

We also provide guided imagery and massage preoperatively.

Dr. Duffy: Healing services is on standing preoperative orders at the hospital. The team goes in proactively and asks, “In addition to your open heart surgery on Wednesday, is there anything we can do to support your emotional and spiritual journey here today?”

Terminology also matters. The term “healing services” is a safe umbrella under which we include biofeedback as one of the services, but it encompasses pastoral care, hospice care, and palliative care. The way it’s integrated into a care model is important. If it’s reserved for end of life, it might be viewed as defective or as a death sentence, so we want the healing services team to be proactive.

Question from audience: How does the primary care physician fit into all of this? I believe that if the physicians in the hospital want to gain patient confidence, they’ll show that they’re communicating well with the primary care physician.

Dr. Gevirtz: The primary care physicians are incredibly open to this idea. They have 12 minutes to deal with people with fibromyalgia, irritable bowel syndrome, chronic pain, noncardiac chest pain, etc. What are they going to do in 12 minutes? They’re grateful if they have a handoff, especially if it’s in the Clinic itself.

Question from audience: Are there any thoughts on making biofeedback part of general training rather than using it just for patients who’ve already experienced trauma?

Dr. Gevirtz: We did a study in which we showed that a biofeedback technician in the primary care setting saved the health maintenance system quite a lot of money, but the administration couldn’t decide whose territory to take to give us an office, so it ended the program.

Dr. Russoniello: How we enable greater access to our intervention is an important question. I see people quit the program if they can’t get access to biofeedback. In an effort to enhance compliance, we’ve incorporated biofeedback into video games, working with a couple of private companies to develop them.The idea is that persons playing the video game can accrue points to enhance their overall score if they perform paced breathing or some other form of biofeedback. Early indications from focus groups are that people will like this.

We have already shown in randomized controlled clinical studies of depression and anxiety that certain video games can improve mood and decrease stress.There is a big movement to get products in people’s hands to help them manage their health.

Question from audience: How much overlap is there between biofeedback methodologies—enhancing heart rate variability, vagal withdrawal, neurofeedback, and electroencephalographic feedback—in the systems you’re targeting and what are the unique contributions of each?

Dr. Gevirtz: We follow a stepped-care model. We start with the simplest and move on to the more complicated technologies. Two published studies with long-term followup showed the effectiveness of a learned breathing technique in alleviating noncardiac chest pain. Simple biofeedback wasn’t even needed. Three years later, the patients were better than they were at the end of the actual training. If you can do it simply, then you do it, and if it doesn’t work, then move on to more and more complicated techniques, with neurofeedback being the last resort.

Question from audience: Has anybody measured the physical impact of stimulating multiple systems on the study subject? In other words, can it be damaging to overstimulate these systems at the same time?

Dr. Gevirtz: We’ve been trying to do that. Recurrent abdominal pain or functional abdominal pain is the most common complaint to pediatric gastroenterologists. We have 1,800 patients a year who make it to the children’s hospital level with this complaint. These are kids who are suffering with very great pain and we we’re pretty sure it’s an autonomically mediated kind of phenomenon. We’re able to measure vagal activity in these kids in ambulatory settings at school and have found very little vagal activity before treatment. After training, they were able to restore vagal activity, and it correlated at the level of 0.63 with a reduction of symptoms. I think it’s important to try to tie the physiology to symptoms. It’s not always easy to do but we’re trying.

Question from audience: I’d like to pick up on two topics that Dr. Duffy raised: the business of medicine and the proposal for informed hope rather than an informed consent before surgery. Something that I see with patients and families at times is this magical expectation promoted by the business side that medicine can do these amazing and wonderful things and doesn’t have any sort of weaknesses. I wonder what role unrealistic expectations promoted by the media, advertising, and others may play in the stress of patients, caregivers, and physicians who need to try to meet the expectations of infallible medicine?

Dr. Duffy: We’ve spun so far the other way with our advanced technology that we’ve lost the human side, especially the concept of a relationship and giving people hope even though they have a terminal condition. It’s a balance between the art and the business of medicine. It’s about setting realistic expectations and realistic hope.

Question from audience: Why does the Cleveland Clinic start its healing services program preoperatively rather than postoperatively?

Dr. Gillinov: We have a fairly well defined preoperative set of medical tests, and during this process nurses present patients with materials that explain the experience, and nurses and doctors make themselves available in special classes to answer patients’ questions. In doing so, we have increasingly identified patients preoperatively who have stress or problems.

Last week I saw a woman who had a leaking mitral valve, but her symptoms were out of proportion to her disease. She had loss of energy and appetite, and she wasn’t eating much. She was depressed and our team picked that up. She actually never had to undergo surgery. We referred her to a psychologist and, according to her son, she started to feel better. By starting preoperatively, we’re sometimes able to pick out things that we should treat instead of heart disease.

We also provide guided imagery and massage preoperatively.

Dr. Duffy: Healing services is on standing preoperative orders at the hospital. The team goes in proactively and asks, “In addition to your open heart surgery on Wednesday, is there anything we can do to support your emotional and spiritual journey here today?”

Terminology also matters. The term “healing services” is a safe umbrella under which we include biofeedback as one of the services, but it encompasses pastoral care, hospice care, and palliative care. The way it’s integrated into a care model is important. If it’s reserved for end of life, it might be viewed as defective or as a death sentence, so we want the healing services team to be proactive.

Question from audience: How does the primary care physician fit into all of this? I believe that if the physicians in the hospital want to gain patient confidence, they’ll show that they’re communicating well with the primary care physician.

Dr. Gevirtz: The primary care physicians are incredibly open to this idea. They have 12 minutes to deal with people with fibromyalgia, irritable bowel syndrome, chronic pain, noncardiac chest pain, etc. What are they going to do in 12 minutes? They’re grateful if they have a handoff, especially if it’s in the Clinic itself.

Question from audience: Are there any thoughts on making biofeedback part of general training rather than using it just for patients who’ve already experienced trauma?

Dr. Gevirtz: We did a study in which we showed that a biofeedback technician in the primary care setting saved the health maintenance system quite a lot of money, but the administration couldn’t decide whose territory to take to give us an office, so it ended the program.

Dr. Russoniello: How we enable greater access to our intervention is an important question. I see people quit the program if they can’t get access to biofeedback. In an effort to enhance compliance, we’ve incorporated biofeedback into video games, working with a couple of private companies to develop them.The idea is that persons playing the video game can accrue points to enhance their overall score if they perform paced breathing or some other form of biofeedback. Early indications from focus groups are that people will like this.

We have already shown in randomized controlled clinical studies of depression and anxiety that certain video games can improve mood and decrease stress.There is a big movement to get products in people’s hands to help them manage their health.

Question from audience: How much overlap is there between biofeedback methodologies—enhancing heart rate variability, vagal withdrawal, neurofeedback, and electroencephalographic feedback—in the systems you’re targeting and what are the unique contributions of each?

Dr. Gevirtz: We follow a stepped-care model. We start with the simplest and move on to the more complicated technologies. Two published studies with long-term followup showed the effectiveness of a learned breathing technique in alleviating noncardiac chest pain. Simple biofeedback wasn’t even needed. Three years later, the patients were better than they were at the end of the actual training. If you can do it simply, then you do it, and if it doesn’t work, then move on to more and more complicated techniques, with neurofeedback being the last resort.

Question from audience: Has anybody measured the physical impact of stimulating multiple systems on the study subject? In other words, can it be damaging to overstimulate these systems at the same time?

Dr. Gevirtz: We’ve been trying to do that. Recurrent abdominal pain or functional abdominal pain is the most common complaint to pediatric gastroenterologists. We have 1,800 patients a year who make it to the children’s hospital level with this complaint. These are kids who are suffering with very great pain and we we’re pretty sure it’s an autonomically mediated kind of phenomenon. We’re able to measure vagal activity in these kids in ambulatory settings at school and have found very little vagal activity before treatment. After training, they were able to restore vagal activity, and it correlated at the level of 0.63 with a reduction of symptoms. I think it’s important to try to tie the physiology to symptoms. It’s not always easy to do but we’re trying.

Question from audience: I’d like to pick up on two topics that Dr. Duffy raised: the business of medicine and the proposal for informed hope rather than an informed consent before surgery. Something that I see with patients and families at times is this magical expectation promoted by the business side that medicine can do these amazing and wonderful things and doesn’t have any sort of weaknesses. I wonder what role unrealistic expectations promoted by the media, advertising, and others may play in the stress of patients, caregivers, and physicians who need to try to meet the expectations of infallible medicine?

Dr. Duffy: We’ve spun so far the other way with our advanced technology that we’ve lost the human side, especially the concept of a relationship and giving people hope even though they have a terminal condition. It’s a balance between the art and the business of medicine. It’s about setting realistic expectations and realistic hope.

Question from audience: Why does the Cleveland Clinic start its healing services program preoperatively rather than postoperatively?

Dr. Gillinov: We have a fairly well defined preoperative set of medical tests, and during this process nurses present patients with materials that explain the experience, and nurses and doctors make themselves available in special classes to answer patients’ questions. In doing so, we have increasingly identified patients preoperatively who have stress or problems.

Last week I saw a woman who had a leaking mitral valve, but her symptoms were out of proportion to her disease. She had loss of energy and appetite, and she wasn’t eating much. She was depressed and our team picked that up. She actually never had to undergo surgery. We referred her to a psychologist and, according to her son, she started to feel better. By starting preoperatively, we’re sometimes able to pick out things that we should treat instead of heart disease.

We also provide guided imagery and massage preoperatively.

Dr. Duffy: Healing services is on standing preoperative orders at the hospital. The team goes in proactively and asks, “In addition to your open heart surgery on Wednesday, is there anything we can do to support your emotional and spiritual journey here today?”

Terminology also matters. The term “healing services” is a safe umbrella under which we include biofeedback as one of the services, but it encompasses pastoral care, hospice care, and palliative care. The way it’s integrated into a care model is important. If it’s reserved for end of life, it might be viewed as defective or as a death sentence, so we want the healing services team to be proactive.

Question from audience: How does the primary care physician fit into all of this? I believe that if the physicians in the hospital want to gain patient confidence, they’ll show that they’re communicating well with the primary care physician.

Dr. Gevirtz: The primary care physicians are incredibly open to this idea. They have 12 minutes to deal with people with fibromyalgia, irritable bowel syndrome, chronic pain, noncardiac chest pain, etc. What are they going to do in 12 minutes? They’re grateful if they have a handoff, especially if it’s in the Clinic itself.

Question from audience: Are there any thoughts on making biofeedback part of general training rather than using it just for patients who’ve already experienced trauma?

Dr. Gevirtz: We did a study in which we showed that a biofeedback technician in the primary care setting saved the health maintenance system quite a lot of money, but the administration couldn’t decide whose territory to take to give us an office, so it ended the program.

Dr. Russoniello: How we enable greater access to our intervention is an important question. I see people quit the program if they can’t get access to biofeedback. In an effort to enhance compliance, we’ve incorporated biofeedback into video games, working with a couple of private companies to develop them.The idea is that persons playing the video game can accrue points to enhance their overall score if they perform paced breathing or some other form of biofeedback. Early indications from focus groups are that people will like this.

We have already shown in randomized controlled clinical studies of depression and anxiety that certain video games can improve mood and decrease stress.There is a big movement to get products in people’s hands to help them manage their health.

Question from audience: How much overlap is there between biofeedback methodologies—enhancing heart rate variability, vagal withdrawal, neurofeedback, and electroencephalographic feedback—in the systems you’re targeting and what are the unique contributions of each?

Dr. Gevirtz: We follow a stepped-care model. We start with the simplest and move on to the more complicated technologies. Two published studies with long-term followup showed the effectiveness of a learned breathing technique in alleviating noncardiac chest pain. Simple biofeedback wasn’t even needed. Three years later, the patients were better than they were at the end of the actual training. If you can do it simply, then you do it, and if it doesn’t work, then move on to more and more complicated techniques, with neurofeedback being the last resort.

Question from audience: Has anybody measured the physical impact of stimulating multiple systems on the study subject? In other words, can it be damaging to overstimulate these systems at the same time?

Dr. Gevirtz: We’ve been trying to do that. Recurrent abdominal pain or functional abdominal pain is the most common complaint to pediatric gastroenterologists. We have 1,800 patients a year who make it to the children’s hospital level with this complaint. These are kids who are suffering with very great pain and we we’re pretty sure it’s an autonomically mediated kind of phenomenon. We’re able to measure vagal activity in these kids in ambulatory settings at school and have found very little vagal activity before treatment. After training, they were able to restore vagal activity, and it correlated at the level of 0.63 with a reduction of symptoms. I think it’s important to try to tie the physiology to symptoms. It’s not always easy to do but we’re trying.

Question from audience: I’d like to pick up on two topics that Dr. Duffy raised: the business of medicine and the proposal for informed hope rather than an informed consent before surgery. Something that I see with patients and families at times is this magical expectation promoted by the business side that medicine can do these amazing and wonderful things and doesn’t have any sort of weaknesses. I wonder what role unrealistic expectations promoted by the media, advertising, and others may play in the stress of patients, caregivers, and physicians who need to try to meet the expectations of infallible medicine?

Dr. Duffy: We’ve spun so far the other way with our advanced technology that we’ve lost the human side, especially the concept of a relationship and giving people hope even though they have a terminal condition. It’s a balance between the art and the business of medicine. It’s about setting realistic expectations and realistic hope.

The effect of emotion on the heart is not confined to depression, but extends to a variety of mental states; as William Harvey described in 1628, “A mental disturbance provoking pain, excessive joy, hope or anxiety extends to the heart, where it affects its temper and rate, impairing general nutrition and vigor.”

In going beyond the well-established role of depression as a risk factor for heart disease, 2010 delivered several important publications recognizing anxiety, anger, and other forms of distress as key factors in the etiology of coronary heart disease (CHD). Other papers of merit elucidated new and overlooked insights into the pathways linking psychosocial stress and cardiovascular risk, and also considered psychologic states that appear to promote healthy functioning.

IMPACT OF NEGATIVE EMOTIONS ON RISK OF INCIDENT CORONARY HEART DISEASE

In a meta-analysis of 20 prospective studies that included 249,846 persons with a mean follow-up of 11.2 years, Roest et al¹ examined the impact of anxiety characterized by the presence of anxiety symptoms or a diagnosis of anxiety disorder on incident CHD. Most of the studies adjusted for a broad array of relevant potential confounders. Findings suggest the presence of anxiety increases the risk of incident CHD by 26% (P P = .003).

In a meta-analysis of 25 prospective studies of 7,160 persons with a mean follow-up exceeding 10 years, Chida and Steptoe² found that anger increased the risk of incident CHD by 19%, after adjustment for standard coronary risk factors. The effect was less stable than that associated with anxiety and depression, and when stratified by gender, the harmful effects of anger were more evident in men than in women. The effect of anger was attenuated when controlling for behavioral covariates. The association between anger and CHD did not hold for all ways of measuring anger, which suggests that the type of anger or the ability to regulate anger may be relevant to the relationship.

A study that did account for the type of anger expression on the risk of incident CHD was conducted by Davidson and Mostofsky.³ The independent effect of three distinct types of anger expression (constructive anger, destructive anger justification, and destructive anger rumination) on 10-year incident CHD was examined, controlling for other psychosocial factors. In men, higher scores for constructive anger were associated with a lower rate of CHD; in both men and women, higher scores for destructive anger justification were associated with an increased risk of CHD.

Insights gained from these studies are as follows:

• The impact of anxiety appears to be comparable to depression, and the effects of anxiety and depression are largely independent.
• If anxiety and depression co-occur, the effect on CHD is synergistic.
• The effects of anger are less clear; its impact may be independent of or dependent on other forms of psychologic distress.
• Distress in general appears to serve as a signal that something is wrong and needs to be addressed. If ignored, it may become chronic and unremitting; because symptoms of distress may lead to systemic dysregulation and increased CHD risk, they may indicate the need for increased surveillance and intervention.

WHY FOCUS ON THE BIOLOGY OF EMOTIONS?

A clear biologic explanation for the influence of emotional factors on physical health would serve to assuage skeptics who doubt that such a link exists or who attribute a common underlying genetic trait to both negative affect and heart disease. Further, focusing on the biology may help answer key questions with respect to emotions and disease processes: What is the damage incurred by negative emotional states and is it reversible? Can compensatory pathways be activated to bypass the mechanisms causing damage or slow the progression of disease?

Cardiac response to worry and stress

In one study attempting to shed light on relevant emotion-related biologic process, the prolonged physiologic effects of worry were examined. Worry episodes and stressful events were recorded hourly along with ambulatory heart rate and heart rate variability in 73 teachers for 4 days.⁴ Autonomic activity, as reflected by a concurrent elevation in heart rate and a decrease in heart rate variability, was increased up to 2 hours after a worry episode. The findings also suggested that the prolonged cardiac effects of separate worry episodes were independent.

Another study sought to determine whether heightened reactivity or delayed recovery to acute stress increases risk of cardiovascular disease.⁵ This meta-analysis included 36 studies to assess whether acute cardiovascular response to various laboratory stressors (ie, cognitive tasks, stress interviews, public speaking). Findings indicated that heightened cardiovascular reactivity was associated with worse cardiovascular outcomes, such as incident hypertension, coronary calcification, carotid intima-media thickness, and cardiovascular events over time.

Role of aldosterone overlooked

Reprinted from Neuroscience and Biobehavioral Reviews (Kubzansky LD, et al. Aldosterone: a forgotten mediator of the relationship between psychological stress and heart disease. Neurosci Biobehav Rev 2010; 34:80–86), © 2010, with permission from Elsevier.

WHY CONSIDER RESILIENCE?

Because the absence of a deficit is not the same as the presence of an asset, greater insight into dysfunction may be gained by explicitly considering what promotes healthy functioning. Ameliorating distress has proven difficult; so, in studying resilience (including the ability to regulate affect), new targets for prevention and intervention may be identified. Although no meta-analysis of resilience factors has been published to date owing to the paucity of data, the studies that have been performed are generally rigorous and have demonstrated consistent findings.

For example, one prospective, well-controlled study of 1,739 men and women demonstrated a protective effect of positive affect (as ascertained by structured interview) against 10-year incident CHD.⁶ The risk of fatal or nonfatal ischemic heart disease events was reduced by 22% (P = .02) for each 1-point increase in positive affect, even after controlling for depression and negative emotions.

Reprinted, with permission, from Archives of General Psychiatry (Kubzansky LD, et al. Arch Gen Psychiatry 2011; 68:400–408), Copyright © 2011 American Medical Association. All rights reserved.

Biology of resilience: Counteracting cellular damage

Genomic changes can be induced by the relaxation response, as evidenced by the differential gene expression profiles of long-term daily practitioners of relaxation (ie, meditation, yoga), short-term (8-week) practitioners of relaxation, and healthy controls.⁸ Alterations in cellular metabolism, oxidative phosphorylation, and generation of reactive oxygen species that counteract proinflammatory responses, indicative of an adaptive response, were observed in both groups that practiced relaxation.

FUTURE DIRECTIONS

Whether and how the sources and effects of psychosocial stress and response to treatment differ across men and women deserves closer examination. A review by Low et al⁹ summarizes the current state of knowledge with respect to psychosocial factors and heart disease in women, noting that the sources of stress associated with increased CHD risk differ across men and women; psychosocial risk factors like depression and anxiety appear to increase risk for both men and women; work-related stress has larger effects in men while stress related to relationships and family responsibilities appear to have larger effects in women.

Although responses to psychosocial stress are not clearly different between men and women, intervention targeted at reducing distress is much less effective in reducing the risk of adverse events in women versus men. The mechanism to explain this difference in effectiveness of intervention urgently requires further exploration.

In conducting this work, several factors are important. The best time to intervene to reduce psychosocial distress is unknown; a key consideration will be, what is the best etiologic window for intervention? Perhaps a life-course approach that targets individuals with chronically high levels of emotional distress who also have multiple coronary risk factors, and that enhances their capacity to regulate emotions would prove superior to waiting until late in the disease process.

Another area that may prove fruitful is to consider in more depth the biology of the placebo effect and whether and how it may inform our understanding of resilience.

More generally, considering why interventions seem to influence outcomes so differently across men and women, applying a life course approach to determine the best etiologic window for prevention and intervention strategies, and conducting a more in-depth exploration of the biology of resilience may lead to improved capacity for population-based approaches to reducing the burden of CHD.

The effect of emotion on the heart is not confined to depression, but extends to a variety of mental states; as William Harvey described in 1628, “A mental disturbance provoking pain, excessive joy, hope or anxiety extends to the heart, where it affects its temper and rate, impairing general nutrition and vigor.”

In going beyond the well-established role of depression as a risk factor for heart disease, 2010 delivered several important publications recognizing anxiety, anger, and other forms of distress as key factors in the etiology of coronary heart disease (CHD). Other papers of merit elucidated new and overlooked insights into the pathways linking psychosocial stress and cardiovascular risk, and also considered psychologic states that appear to promote healthy functioning.

IMPACT OF NEGATIVE EMOTIONS ON RISK OF INCIDENT CORONARY HEART DISEASE

In a meta-analysis of 20 prospective studies that included 249,846 persons with a mean follow-up of 11.2 years, Roest et al¹ examined the impact of anxiety characterized by the presence of anxiety symptoms or a diagnosis of anxiety disorder on incident CHD. Most of the studies adjusted for a broad array of relevant potential confounders. Findings suggest the presence of anxiety increases the risk of incident CHD by 26% (P P = .003).

In a meta-analysis of 25 prospective studies of 7,160 persons with a mean follow-up exceeding 10 years, Chida and Steptoe² found that anger increased the risk of incident CHD by 19%, after adjustment for standard coronary risk factors. The effect was less stable than that associated with anxiety and depression, and when stratified by gender, the harmful effects of anger were more evident in men than in women. The effect of anger was attenuated when controlling for behavioral covariates. The association between anger and CHD did not hold for all ways of measuring anger, which suggests that the type of anger or the ability to regulate anger may be relevant to the relationship.

A study that did account for the type of anger expression on the risk of incident CHD was conducted by Davidson and Mostofsky.³ The independent effect of three distinct types of anger expression (constructive anger, destructive anger justification, and destructive anger rumination) on 10-year incident CHD was examined, controlling for other psychosocial factors. In men, higher scores for constructive anger were associated with a lower rate of CHD; in both men and women, higher scores for destructive anger justification were associated with an increased risk of CHD.

Insights gained from these studies are as follows:

• The impact of anxiety appears to be comparable to depression, and the effects of anxiety and depression are largely independent.
• If anxiety and depression co-occur, the effect on CHD is synergistic.
• The effects of anger are less clear; its impact may be independent of or dependent on other forms of psychologic distress.
• Distress in general appears to serve as a signal that something is wrong and needs to be addressed. If ignored, it may become chronic and unremitting; because symptoms of distress may lead to systemic dysregulation and increased CHD risk, they may indicate the need for increased surveillance and intervention.

WHY FOCUS ON THE BIOLOGY OF EMOTIONS?

A clear biologic explanation for the influence of emotional factors on physical health would serve to assuage skeptics who doubt that such a link exists or who attribute a common underlying genetic trait to both negative affect and heart disease. Further, focusing on the biology may help answer key questions with respect to emotions and disease processes: What is the damage incurred by negative emotional states and is it reversible? Can compensatory pathways be activated to bypass the mechanisms causing damage or slow the progression of disease?

Cardiac response to worry and stress

In one study attempting to shed light on relevant emotion-related biologic process, the prolonged physiologic effects of worry were examined. Worry episodes and stressful events were recorded hourly along with ambulatory heart rate and heart rate variability in 73 teachers for 4 days.⁴ Autonomic activity, as reflected by a concurrent elevation in heart rate and a decrease in heart rate variability, was increased up to 2 hours after a worry episode. The findings also suggested that the prolonged cardiac effects of separate worry episodes were independent.

Another study sought to determine whether heightened reactivity or delayed recovery to acute stress increases risk of cardiovascular disease.⁵ This meta-analysis included 36 studies to assess whether acute cardiovascular response to various laboratory stressors (ie, cognitive tasks, stress interviews, public speaking). Findings indicated that heightened cardiovascular reactivity was associated with worse cardiovascular outcomes, such as incident hypertension, coronary calcification, carotid intima-media thickness, and cardiovascular events over time.

Role of aldosterone overlooked

Reprinted from Neuroscience and Biobehavioral Reviews (Kubzansky LD, et al. Aldosterone: a forgotten mediator of the relationship between psychological stress and heart disease. Neurosci Biobehav Rev 2010; 34:80–86), © 2010, with permission from Elsevier.

WHY CONSIDER RESILIENCE?

Because the absence of a deficit is not the same as the presence of an asset, greater insight into dysfunction may be gained by explicitly considering what promotes healthy functioning. Ameliorating distress has proven difficult; so, in studying resilience (including the ability to regulate affect), new targets for prevention and intervention may be identified. Although no meta-analysis of resilience factors has been published to date owing to the paucity of data, the studies that have been performed are generally rigorous and have demonstrated consistent findings.

For example, one prospective, well-controlled study of 1,739 men and women demonstrated a protective effect of positive affect (as ascertained by structured interview) against 10-year incident CHD.⁶ The risk of fatal or nonfatal ischemic heart disease events was reduced by 22% (P = .02) for each 1-point increase in positive affect, even after controlling for depression and negative emotions.

Reprinted, with permission, from Archives of General Psychiatry (Kubzansky LD, et al. Arch Gen Psychiatry 2011; 68:400–408), Copyright © 2011 American Medical Association. All rights reserved.

Biology of resilience: Counteracting cellular damage

Genomic changes can be induced by the relaxation response, as evidenced by the differential gene expression profiles of long-term daily practitioners of relaxation (ie, meditation, yoga), short-term (8-week) practitioners of relaxation, and healthy controls.⁸ Alterations in cellular metabolism, oxidative phosphorylation, and generation of reactive oxygen species that counteract proinflammatory responses, indicative of an adaptive response, were observed in both groups that practiced relaxation.

FUTURE DIRECTIONS

Whether and how the sources and effects of psychosocial stress and response to treatment differ across men and women deserves closer examination. A review by Low et al⁹ summarizes the current state of knowledge with respect to psychosocial factors and heart disease in women, noting that the sources of stress associated with increased CHD risk differ across men and women; psychosocial risk factors like depression and anxiety appear to increase risk for both men and women; work-related stress has larger effects in men while stress related to relationships and family responsibilities appear to have larger effects in women.

Although responses to psychosocial stress are not clearly different between men and women, intervention targeted at reducing distress is much less effective in reducing the risk of adverse events in women versus men. The mechanism to explain this difference in effectiveness of intervention urgently requires further exploration.

In conducting this work, several factors are important. The best time to intervene to reduce psychosocial distress is unknown; a key consideration will be, what is the best etiologic window for intervention? Perhaps a life-course approach that targets individuals with chronically high levels of emotional distress who also have multiple coronary risk factors, and that enhances their capacity to regulate emotions would prove superior to waiting until late in the disease process.

Another area that may prove fruitful is to consider in more depth the biology of the placebo effect and whether and how it may inform our understanding of resilience.

More generally, considering why interventions seem to influence outcomes so differently across men and women, applying a life course approach to determine the best etiologic window for prevention and intervention strategies, and conducting a more in-depth exploration of the biology of resilience may lead to improved capacity for population-based approaches to reducing the burden of CHD.

The effect of emotion on the heart is not confined to depression, but extends to a variety of mental states; as William Harvey described in 1628, “A mental disturbance provoking pain, excessive joy, hope or anxiety extends to the heart, where it affects its temper and rate, impairing general nutrition and vigor.”

In going beyond the well-established role of depression as a risk factor for heart disease, 2010 delivered several important publications recognizing anxiety, anger, and other forms of distress as key factors in the etiology of coronary heart disease (CHD). Other papers of merit elucidated new and overlooked insights into the pathways linking psychosocial stress and cardiovascular risk, and also considered psychologic states that appear to promote healthy functioning.

IMPACT OF NEGATIVE EMOTIONS ON RISK OF INCIDENT CORONARY HEART DISEASE

In a meta-analysis of 20 prospective studies that included 249,846 persons with a mean follow-up of 11.2 years, Roest et al¹ examined the impact of anxiety characterized by the presence of anxiety symptoms or a diagnosis of anxiety disorder on incident CHD. Most of the studies adjusted for a broad array of relevant potential confounders. Findings suggest the presence of anxiety increases the risk of incident CHD by 26% (P P = .003).

In a meta-analysis of 25 prospective studies of 7,160 persons with a mean follow-up exceeding 10 years, Chida and Steptoe² found that anger increased the risk of incident CHD by 19%, after adjustment for standard coronary risk factors. The effect was less stable than that associated with anxiety and depression, and when stratified by gender, the harmful effects of anger were more evident in men than in women. The effect of anger was attenuated when controlling for behavioral covariates. The association between anger and CHD did not hold for all ways of measuring anger, which suggests that the type of anger or the ability to regulate anger may be relevant to the relationship.

A study that did account for the type of anger expression on the risk of incident CHD was conducted by Davidson and Mostofsky.³ The independent effect of three distinct types of anger expression (constructive anger, destructive anger justification, and destructive anger rumination) on 10-year incident CHD was examined, controlling for other psychosocial factors. In men, higher scores for constructive anger were associated with a lower rate of CHD; in both men and women, higher scores for destructive anger justification were associated with an increased risk of CHD.

Insights gained from these studies are as follows:

• The impact of anxiety appears to be comparable to depression, and the effects of anxiety and depression are largely independent.
• If anxiety and depression co-occur, the effect on CHD is synergistic.
• The effects of anger are less clear; its impact may be independent of or dependent on other forms of psychologic distress.
• Distress in general appears to serve as a signal that something is wrong and needs to be addressed. If ignored, it may become chronic and unremitting; because symptoms of distress may lead to systemic dysregulation and increased CHD risk, they may indicate the need for increased surveillance and intervention.

WHY FOCUS ON THE BIOLOGY OF EMOTIONS?

A clear biologic explanation for the influence of emotional factors on physical health would serve to assuage skeptics who doubt that such a link exists or who attribute a common underlying genetic trait to both negative affect and heart disease. Further, focusing on the biology may help answer key questions with respect to emotions and disease processes: What is the damage incurred by negative emotional states and is it reversible? Can compensatory pathways be activated to bypass the mechanisms causing damage or slow the progression of disease?

Cardiac response to worry and stress

In one study attempting to shed light on relevant emotion-related biologic process, the prolonged physiologic effects of worry were examined. Worry episodes and stressful events were recorded hourly along with ambulatory heart rate and heart rate variability in 73 teachers for 4 days.⁴ Autonomic activity, as reflected by a concurrent elevation in heart rate and a decrease in heart rate variability, was increased up to 2 hours after a worry episode. The findings also suggested that the prolonged cardiac effects of separate worry episodes were independent.

Another study sought to determine whether heightened reactivity or delayed recovery to acute stress increases risk of cardiovascular disease.⁵ This meta-analysis included 36 studies to assess whether acute cardiovascular response to various laboratory stressors (ie, cognitive tasks, stress interviews, public speaking). Findings indicated that heightened cardiovascular reactivity was associated with worse cardiovascular outcomes, such as incident hypertension, coronary calcification, carotid intima-media thickness, and cardiovascular events over time.

Role of aldosterone overlooked

Reprinted from Neuroscience and Biobehavioral Reviews (Kubzansky LD, et al. Aldosterone: a forgotten mediator of the relationship between psychological stress and heart disease. Neurosci Biobehav Rev 2010; 34:80–86), © 2010, with permission from Elsevier.

WHY CONSIDER RESILIENCE?

Because the absence of a deficit is not the same as the presence of an asset, greater insight into dysfunction may be gained by explicitly considering what promotes healthy functioning. Ameliorating distress has proven difficult; so, in studying resilience (including the ability to regulate affect), new targets for prevention and intervention may be identified. Although no meta-analysis of resilience factors has been published to date owing to the paucity of data, the studies that have been performed are generally rigorous and have demonstrated consistent findings.

For example, one prospective, well-controlled study of 1,739 men and women demonstrated a protective effect of positive affect (as ascertained by structured interview) against 10-year incident CHD.⁶ The risk of fatal or nonfatal ischemic heart disease events was reduced by 22% (P = .02) for each 1-point increase in positive affect, even after controlling for depression and negative emotions.

Reprinted, with permission, from Archives of General Psychiatry (Kubzansky LD, et al. Arch Gen Psychiatry 2011; 68:400–408), Copyright © 2011 American Medical Association. All rights reserved.

Biology of resilience: Counteracting cellular damage

Genomic changes can be induced by the relaxation response, as evidenced by the differential gene expression profiles of long-term daily practitioners of relaxation (ie, meditation, yoga), short-term (8-week) practitioners of relaxation, and healthy controls.⁸ Alterations in cellular metabolism, oxidative phosphorylation, and generation of reactive oxygen species that counteract proinflammatory responses, indicative of an adaptive response, were observed in both groups that practiced relaxation.

FUTURE DIRECTIONS

Whether and how the sources and effects of psychosocial stress and response to treatment differ across men and women deserves closer examination. A review by Low et al⁹ summarizes the current state of knowledge with respect to psychosocial factors and heart disease in women, noting that the sources of stress associated with increased CHD risk differ across men and women; psychosocial risk factors like depression and anxiety appear to increase risk for both men and women; work-related stress has larger effects in men while stress related to relationships and family responsibilities appear to have larger effects in women.

Although responses to psychosocial stress are not clearly different between men and women, intervention targeted at reducing distress is much less effective in reducing the risk of adverse events in women versus men. The mechanism to explain this difference in effectiveness of intervention urgently requires further exploration.

In conducting this work, several factors are important. The best time to intervene to reduce psychosocial distress is unknown; a key consideration will be, what is the best etiologic window for intervention? Perhaps a life-course approach that targets individuals with chronically high levels of emotional distress who also have multiple coronary risk factors, and that enhances their capacity to regulate emotions would prove superior to waiting until late in the disease process.

Another area that may prove fruitful is to consider in more depth the biology of the placebo effect and whether and how it may inform our understanding of resilience.

More generally, considering why interventions seem to influence outcomes so differently across men and women, applying a life course approach to determine the best etiologic window for prevention and intervention strategies, and conducting a more in-depth exploration of the biology of resilience may lead to improved capacity for population-based approaches to reducing the burden of CHD.

The autonomic nervous system (ANS), composed of the sympathetic and parasympathetic nervous systems, governs our adaptation to changing environments such as physical threats or changes in temperature. It has been difficult to elucidate this process in humans, however, because of limitations in neuroimaging caused by artifacts from cardiorespiratory sources. This article reviews structural and functional imaging that can provide insights into the ANS.

STRUCTURAL IMAGING

The two main subcortical areas of interest for imaging are the lateral hypothalamic area and the paraventricular nucleus, but visualization is difficult. The hypothalamus occupies a volumetric area of the brain no larger than 20 voxels; individual substructures of the hypothalamus therefore cannot easily be viewed by conventional imaging. The larger voxel size of functional MRI (fMRI) mean that fMRI of the hypothalamus can display 1 voxel at most.

Most brainstem nuclei are motor nuclei that affect autonomic responses, either sympathetic or parasympathetic. These nuclei are difficult to visualize on conventional MRI for two reasons: the nuclei are small, and may be the size of only 1 to 2 voxels. More important, MRI contrast between these nuclei and surrounding parenchyma is minimal because these structures “blend in” with the surrounding brain and are difficult to visualize singly. Examples of these major brainstem sympathetic nuclei are the periaqueductal gray substance, parabrachial nuclei, solitary nucleus, and the hypothalamospinal tract; examples of the major brainstem parasympathetic nuclei are the dorsal nucleus of the vagus nerve and the nucleus ambiguus.

The areas of the ANS under cortical control are more integrative, with influence from higher cognitive function—for example, the panic or fear associated with public speaking. Regions of subcortical control involve the basal ganglia and hypothalamus, which regulate primitive, subconscious activity, such as “fight or flight” response, pain reaction, and fear of snakes, all of which affect multiple motor nuclei. Several specific sympathetic and parasympathetic motor nuclei directly affect heart rate and blood pressure and act as relay stations for sensory impulses that reach the cerebral cortex.

NEUROLOGIC PROCESSES AND CARDIAC EFFECTS

MS is classically a disease of white matter, although it can also affect gray matter. Autonomic dysfunction is common, affecting as many as 50% of MS patients with symptoms that include orthostatic dizziness, bladder disturbances, temperature instability, gastrointestinal disturbances, and sweating.^1–4 The effect of autonomic dysfunction on disease activity is unclear. Multiple brainstem lesions are evident on MRI, and may be linked to cardiac autonomic dysfunction. The variability of MS contributes to the difficulty of using imaging to identify culprit lesions.

Stroke causes autonomic dysfunction, with the specific manifestations dependent on the region of the brain involved. In cases of right middle cerebral artery infarct affecting the right insula, an increased incidence of cardiac arrhythmias, cardiac death, and catecholamine production ensues.^5–7 Medullary infarcts have been shown to produce significant autonomic dysfunction.^8,9

Ictal and interictal cardiac manifestations in epilepsy often precede seizure onset.¹ Common cardiac changes are ictal tachycardia or ictal bradycardia, or both, with no clear relationship to the location or type of seizure. Evidence suggests that heart rate variability changes in epilepsy result from interictal autonomic alterations, including sympathetic or parasympathetic dominance. Investigation of baroreflex responses with temporal lobe epilepsy has uncovered decreased baroreflex sensitivity. There is no reliable correlation between sympathetic or parasympathetic upregulation or downregulation and brain MRI findings, however.

Autonomic dysfunction in the form of orthostatic hypotension has been documented in patients with mass effect from tumors, for example posterior fossa epidermoid tumors, wherein tumor resection results in improved autonomic function.¹⁰

FUNCTIONAL BRAIN IMAGING IN GENERAL

Direct visualization of heart-brain interactions is the goal when assessing ANS function. Positron emission tomography (PET) produces quantitative images, but spatial and temporal resolutions are vastly superior with fMRI.¹¹ Further, radiation exposure is low with fMRI, allowing for safe repeat imaging.

Ogawa et al¹² first demonstrated that in vivo images of brain microvasculature are affected by blood oxygen level, and that blood oxygenation reduced vascular signal loss. Therefore, blood oxygenation level–dependent (BOLD) contrast added to MRI could complement PET-like measurements in the study of regional brain activity.

Bilateral finger tapping with intermittent periods of rest is associated with a pattern of increasing and decreasing intensity of fMRI signals in involved brain regions that reflect the periods of activity and rest. This technique has been used to locate brain voxels with similar patterns of activity, enabling the creation of familiar color brain mapping. A challenge posed by autonomic fMRI in such brain mapping is that fMRI is susceptible to artifacts (Figure 3). For example, a movement of the head as little as 1 mm inside the MRI scanner—a distance comparable to the size of autonomic structures—can produce a motion artifact (false activation of brain regions) that can affect statistical significance. In addition, many ANS regions of the brain are near osseous structures (for example the brainstem and skull base) that cause signal distortion and loss.

REQUIREMENTS FOR AUTONOMIC fMRI

The tasks chosen to visualize brain control of autonomic function must naturally elicit an autonomic response. The difficulty is that untrained persons have little or no volitional control over autonomic functions, so the task and its analysis must be designed carefully and be MRI-compatible. Any motion will degrade the image; further, the capacity for the MRI environment to corrupt the measurements can limit the potential tasks for measurement.

Possible stimuli for eliciting a sympathetic response include pain, fear, anticipation, anxiety, concentration or memory, cold pressor, Stroop test, breathing tests, and maximal hand grip. Examples of parasympathetic stimuli are the Valsalva maneuver and paced breathing. The responses to stimuli (ie, heart rate, heart rate variability, blood pressure, galvanic skin response, papillary response) must be monitored to compare the data obtained from fMRI. MRI-compatible equipment is now available for measuring many of these responses.

Identifying areas activated during tasks

Functional neuroimaging with PET and fMRI has shown consistently that the anterior cingulate is activated during multiple tasks designed to elicit an autonomic response (gambling anticipation, emotional response to faces, Stroop test).¹¹

In a study designed to test autonomic interoceptive awareness, subjects underwent fMRI while they were asked to judge the timing of their heartbeats to auditory tones that were either synchronized with their heartbeat or delayed by 500 msec.¹³ Areas of enhanced activity during the task were the right insular cortex, anterior cingulate, parietal lobes, and operculum.

Characterizing brainstem sites

It is difficult to achieve visualization of areas within the brainstem that govern autonomic responses. These regions are small and motion artifacts are common because of brainstem movement with the cardiac pulse. With fMRI, Topolovec et al¹⁴ were able to characterize brainstem sites involved in autonomic control, demonstrating activation of the nucleus of the solitary tract and parabrachial nucleus.

Reprinted from NeuroImage (Napadow V, et al. Brain correlates of autonomic modulation: combining heart rate variability with fMRI. Neuro-Image 2008; 42:169–177), Copyright © 2008, with permission from Elsevier.

A review of four fMRI studies of stressor-evoked blood pressure reactivity demonstrated activation in corticolimbic areas, including the cingulate cortex, insula, amygdala, and cortical and subcortical areas that are involved in hemodynamic and metabolic support for stress-related behavioral responses.¹⁶

FUNCTIONAL BRAIN IMAGING IN DISEASE STATES

There are few studies of functional brain imaging in patients with disease because of the challenges involved. The studies are difficult to perform on sick patients because of the unfriendly MRI environment, with struct requirements for attention and participation. Furthermore, autonomic responses may be blunted, making physiologic comparisons difficult. In addition, there is evidence that BOLD may be intrinsically impaired in disease states. Unlike fMRI studies to locate brain regions involved in simple tasks such as finger tapping, which can be performed in a single subject, detecting changes in autonomic responses in disease states requires averaging over studies of multiple patients.

Woo et al¹⁷ used fMRI to compare brain regions of activation in six patients with heart failure and 16 controls upon a forehead cold pressor challenge. Increases in heart rate were measured in the patients with heart failure with application of the cold stimulus. Larger neural fMRI signal responses in patients with heart failure were observed in 14 brain regions, whereas reduced fMRI activity was observed in 15 other brain regions in the heart failure patients. Based on the results, the investigators suggested that heart failure may be associated with altered sympathetic and parasympathetic activity, and that these dysfunctions might contribute to the progression of heart failure.

Gianaros et al¹⁸ found fMRI evidence for a correlation between carotid artery intima-media thickness, a surrogate measure for carotid artery or coronary artery disease, and altered ANS reaction to fear using a fearful faces paradigm.

CONCLUSION

Functional MRI of heart-brain interactions has strong potential for normal subjects, in whom the BOLD effect is small, within the limits of motion and susceptibility artifacts. Typically, such applications require averaging results over multiple subjects. Its potential utility in disease states is less significant because of the additional limitations of MRI with sick patients (the MRI environment, blunting of autonomic response in disease, possible impairment of BOLD), but continued investigation is warranted.

The autonomic nervous system (ANS), composed of the sympathetic and parasympathetic nervous systems, governs our adaptation to changing environments such as physical threats or changes in temperature. It has been difficult to elucidate this process in humans, however, because of limitations in neuroimaging caused by artifacts from cardiorespiratory sources. This article reviews structural and functional imaging that can provide insights into the ANS.

STRUCTURAL IMAGING

The two main subcortical areas of interest for imaging are the lateral hypothalamic area and the paraventricular nucleus, but visualization is difficult. The hypothalamus occupies a volumetric area of the brain no larger than 20 voxels; individual substructures of the hypothalamus therefore cannot easily be viewed by conventional imaging. The larger voxel size of functional MRI (fMRI) mean that fMRI of the hypothalamus can display 1 voxel at most.

Most brainstem nuclei are motor nuclei that affect autonomic responses, either sympathetic or parasympathetic. These nuclei are difficult to visualize on conventional MRI for two reasons: the nuclei are small, and may be the size of only 1 to 2 voxels. More important, MRI contrast between these nuclei and surrounding parenchyma is minimal because these structures “blend in” with the surrounding brain and are difficult to visualize singly. Examples of these major brainstem sympathetic nuclei are the periaqueductal gray substance, parabrachial nuclei, solitary nucleus, and the hypothalamospinal tract; examples of the major brainstem parasympathetic nuclei are the dorsal nucleus of the vagus nerve and the nucleus ambiguus.

The areas of the ANS under cortical control are more integrative, with influence from higher cognitive function—for example, the panic or fear associated with public speaking. Regions of subcortical control involve the basal ganglia and hypothalamus, which regulate primitive, subconscious activity, such as “fight or flight” response, pain reaction, and fear of snakes, all of which affect multiple motor nuclei. Several specific sympathetic and parasympathetic motor nuclei directly affect heart rate and blood pressure and act as relay stations for sensory impulses that reach the cerebral cortex.

NEUROLOGIC PROCESSES AND CARDIAC EFFECTS

MS is classically a disease of white matter, although it can also affect gray matter. Autonomic dysfunction is common, affecting as many as 50% of MS patients with symptoms that include orthostatic dizziness, bladder disturbances, temperature instability, gastrointestinal disturbances, and sweating.^1–4 The effect of autonomic dysfunction on disease activity is unclear. Multiple brainstem lesions are evident on MRI, and may be linked to cardiac autonomic dysfunction. The variability of MS contributes to the difficulty of using imaging to identify culprit lesions.

Stroke causes autonomic dysfunction, with the specific manifestations dependent on the region of the brain involved. In cases of right middle cerebral artery infarct affecting the right insula, an increased incidence of cardiac arrhythmias, cardiac death, and catecholamine production ensues.^5–7 Medullary infarcts have been shown to produce significant autonomic dysfunction.^8,9

Ictal and interictal cardiac manifestations in epilepsy often precede seizure onset.¹ Common cardiac changes are ictal tachycardia or ictal bradycardia, or both, with no clear relationship to the location or type of seizure. Evidence suggests that heart rate variability changes in epilepsy result from interictal autonomic alterations, including sympathetic or parasympathetic dominance. Investigation of baroreflex responses with temporal lobe epilepsy has uncovered decreased baroreflex sensitivity. There is no reliable correlation between sympathetic or parasympathetic upregulation or downregulation and brain MRI findings, however.

Autonomic dysfunction in the form of orthostatic hypotension has been documented in patients with mass effect from tumors, for example posterior fossa epidermoid tumors, wherein tumor resection results in improved autonomic function.¹⁰

FUNCTIONAL BRAIN IMAGING IN GENERAL

Direct visualization of heart-brain interactions is the goal when assessing ANS function. Positron emission tomography (PET) produces quantitative images, but spatial and temporal resolutions are vastly superior with fMRI.¹¹ Further, radiation exposure is low with fMRI, allowing for safe repeat imaging.

Ogawa et al¹² first demonstrated that in vivo images of brain microvasculature are affected by blood oxygen level, and that blood oxygenation reduced vascular signal loss. Therefore, blood oxygenation level–dependent (BOLD) contrast added to MRI could complement PET-like measurements in the study of regional brain activity.

Bilateral finger tapping with intermittent periods of rest is associated with a pattern of increasing and decreasing intensity of fMRI signals in involved brain regions that reflect the periods of activity and rest. This technique has been used to locate brain voxels with similar patterns of activity, enabling the creation of familiar color brain mapping. A challenge posed by autonomic fMRI in such brain mapping is that fMRI is susceptible to artifacts (Figure 3). For example, a movement of the head as little as 1 mm inside the MRI scanner—a distance comparable to the size of autonomic structures—can produce a motion artifact (false activation of brain regions) that can affect statistical significance. In addition, many ANS regions of the brain are near osseous structures (for example the brainstem and skull base) that cause signal distortion and loss.

REQUIREMENTS FOR AUTONOMIC fMRI

The tasks chosen to visualize brain control of autonomic function must naturally elicit an autonomic response. The difficulty is that untrained persons have little or no volitional control over autonomic functions, so the task and its analysis must be designed carefully and be MRI-compatible. Any motion will degrade the image; further, the capacity for the MRI environment to corrupt the measurements can limit the potential tasks for measurement.

Possible stimuli for eliciting a sympathetic response include pain, fear, anticipation, anxiety, concentration or memory, cold pressor, Stroop test, breathing tests, and maximal hand grip. Examples of parasympathetic stimuli are the Valsalva maneuver and paced breathing. The responses to stimuli (ie, heart rate, heart rate variability, blood pressure, galvanic skin response, papillary response) must be monitored to compare the data obtained from fMRI. MRI-compatible equipment is now available for measuring many of these responses.

Identifying areas activated during tasks

Functional neuroimaging with PET and fMRI has shown consistently that the anterior cingulate is activated during multiple tasks designed to elicit an autonomic response (gambling anticipation, emotional response to faces, Stroop test).¹¹

In a study designed to test autonomic interoceptive awareness, subjects underwent fMRI while they were asked to judge the timing of their heartbeats to auditory tones that were either synchronized with their heartbeat or delayed by 500 msec.¹³ Areas of enhanced activity during the task were the right insular cortex, anterior cingulate, parietal lobes, and operculum.

Characterizing brainstem sites

It is difficult to achieve visualization of areas within the brainstem that govern autonomic responses. These regions are small and motion artifacts are common because of brainstem movement with the cardiac pulse. With fMRI, Topolovec et al¹⁴ were able to characterize brainstem sites involved in autonomic control, demonstrating activation of the nucleus of the solitary tract and parabrachial nucleus.

Reprinted from NeuroImage (Napadow V, et al. Brain correlates of autonomic modulation: combining heart rate variability with fMRI. Neuro-Image 2008; 42:169–177), Copyright © 2008, with permission from Elsevier.

A review of four fMRI studies of stressor-evoked blood pressure reactivity demonstrated activation in corticolimbic areas, including the cingulate cortex, insula, amygdala, and cortical and subcortical areas that are involved in hemodynamic and metabolic support for stress-related behavioral responses.¹⁶

FUNCTIONAL BRAIN IMAGING IN DISEASE STATES

There are few studies of functional brain imaging in patients with disease because of the challenges involved. The studies are difficult to perform on sick patients because of the unfriendly MRI environment, with struct requirements for attention and participation. Furthermore, autonomic responses may be blunted, making physiologic comparisons difficult. In addition, there is evidence that BOLD may be intrinsically impaired in disease states. Unlike fMRI studies to locate brain regions involved in simple tasks such as finger tapping, which can be performed in a single subject, detecting changes in autonomic responses in disease states requires averaging over studies of multiple patients.

Woo et al¹⁷ used fMRI to compare brain regions of activation in six patients with heart failure and 16 controls upon a forehead cold pressor challenge. Increases in heart rate were measured in the patients with heart failure with application of the cold stimulus. Larger neural fMRI signal responses in patients with heart failure were observed in 14 brain regions, whereas reduced fMRI activity was observed in 15 other brain regions in the heart failure patients. Based on the results, the investigators suggested that heart failure may be associated with altered sympathetic and parasympathetic activity, and that these dysfunctions might contribute to the progression of heart failure.

Gianaros et al¹⁸ found fMRI evidence for a correlation between carotid artery intima-media thickness, a surrogate measure for carotid artery or coronary artery disease, and altered ANS reaction to fear using a fearful faces paradigm.

CONCLUSION

Functional MRI of heart-brain interactions has strong potential for normal subjects, in whom the BOLD effect is small, within the limits of motion and susceptibility artifacts. Typically, such applications require averaging results over multiple subjects. Its potential utility in disease states is less significant because of the additional limitations of MRI with sick patients (the MRI environment, blunting of autonomic response in disease, possible impairment of BOLD), but continued investigation is warranted.

The autonomic nervous system (ANS), composed of the sympathetic and parasympathetic nervous systems, governs our adaptation to changing environments such as physical threats or changes in temperature. It has been difficult to elucidate this process in humans, however, because of limitations in neuroimaging caused by artifacts from cardiorespiratory sources. This article reviews structural and functional imaging that can provide insights into the ANS.

STRUCTURAL IMAGING

The two main subcortical areas of interest for imaging are the lateral hypothalamic area and the paraventricular nucleus, but visualization is difficult. The hypothalamus occupies a volumetric area of the brain no larger than 20 voxels; individual substructures of the hypothalamus therefore cannot easily be viewed by conventional imaging. The larger voxel size of functional MRI (fMRI) mean that fMRI of the hypothalamus can display 1 voxel at most.

Most brainstem nuclei are motor nuclei that affect autonomic responses, either sympathetic or parasympathetic. These nuclei are difficult to visualize on conventional MRI for two reasons: the nuclei are small, and may be the size of only 1 to 2 voxels. More important, MRI contrast between these nuclei and surrounding parenchyma is minimal because these structures “blend in” with the surrounding brain and are difficult to visualize singly. Examples of these major brainstem sympathetic nuclei are the periaqueductal gray substance, parabrachial nuclei, solitary nucleus, and the hypothalamospinal tract; examples of the major brainstem parasympathetic nuclei are the dorsal nucleus of the vagus nerve and the nucleus ambiguus.

The areas of the ANS under cortical control are more integrative, with influence from higher cognitive function—for example, the panic or fear associated with public speaking. Regions of subcortical control involve the basal ganglia and hypothalamus, which regulate primitive, subconscious activity, such as “fight or flight” response, pain reaction, and fear of snakes, all of which affect multiple motor nuclei. Several specific sympathetic and parasympathetic motor nuclei directly affect heart rate and blood pressure and act as relay stations for sensory impulses that reach the cerebral cortex.

NEUROLOGIC PROCESSES AND CARDIAC EFFECTS

MS is classically a disease of white matter, although it can also affect gray matter. Autonomic dysfunction is common, affecting as many as 50% of MS patients with symptoms that include orthostatic dizziness, bladder disturbances, temperature instability, gastrointestinal disturbances, and sweating.^1–4 The effect of autonomic dysfunction on disease activity is unclear. Multiple brainstem lesions are evident on MRI, and may be linked to cardiac autonomic dysfunction. The variability of MS contributes to the difficulty of using imaging to identify culprit lesions.

Stroke causes autonomic dysfunction, with the specific manifestations dependent on the region of the brain involved. In cases of right middle cerebral artery infarct affecting the right insula, an increased incidence of cardiac arrhythmias, cardiac death, and catecholamine production ensues.^5–7 Medullary infarcts have been shown to produce significant autonomic dysfunction.^8,9

Ictal and interictal cardiac manifestations in epilepsy often precede seizure onset.¹ Common cardiac changes are ictal tachycardia or ictal bradycardia, or both, with no clear relationship to the location or type of seizure. Evidence suggests that heart rate variability changes in epilepsy result from interictal autonomic alterations, including sympathetic or parasympathetic dominance. Investigation of baroreflex responses with temporal lobe epilepsy has uncovered decreased baroreflex sensitivity. There is no reliable correlation between sympathetic or parasympathetic upregulation or downregulation and brain MRI findings, however.

Autonomic dysfunction in the form of orthostatic hypotension has been documented in patients with mass effect from tumors, for example posterior fossa epidermoid tumors, wherein tumor resection results in improved autonomic function.¹⁰

FUNCTIONAL BRAIN IMAGING IN GENERAL

Direct visualization of heart-brain interactions is the goal when assessing ANS function. Positron emission tomography (PET) produces quantitative images, but spatial and temporal resolutions are vastly superior with fMRI.¹¹ Further, radiation exposure is low with fMRI, allowing for safe repeat imaging.

Ogawa et al¹² first demonstrated that in vivo images of brain microvasculature are affected by blood oxygen level, and that blood oxygenation reduced vascular signal loss. Therefore, blood oxygenation level–dependent (BOLD) contrast added to MRI could complement PET-like measurements in the study of regional brain activity.

Bilateral finger tapping with intermittent periods of rest is associated with a pattern of increasing and decreasing intensity of fMRI signals in involved brain regions that reflect the periods of activity and rest. This technique has been used to locate brain voxels with similar patterns of activity, enabling the creation of familiar color brain mapping. A challenge posed by autonomic fMRI in such brain mapping is that fMRI is susceptible to artifacts (Figure 3). For example, a movement of the head as little as 1 mm inside the MRI scanner—a distance comparable to the size of autonomic structures—can produce a motion artifact (false activation of brain regions) that can affect statistical significance. In addition, many ANS regions of the brain are near osseous structures (for example the brainstem and skull base) that cause signal distortion and loss.

REQUIREMENTS FOR AUTONOMIC fMRI

The tasks chosen to visualize brain control of autonomic function must naturally elicit an autonomic response. The difficulty is that untrained persons have little or no volitional control over autonomic functions, so the task and its analysis must be designed carefully and be MRI-compatible. Any motion will degrade the image; further, the capacity for the MRI environment to corrupt the measurements can limit the potential tasks for measurement.

Possible stimuli for eliciting a sympathetic response include pain, fear, anticipation, anxiety, concentration or memory, cold pressor, Stroop test, breathing tests, and maximal hand grip. Examples of parasympathetic stimuli are the Valsalva maneuver and paced breathing. The responses to stimuli (ie, heart rate, heart rate variability, blood pressure, galvanic skin response, papillary response) must be monitored to compare the data obtained from fMRI. MRI-compatible equipment is now available for measuring many of these responses.

Identifying areas activated during tasks

Functional neuroimaging with PET and fMRI has shown consistently that the anterior cingulate is activated during multiple tasks designed to elicit an autonomic response (gambling anticipation, emotional response to faces, Stroop test).¹¹

In a study designed to test autonomic interoceptive awareness, subjects underwent fMRI while they were asked to judge the timing of their heartbeats to auditory tones that were either synchronized with their heartbeat or delayed by 500 msec.¹³ Areas of enhanced activity during the task were the right insular cortex, anterior cingulate, parietal lobes, and operculum.

Characterizing brainstem sites

It is difficult to achieve visualization of areas within the brainstem that govern autonomic responses. These regions are small and motion artifacts are common because of brainstem movement with the cardiac pulse. With fMRI, Topolovec et al¹⁴ were able to characterize brainstem sites involved in autonomic control, demonstrating activation of the nucleus of the solitary tract and parabrachial nucleus.

Reprinted from NeuroImage (Napadow V, et al. Brain correlates of autonomic modulation: combining heart rate variability with fMRI. Neuro-Image 2008; 42:169–177), Copyright © 2008, with permission from Elsevier.

A review of four fMRI studies of stressor-evoked blood pressure reactivity demonstrated activation in corticolimbic areas, including the cingulate cortex, insula, amygdala, and cortical and subcortical areas that are involved in hemodynamic and metabolic support for stress-related behavioral responses.¹⁶

FUNCTIONAL BRAIN IMAGING IN DISEASE STATES

There are few studies of functional brain imaging in patients with disease because of the challenges involved. The studies are difficult to perform on sick patients because of the unfriendly MRI environment, with struct requirements for attention and participation. Furthermore, autonomic responses may be blunted, making physiologic comparisons difficult. In addition, there is evidence that BOLD may be intrinsically impaired in disease states. Unlike fMRI studies to locate brain regions involved in simple tasks such as finger tapping, which can be performed in a single subject, detecting changes in autonomic responses in disease states requires averaging over studies of multiple patients.

Woo et al¹⁷ used fMRI to compare brain regions of activation in six patients with heart failure and 16 controls upon a forehead cold pressor challenge. Increases in heart rate were measured in the patients with heart failure with application of the cold stimulus. Larger neural fMRI signal responses in patients with heart failure were observed in 14 brain regions, whereas reduced fMRI activity was observed in 15 other brain regions in the heart failure patients. Based on the results, the investigators suggested that heart failure may be associated with altered sympathetic and parasympathetic activity, and that these dysfunctions might contribute to the progression of heart failure.

Gianaros et al¹⁸ found fMRI evidence for a correlation between carotid artery intima-media thickness, a surrogate measure for carotid artery or coronary artery disease, and altered ANS reaction to fear using a fearful faces paradigm.

CONCLUSION

Functional MRI of heart-brain interactions has strong potential for normal subjects, in whom the BOLD effect is small, within the limits of motion and susceptibility artifacts. Typically, such applications require averaging results over multiple subjects. Its potential utility in disease states is less significant because of the additional limitations of MRI with sick patients (the MRI environment, blunting of autonomic response in disease, possible impairment of BOLD), but continued investigation is warranted.