The Baroreflex as a Novel Mechanism of Behavior Charge

10th Annual Mechanisms of Behavior Change Satellite Meeting

Bellevue, WA, June 21, 2014

Marsha E. Bates& the Cardiac Neuroscience Laboratory

Preoccupation/Anticipation Craving

Withdrawal/Negative Affect

Binge/Intoxication

Koob & Volkow, 2009

e.g., negative affect: Not only PFC, but major projections of the extended

amygdala to the hypothalamusand brainstem

Koob & Volkow, 2009

SOMATIC MARKER HYPOTHESIS

Bechara & Damasio, 2005

Baroreflex Mechanism Definition• The biofeedback loop through which the heart

and brain maintain continuous communication through the central autonomic network-mediated efferent stream and the baroreceptor-mediated afferent stream.

• Operates automatically & usually outside of conscious awareness to support physical health (make sure that you’re breathing and don’t have a stroke), but also critical role in attention allocation, modulating emotional arousal, self- regulating affect, and supporting cognition

Heart(e.g., Sinoatrial Node)

ACh (nicotinic, +)

ACh (nicotinic, +)

Norepinephrine (+) ACh (muscarinic, -)

Ganglionic Neurons

Preganglionic Fibers

Postganglionic Fibers

Cranial/Sacral Nervesof the Spinal Cord

Intermediolateral Column of the Spinal Cord

Nucleus Tractus Solitarius (Medulla)

Spinal nervesCaudal VL Medulla

Nucleus Ambiguus*

(Medulla)

Rostral VL Medulla*

Glutamate (+) Glutamate (+)

GABA (-)SYMPATHETIC PARASYMPATHETIC

Receptors(e.g., baroreceptors Aortic arch & Carotid Sinus)

Vagu

sN

erve

Baroreflex Closed Loop

•Efferent stream: what messages go body?• Afferent stream: what messages does the body send back to the brain?

Sympathetic Parasympathetic

THE CENTRAL AUTONOMIC NETWORK

THAYER J F Cleveland Clinic Journal of Medicine 2009;76:S23-S26

©2009 by Cleveland Clinic

MPCACCISCAMY+HYP

PAG

PBN

VLMNANTS

NeurovisceralIntegration

Brain structures in the central autonomic network

Insular Cortex

Amygdala

The central autonomic network modulates arousal by initiating precise adjustments in HR, BP, VT

Hypothalamus

Periaqueductal Gray Matter

PrefrontalCortex

Anterior Cingulate

Cortex

and integrates reflective and reflexive brain region responses,connecting neural activity to visceral cognitive emotional states

EmotionCravingAppetitive Learning

THAYER J F Cleveland Clinic Journal of Medicine 2009;76:S23-S26

©2009 by Cleveland Clinic

Body BrainFeedback:The afferentpathway is needed to complete thebaroreflex loop

MPCACCISCAMY+HYP

PAG

PBN

VLMNANTS

Structures in the central autonomic network.

The baroreflex feedback loop influences higher- order brain processes through the central- autonomic network which coordinates cardiovascular changes with cognition and emotions (e.g., by automatically modulating arousal levels and the allocation of attention) (Agelink, Boz, Ullrich, & Andrich, 2002; Bates & Buckman, 2013; Benarroch,1997; Duschek, Muckenthaler, Werner, & Reyes del Paso, 2009; Reyes Del Paso, Gonzalez, Hernandez, Duschek, & Gutierrez, 2009; Reyes del Paso, Mata, & Martin-Vazquez, 2012; Virtanen et al., 2003; Yasumasu et al., 2006).

We hypothesize that BRS is a mechanism that is protective by increasing HRV and stress resilience,and dampening cue reactivity and craving responses.

Baroreflex Sensitivity – Operational Definition

Cardiovagal BRS = changes in the R-R interval per unit change in systolic blood pressure that is mediated by the arterial baroreflex.

The baroreflex loop is malleable through non- invasive and non-pharmacological behavioral approaches (e.g., resonance breathing, HRV biofeedback, rhythmical muscle tension)

Increases in BRS likely also account for some of clinical benefit of other behavioral interventions such as physical exercise and mediation

Common proxy for baroreflex sensitivity:Heart rate variability - Operational Definition

Heart Rate Variability (HRV): changes in the time interval between heart beats

Not heart rate/beats-per-minute; rather time series of R spike to R spike intervals

Window into brain cardiovascular modulation of arousal, attention, emotion, behavioral flexibility

R to R spike of the ECG

Acute intoxication and heavy, chronic alcohol use decrease HRV

Chronic, heavy alcohol consumption impairs baroreflex loop biofeedback

increases sympathetic arousal, as measured by muscle sympathetic activity (van de Borne, Mark, Montano, Mion, & Somers, 1997)

decrease vagus nerve activity (Levanon, Goss, & Chen, 2002; Reed, Porges, & Newlin, 1999)

negatively influences blood vessels (Bau, Bau, Rosito, Manfroi, & Fuchs, 2007)

dampens HR baroreflex (Bar et al., 2006; Romanowicz, Schmidt, Bostwick, Mrazek, & Karpyak, 2011).

Reduced HRV is correlated with:

Stress

Anxiety

Depression

Less ability to adapt to challenges (over or under response; slow return to restful state)

Lower cognitive function

Reduced immune function

(Agelink et al., 2002 ; Appelhans & Luechen, 2006; Bates et al., 2011; Hughes & Stoney, 2000; Musselman, 1998; Thayer et al., 2009;Tracey, 2009; Vrijkatte, 2000; Yeragani, 2000)

What does HRV predict?

Higher resting state HRV predicts: physical stamina, survival after cardiac arrest & surgery, increased resiliency of children to stress, better cognitive functioning

Lower resting state HRV predicts: symptoms of depression and anxiety, negative emotions, physical disease, prospective development of externalizing and internalizing behaviors in adolescence

‘a’ and ‘b’ paths depend on when, why researchers assess HRV: Risk and consequence

Acute and chronic stress decrease HRV

Allostasis: Slow re-setting & change in set-points

e.g. baroreflex mechanism over time will maintain moment-to-moment adjustments in blood pressure and heart rate within less healthy ranges (Tracey, 2009)

“Spontaneous” increases in HRV found following:

Cognitive Behavioral Therapy (Stein et al., 2000)

SSRI therapy (Balogh et al., 1993)

Successful treatment of depression (Apelbaum, 2001; Chambers & Allen, 2002)

Cessation of Heavy Drinking (Vaschillo et al., in review; Weiss et al, 2001)

Baroreflex Sensitivity

Recruited from a randomized clinical trial of 12 wk individual or group CBT for women with alcohol dependence (PI Epstein) Pilot study of first 34 women who also agreed to participate in this study.25 – 61 years of age (M=48.3, SD=10.3)Pre-Treatment/Post-treatment design

(DF = 32, F = 4.28, p < 0.047)

Log Baroreflex Sensitivity

Log

Tota

l 30-

day

Alc

ohol

Pre

-Tx

Participants divided into two groups based on BRS change pre- to post-treatment:Those who showed increased BRS Those who showed no change or decreased BRS

Post Tx

Pre Tx*

19 15 23 11Subgroup n’s

Post Tx

Pre Tx

PERCENT DRINKING DAYS

6 breaths per minute

rest

PERCENT HEAVY DRINKING DAYS

Summary: Spontaneous changes (reduced drinking, improved health)

Baroreflex sensitivity inversely related to

women’s alcohol consumption pre-treatment Those who showed increases in BRSDecreased sympathetic activationIncreased HRVDecreased frequency of drinking days and heavy drinking days

THE BAROREFLEX ARC FEEDBACK LOOP IS MALLEABLE

Heart rate and respiration phase changes during resonance breathing

Respiration ~6/min

heart rate

HRV Biofeedback to ‘tune’ the baroreflex loop improves clinical symptoms in disorders

characterized by ANS and affective dysfunction

Asthma (Lehrer et al., 2009)

Depression (Nolan et al., 2005; Siepman et al., 2008; Karavidas et al., 2007)

Cognitive and emotional regulation in brain damage (Kim et al., 2009)

PTSD (Tan et al., 2011; Zucker et al., 2009)

Hypertension and pre-hypertension (Lin et al., 2012; Sharma et al., 2011)

HRV BFB Acute effects: Increased LF power,heightened brainstem & cerebellar activation,deactivation in prefrontal cortex

Total reduction in alcohol and drug craving from session 1 to session 3, by group.

t(39) = .99, p = .33, d = .35

-7

-6

-5

-4

-3

-2

-1

0

Total R

educ

on in

Craving

(Session

1 –

3)

Experimental Group Control Group 95% CI [-7.5, -3.2] 95% CI [-6.4, -1.1]

Experimental Group Control Group (TAU)

Potential imitations of traditional ‘mechanism’ criteria when studying dynamical systems with feedback

Temporal relations may not be linear in dynamic feedback loops

Specificity may not be likely (or desirable) for fundamental biofeedback mechanisms

These complications balanced by unique ability to directly target the a priori BRS mechanism with efficacious interventions

Translation to intervention development

New intervention targets to enhance ability to modulate arousal and stress:Behavioral Approaches:, resonance breathing to

enhance neurocardiac signalingStrategic use of HRV biofeedback, resonance

breathing “in the moment” in anticipation of, or during, stress and challenge

Translational questions about the baroreflex mechanism for future research

• Does HRV biofeedback produce clinical benefit through cumulative, chronic improvements in baroreflex sensitivity, increased vagal tone, and/or increased HRV (6-10 wk Tx)

• Can HRV biofeedback be used strategically, in-the- moment, to reduce craving, negative affect and other drinking/drug use triggers (5 min)? Can strategic use become an automatic process over time?

• Can we distinguish direct effects of resonance breathing/HRV biofeedback on behavioral regulation, and indirect effects mediated through heightened cognitive control?

NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

NATIONAL INSTITUTE ON DRUG ABUSE

RUTGERS UNIVERSITY

CENTER OF ALCOHOL STUDIES

ACKNOWLEDGEMENTS

CARDIAC NEUROSCIENCE LABORATORY

Finding time to integrate work outside your area

Designing multilevel experiments: Incongruent methodologies

Lack of transdisciplinary conceptual models

Extended start-up time and pilot testing

Infrastructure to coordinate and keep up momentum

Challenges for translational team scienceand discovery research