the baroreflex as a novel mechanism of behavior charge
TRANSCRIPT
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
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
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
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
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
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
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