- Email: [email protected]
Extinction of Avoidance by Response Prevention: Translation From an Animal Model to the Clinic
Early Career Investigator Commentary
Biological Psychiatry
Extinction of Avoidance by Response Prevention: Translation From an Animal Model to the Clinic Iris Lange Excessive avoidance of anxiety and feared stimuli or situations can be regarded as one of the most disabling aspects of anxiety disorders, posttraumatic stress disorder, and obsessive-compulsive disorder (OCD) (1). Active avoidance is a prominent feature of OCD; patients suffering from OCD perform compulsions to neutralize distress associated with an obsession or to prevent expected harm. These persistent avoidance behaviors can be highly timeconsuming and greatly interfere with daily functioning. Compulsion severity and duration can increase without proper treatment and become more habitual over the course of the illness (2). The most common form of psychological treatment for OCD is exposure with response prevention (ERP). ERP targets the extinction of avoidance behaviors. During ERP, the patient is gradually exposed to distress-provoking situations but the execution of compulsions is prevented. In this way, the patient is confronted with the feared situation and learns that the feared outcome will not occur. This allows for disconfirmation of maladaptive beliefs. In addition, by preventing the compulsions during exposure, the patient can experience that distress and the urge for compulsions reduce over time. The majority of patients respond well to ERP, but the rate of dropout, nonresponding, and relapse is relatively high (3). It is important to gain more insight into the mechanisms of ERP and persistent avoidance after ERP to be able to improve therapy outcomes for treatment-resistant patients. By exploring the underlying neurobiological mechanisms of ERP using animal models and human neuroimaging studies, new treatments can be developed. In the current issue of Biological Psychiatry, RodriguezRomaguera et al. present a novel animal model of ERP, extinction with response prevention (Ext-RP), which provides a translational approach to investigate the neural mechanisms of ERP success and failure (4). Over the course of 10 days, rodents learned to avoid a tone-signaled shock by stepping onto a nearby platform. During the subsequent 3 days, they received Ext-RP. During these days, the tone was presented alone and access to the platform was blocked. At the test day, rodents were exposed to the tone alone again, but the blockage to the platform was removed. The percent of time avoiding, freezing, and bar-pressing for food at the opposite side of the platform were evaluated. Most rodents exhibited successful Ext-RP by showing a reduction in avoidance. A subset of the rodents showing persistent avoidance after Ext-RP (i.e., Ext-RP failure) and overall high freezing responses (25%) was subsequently implanted with stimulating electrodes in the dorsal ventral striatum (VS). This failed Ext-RP group
received either deep brain stimulation (DBS)–like highfrequency stimulation or sham during an extra session of Ext-RP. Similarly, patients with OCD who fail to respond to ERP and pharmacological treatments may be eligible for DBS of the ventral capsule (VC)/VS, the human homolog of the rodent VS. VC/VS DBS has emerged as a promising DBS target for patients with therapy-resistant OCD (5). It modulates several cortical and subcortical regions, including the dorsal prefrontal cortex, the ventromedial PFC (vmPFC), the orbitofrontal cortices, the dorsal anterior cingulate cortex, the basal ganglia, the amygdala, and the brain stem (6). Improvements are most optimal when DBS is combined with ERP (4). However, not all patients have a positive response to DBS. In addition, the mechanism of action is unknown. The current animal model can help our understanding of how DBS works in patients with OCD and aid in further refinement of this tool (e.g., by exploring various locations and DBS parameters). It provides an approach to explore the optimal target for boosting the neural circuitry involved in extinction processes during ERP. The failed Ext-RP group was reevaluated after an extra session of Ext-RP combined with either VS DBS or sham. DBS was off at test. Compared to the sham-operated rats, DBS during Ext-RP abolished persistent avoidance. There was no effect of DBS on freezing behavior. Another group of rodents also underwent Ext-RP. These rodents were subdivided into two groups based on freezing behavior during Ext-RP (i.e., low-freezing [presumed success] or high-freezing [presumed failure]). Both groups were injected with either muscimol (for pharmacological inactivation) or saline in the lateral orbitofrontal cortex (lOFC) before evaluating persistent avoidance and freezing. Pharmacological inactivation of the lOFC, compared to saline, decreased avoidance behavior in the high-freezing group. Remarkably, pharmacological inactivation of the lOFC in the successful ERP group increased persistent avoidance behaviors compared to saline. There was no effect of lOFC inactivation on freezing behavior. This animal model provides an avenue to gain more insight into the neural mechanisms of avoidance extinction with respect to ERP. The results indicate that the lOFC plays a significant role in the expression and extinction of avoidance, and thereby in the response to ERP. The data also show that neuromodulation techniques can facilitate therapy outcomes and prevent relapse. Both pharmacological inactivation of the lOFC and DBS of the VS—which is thought to inhibit the lOFC —lowered persistent avoidance after ERP. The major underlying mechanism of exposure-based treatment for OCD, anxiety disorder, and posttraumatic stress
SEE CORRESPONDING ARTICLE ON PAGE 534
http://dx.doi.org/10.1016/j.biopsych.2016.08.004 ISSN: 0006-3223
& 2016 Society of Biological Psychiatry. e51 Biological Psychiatry October 1, 2016; 80:e51–e53 www.sobp.org/journal
Biological Psychiatry
Early Career Investigator Commentary
disorder is thought to be fear extinction. Fear extinction has been studied extensively in animal research and human studies using highly translational protocols, with the result that the neural fear extinction network is well-known (7). Patients suffering from OCD show deficits during recall of extinction learning, with associated aberrant neural activation in the vmPFC, a critical node in the fear extinction network (8). However, in these fear extinction protocols, the component of response prevention and the focus on extinction of avoidance are usually lacking. The protocol of Rodriguez-Romaguera et al. incorporates these aspects, thereby modeling additional aspects of the therapy process. The integration of avoidance extinction in the model represents a novel approach to explore strategies for therapy augmentation or prevention of persistent avoidance, which improves the translational usefulness to the clinic. The lOFC has previously been reported to be involved in negative affect, obsessions, maintenance of compulsive behaviors, and value representation (9). The authors suggest that hyperactivity of the lOFC could result in deficient devaluation of avoidance responses, while DBS-induced or pharmacological inactivation of this region could restore the devaluation process and thereby eliminate persistent avoidance. Remarkably, in the low-freezing group, inactivation of the lOFC diminished the effectiveness of ERP in reducing avoidance. This result could probably be better understood when further exploring the avoidance extinction network in these two subsets of animals, possibly by examining the expression of neural activity markers or neuronal plasticity markers critical for learning and memory in other brain regions. In addition, to gain more insight into ERP mechanisms and its augmentation, it is highly important to investigate the interaction between fear extinction and avoidance extinction and the corresponding brain circuits, and how these circuits are precisely influenced by VC/VS DBS. The rodent VS encompasses not only lateral but also medial orbitofrontothalamic fibers. The individual morphology of these fibers is complex and varies highly between individuals (6). Numerous studies have also pointed to the medial OFC (mOFC) as an important region in the pathophysiology of OCD. Most studies reporting inhibitory control in patients with OCD report mixed findings regarding vmPFC/mOFC hypo- or hyperactivity (9). However, recent studies show hyperactivity in OCD patients during avoidance learning (2) and fear extinction recall (8). Animal studies have shown that DBSlike stimulation in the dorsal VC/VS, which encompasses mOFC fibers, enhances fear extinction learning, possibly indirectly via the infralimbic region, the rodent homologue of the vmPFC (10). The degree to which ERP processes rely on the mOFC versus lOFC circuitry still needs to be investigated, as does the relative outcome of DBS according to greater or lesser engagement of these circuits. Engagement of the two different circuits could possibly drive the ERP process via separate mechanisms. Neurobiological augmentation of ERP could be the next avenue for improving therapy effects, and human studies could therefore further investigate other device-based brain stimulation techniques aside from DBS to augment exposurebased therapy. The current animal model could assist in identifying optimal targets for these other techniques.
e52
In addition, pharmacological augmentation could be further explored by using this animal model. Another important factor that could be explored is the timing of neuromodulation; VS DBS during Ext-RP and lOFC inactivation after Ext-RP both resulted in elimination of persistent avoidance during the test. In addition, because DBS in OCD patients is continuously provided, the effects of continuous VS stimulation on ERP outcomes need to be tested. It takes several weeks to months before VC/VS DBS maximally reduces OCD symptoms; it is therefore still questionable if ERP sessions should be optimally planned after receiving DBS for a specific amount of time. Human neuroimaging studies exploring the interaction between fear and avoidance extinction and the corresponding neural circuits are still warranted. A recent human avoidance protocol with a similar procedure to the rodent model allows for translational bridging (1). In addition, the extinction of avoidance behaviors is a critical aspect of cognitivebehavioral therapies for anxiety disorders and posttraumatic stress disorder. The current animal model could therefore contribute to our understanding of persistent avoidance and therapy outcome in other avoidance-related disorders, and might help guide new treatment options.
Acknowledgments and Disclosures Early Career Investigator Commentaries are solicited in partnership with the Education Committee of the Society of Biological Psychiatry. As part of the educational mission of the Society, all authors of such commentaries are mentored by a senior investigator. This work was mentored by Mohammed Milad, Ph.D. This work was supported by the Boehringer Ingelheim Fonds. I thank Dr. Milad for his mentorship during the preparation of this commentary. The author reports no biomedical financial interests or potential conflicts of interest.
Article Information From the Departments of Psychiatry at Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Address correspondence to Iris Lange, MSc., Massachusetts General Hospital, Psychiatry, 149 13th Street, Office 2.506, Charlestown, MA 02129; E-mail: [email protected]. Received July 26, 2016; revised Aug 8, 2016; accepted Aug 9, 2016.
References 1. 2.
3.
4.
5.
6.
Vervliet B, Indekeu E (2015): Low-cost avoidance behaviors are resistant to fear extinction in humans. Front Behav Neurosci 9:351. Gillan CM, Apergis-Schoute AM, Morein-Zamir S, Urcelay GP, Sule A, Fineberg NA, et al. (2014): Functional neuroimaging of avoidance habits in obsessive-compulsive disorder. Am J Psychiatry 172:284–293. Schruers K, Koning K, Luermans J, Haack M, Griez E (2005): Obsessive–compulsive disorder: a critical review of therapeutic perspectives. Acta Psychiatr Scand 111:261–271. Rodriguez-Romaguera J, Greenberg BD, Rasmussen SA, Quirk GJ (2016): An avoidance-based rodent model of exposure with response prevention therapy for obsessive-compulsive disorder. Biol Psychiatry 80:534–540. Greenberg B, Gabriels L, Malone D, Rezai A, Friehs G, Okun M, et al. (2010): Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol Psychiatry 15:64–79. Makris N, Rathi Y, Mouradian P, Bonmassar G, Papadimitriou G, Ing WI, et al. (2015): Variability and anatomical specificity of the
Biological Psychiatry October 1, 2016; 80:e51–e53 www.sobp.org/journal
Biological Psychiatry
Early Career Investigator Commentary
7. 8.
orbitofrontothalamic fibers of passage in the ventral capsule/ventral striatum (VC/VS): precision care for patient-specific tractographyguided targeting of deep brain stimulation (DBS) in obsessive compulsive disorder (OCD) [published online ahead of print Oct 30]. Brain Imaging Behav. Milad MR, Quirk GJ (2012): Fear extinction as a model for translational neuroscience: ten years of progress. Ann Rev Psychol 63:129–151. Milad MR, Furtak SC, Greenberg JL, Keshaviah A, Im JJ, Falkenstein MJ, et al. (2013): Deficits in conditioned fear extinction in obsessive-
9.
10.
compulsive disorder and neurobiological changes in the fear circuit. JAMA Psychiatry 70:608–618. Milad MR, Rauch SL (2012): Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci 16: 43–51. Rodriguez-Romaguera J, Do-Monte FH, Tanimura Y, Quirk GJ, Haber SN (2015): Enhancement of fear extinction with deep brain stimulation: evidence for medial orbitofrontal involvement. Neuropsychopharmacology 40:1726–1733.
Biological Psychiatry October 1, 2016; 80:e51–e53 www.sobp.org/journal
e53
Biological Psychiatry
Extinction of Avoidance by Response Prevention: Translation From an Animal Model to the Clinic Iris Lange Excessive avoidance of anxiety and feared stimuli or situations can be regarded as one of the most disabling aspects of anxiety disorders, posttraumatic stress disorder, and obsessive-compulsive disorder (OCD) (1). Active avoidance is a prominent feature of OCD; patients suffering from OCD perform compulsions to neutralize distress associated with an obsession or to prevent expected harm. These persistent avoidance behaviors can be highly timeconsuming and greatly interfere with daily functioning. Compulsion severity and duration can increase without proper treatment and become more habitual over the course of the illness (2). The most common form of psychological treatment for OCD is exposure with response prevention (ERP). ERP targets the extinction of avoidance behaviors. During ERP, the patient is gradually exposed to distress-provoking situations but the execution of compulsions is prevented. In this way, the patient is confronted with the feared situation and learns that the feared outcome will not occur. This allows for disconfirmation of maladaptive beliefs. In addition, by preventing the compulsions during exposure, the patient can experience that distress and the urge for compulsions reduce over time. The majority of patients respond well to ERP, but the rate of dropout, nonresponding, and relapse is relatively high (3). It is important to gain more insight into the mechanisms of ERP and persistent avoidance after ERP to be able to improve therapy outcomes for treatment-resistant patients. By exploring the underlying neurobiological mechanisms of ERP using animal models and human neuroimaging studies, new treatments can be developed. In the current issue of Biological Psychiatry, RodriguezRomaguera et al. present a novel animal model of ERP, extinction with response prevention (Ext-RP), which provides a translational approach to investigate the neural mechanisms of ERP success and failure (4). Over the course of 10 days, rodents learned to avoid a tone-signaled shock by stepping onto a nearby platform. During the subsequent 3 days, they received Ext-RP. During these days, the tone was presented alone and access to the platform was blocked. At the test day, rodents were exposed to the tone alone again, but the blockage to the platform was removed. The percent of time avoiding, freezing, and bar-pressing for food at the opposite side of the platform were evaluated. Most rodents exhibited successful Ext-RP by showing a reduction in avoidance. A subset of the rodents showing persistent avoidance after Ext-RP (i.e., Ext-RP failure) and overall high freezing responses (25%) was subsequently implanted with stimulating electrodes in the dorsal ventral striatum (VS). This failed Ext-RP group
received either deep brain stimulation (DBS)–like highfrequency stimulation or sham during an extra session of Ext-RP. Similarly, patients with OCD who fail to respond to ERP and pharmacological treatments may be eligible for DBS of the ventral capsule (VC)/VS, the human homolog of the rodent VS. VC/VS DBS has emerged as a promising DBS target for patients with therapy-resistant OCD (5). It modulates several cortical and subcortical regions, including the dorsal prefrontal cortex, the ventromedial PFC (vmPFC), the orbitofrontal cortices, the dorsal anterior cingulate cortex, the basal ganglia, the amygdala, and the brain stem (6). Improvements are most optimal when DBS is combined with ERP (4). However, not all patients have a positive response to DBS. In addition, the mechanism of action is unknown. The current animal model can help our understanding of how DBS works in patients with OCD and aid in further refinement of this tool (e.g., by exploring various locations and DBS parameters). It provides an approach to explore the optimal target for boosting the neural circuitry involved in extinction processes during ERP. The failed Ext-RP group was reevaluated after an extra session of Ext-RP combined with either VS DBS or sham. DBS was off at test. Compared to the sham-operated rats, DBS during Ext-RP abolished persistent avoidance. There was no effect of DBS on freezing behavior. Another group of rodents also underwent Ext-RP. These rodents were subdivided into two groups based on freezing behavior during Ext-RP (i.e., low-freezing [presumed success] or high-freezing [presumed failure]). Both groups were injected with either muscimol (for pharmacological inactivation) or saline in the lateral orbitofrontal cortex (lOFC) before evaluating persistent avoidance and freezing. Pharmacological inactivation of the lOFC, compared to saline, decreased avoidance behavior in the high-freezing group. Remarkably, pharmacological inactivation of the lOFC in the successful ERP group increased persistent avoidance behaviors compared to saline. There was no effect of lOFC inactivation on freezing behavior. This animal model provides an avenue to gain more insight into the neural mechanisms of avoidance extinction with respect to ERP. The results indicate that the lOFC plays a significant role in the expression and extinction of avoidance, and thereby in the response to ERP. The data also show that neuromodulation techniques can facilitate therapy outcomes and prevent relapse. Both pharmacological inactivation of the lOFC and DBS of the VS—which is thought to inhibit the lOFC —lowered persistent avoidance after ERP. The major underlying mechanism of exposure-based treatment for OCD, anxiety disorder, and posttraumatic stress
SEE CORRESPONDING ARTICLE ON PAGE 534
http://dx.doi.org/10.1016/j.biopsych.2016.08.004 ISSN: 0006-3223
& 2016 Society of Biological Psychiatry. e51 Biological Psychiatry October 1, 2016; 80:e51–e53 www.sobp.org/journal
Biological Psychiatry
Early Career Investigator Commentary
disorder is thought to be fear extinction. Fear extinction has been studied extensively in animal research and human studies using highly translational protocols, with the result that the neural fear extinction network is well-known (7). Patients suffering from OCD show deficits during recall of extinction learning, with associated aberrant neural activation in the vmPFC, a critical node in the fear extinction network (8). However, in these fear extinction protocols, the component of response prevention and the focus on extinction of avoidance are usually lacking. The protocol of Rodriguez-Romaguera et al. incorporates these aspects, thereby modeling additional aspects of the therapy process. The integration of avoidance extinction in the model represents a novel approach to explore strategies for therapy augmentation or prevention of persistent avoidance, which improves the translational usefulness to the clinic. The lOFC has previously been reported to be involved in negative affect, obsessions, maintenance of compulsive behaviors, and value representation (9). The authors suggest that hyperactivity of the lOFC could result in deficient devaluation of avoidance responses, while DBS-induced or pharmacological inactivation of this region could restore the devaluation process and thereby eliminate persistent avoidance. Remarkably, in the low-freezing group, inactivation of the lOFC diminished the effectiveness of ERP in reducing avoidance. This result could probably be better understood when further exploring the avoidance extinction network in these two subsets of animals, possibly by examining the expression of neural activity markers or neuronal plasticity markers critical for learning and memory in other brain regions. In addition, to gain more insight into ERP mechanisms and its augmentation, it is highly important to investigate the interaction between fear extinction and avoidance extinction and the corresponding brain circuits, and how these circuits are precisely influenced by VC/VS DBS. The rodent VS encompasses not only lateral but also medial orbitofrontothalamic fibers. The individual morphology of these fibers is complex and varies highly between individuals (6). Numerous studies have also pointed to the medial OFC (mOFC) as an important region in the pathophysiology of OCD. Most studies reporting inhibitory control in patients with OCD report mixed findings regarding vmPFC/mOFC hypo- or hyperactivity (9). However, recent studies show hyperactivity in OCD patients during avoidance learning (2) and fear extinction recall (8). Animal studies have shown that DBSlike stimulation in the dorsal VC/VS, which encompasses mOFC fibers, enhances fear extinction learning, possibly indirectly via the infralimbic region, the rodent homologue of the vmPFC (10). The degree to which ERP processes rely on the mOFC versus lOFC circuitry still needs to be investigated, as does the relative outcome of DBS according to greater or lesser engagement of these circuits. Engagement of the two different circuits could possibly drive the ERP process via separate mechanisms. Neurobiological augmentation of ERP could be the next avenue for improving therapy effects, and human studies could therefore further investigate other device-based brain stimulation techniques aside from DBS to augment exposurebased therapy. The current animal model could assist in identifying optimal targets for these other techniques.
e52
In addition, pharmacological augmentation could be further explored by using this animal model. Another important factor that could be explored is the timing of neuromodulation; VS DBS during Ext-RP and lOFC inactivation after Ext-RP both resulted in elimination of persistent avoidance during the test. In addition, because DBS in OCD patients is continuously provided, the effects of continuous VS stimulation on ERP outcomes need to be tested. It takes several weeks to months before VC/VS DBS maximally reduces OCD symptoms; it is therefore still questionable if ERP sessions should be optimally planned after receiving DBS for a specific amount of time. Human neuroimaging studies exploring the interaction between fear and avoidance extinction and the corresponding neural circuits are still warranted. A recent human avoidance protocol with a similar procedure to the rodent model allows for translational bridging (1). In addition, the extinction of avoidance behaviors is a critical aspect of cognitivebehavioral therapies for anxiety disorders and posttraumatic stress disorder. The current animal model could therefore contribute to our understanding of persistent avoidance and therapy outcome in other avoidance-related disorders, and might help guide new treatment options.
Acknowledgments and Disclosures Early Career Investigator Commentaries are solicited in partnership with the Education Committee of the Society of Biological Psychiatry. As part of the educational mission of the Society, all authors of such commentaries are mentored by a senior investigator. This work was mentored by Mohammed Milad, Ph.D. This work was supported by the Boehringer Ingelheim Fonds. I thank Dr. Milad for his mentorship during the preparation of this commentary. The author reports no biomedical financial interests or potential conflicts of interest.
Article Information From the Departments of Psychiatry at Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Address correspondence to Iris Lange, MSc., Massachusetts General Hospital, Psychiatry, 149 13th Street, Office 2.506, Charlestown, MA 02129; E-mail: [email protected]. Received July 26, 2016; revised Aug 8, 2016; accepted Aug 9, 2016.
References 1. 2.
3.
4.
5.
6.
Vervliet B, Indekeu E (2015): Low-cost avoidance behaviors are resistant to fear extinction in humans. Front Behav Neurosci 9:351. Gillan CM, Apergis-Schoute AM, Morein-Zamir S, Urcelay GP, Sule A, Fineberg NA, et al. (2014): Functional neuroimaging of avoidance habits in obsessive-compulsive disorder. Am J Psychiatry 172:284–293. Schruers K, Koning K, Luermans J, Haack M, Griez E (2005): Obsessive–compulsive disorder: a critical review of therapeutic perspectives. Acta Psychiatr Scand 111:261–271. Rodriguez-Romaguera J, Greenberg BD, Rasmussen SA, Quirk GJ (2016): An avoidance-based rodent model of exposure with response prevention therapy for obsessive-compulsive disorder. Biol Psychiatry 80:534–540. Greenberg B, Gabriels L, Malone D, Rezai A, Friehs G, Okun M, et al. (2010): Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol Psychiatry 15:64–79. Makris N, Rathi Y, Mouradian P, Bonmassar G, Papadimitriou G, Ing WI, et al. (2015): Variability and anatomical specificity of the
Biological Psychiatry October 1, 2016; 80:e51–e53 www.sobp.org/journal
Biological Psychiatry
Early Career Investigator Commentary
7. 8.
orbitofrontothalamic fibers of passage in the ventral capsule/ventral striatum (VC/VS): precision care for patient-specific tractographyguided targeting of deep brain stimulation (DBS) in obsessive compulsive disorder (OCD) [published online ahead of print Oct 30]. Brain Imaging Behav. Milad MR, Quirk GJ (2012): Fear extinction as a model for translational neuroscience: ten years of progress. Ann Rev Psychol 63:129–151. Milad MR, Furtak SC, Greenberg JL, Keshaviah A, Im JJ, Falkenstein MJ, et al. (2013): Deficits in conditioned fear extinction in obsessive-
9.
10.
compulsive disorder and neurobiological changes in the fear circuit. JAMA Psychiatry 70:608–618. Milad MR, Rauch SL (2012): Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci 16: 43–51. Rodriguez-Romaguera J, Do-Monte FH, Tanimura Y, Quirk GJ, Haber SN (2015): Enhancement of fear extinction with deep brain stimulation: evidence for medial orbitofrontal involvement. Neuropsychopharmacology 40:1726–1733.
Biological Psychiatry October 1, 2016; 80:e51–e53 www.sobp.org/journal
e53