Mapping Compulsivity in the DSM-5 Obsessive Compulsive and Related Disorders: Cognitive Domains, Neural Circuitry, and Treatment

Mapping Compulsivity in the DSM-5 Obsessive Compulsive and Related Disorders: Cognitive Domains,... Compulsions are repetitive, stereotyped thoughts and behaviors designed to reduce harm. Growing evidence suggests that the neurocognitive mechanisms mediating behavioral inhibition (motor inhibition, cognitive inflexibility) reversal learning and habit formation (shift from goal-directed to habitual responding) contribute toward compulsive activity in a broad range of disorders. In obsessive compulsive disorder, distributed network perturbation appears focused around the prefrontal cortex, caudate, putamen, and associated neuro-circuitry. Obsessive compulsive disorder-related attentional set-shifting deficits correlated with reduced resting state functional connectivity between the dorsal caudate and the ventrolateral prefrontal cortex on neuroimaging. In contrast, experimental provocation of obsessive compulsive disorder symptoms reduced neural activation in brain regions implicated in goal-directed behavioral control (ventromedial prefrontal cortex, caudate) with concordant increased activation in regions implicated in habit learning (presupplementary motor area, putamen). The ventromedial prefrontal cortex plays a multifaceted role, integrating affective evaluative processes, flexible behavior, and fear learning. Findings from a neuroimaging study of Pavlovian fear reversal, in which obsessive compulsive disorder patients failed to flexibly update fear responses despite normal initial fear conditioning, suggest there is an absence of ventromedial prefrontal cortex safety signaling in obsessive compulsive disorder, which potentially undermines explicit Received: April 27, 2017; Revised: August 23, 2017; Accepted: September 18, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is 42 properly cited. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Fineberg et al. | 43 International Journal of Neuropsychopharmacology (2018) 21(1): 42–58 contingency knowledge and may help to explain the link between cognitive inflexibility, fear, and anxiety processing in doi:10.1093/ijnp/pyx088 compulsive disorders such as obsessive compulsive disorder. Advance Access Publication: September 23, 2017 Review Keywords: cognitive domains, neural circuitry, and treatment Introduction Compulsions are stereotyped behaviors, performed according Based on emerging data from the neurosciences, this nar- to rigid rules and designed to reduce or avoid unpleasant con- rative review, which was first delivered as a plenary lecture sequences (Chamberlain et al., 2009). The newly created DSM-5 at the 2016 Annual Congress of the International College of Obsessive Compulsive and Related Disorders (OCRDs) (APA 2013) Neuropsychopharmacology (Fineberg et  al., 2016), appraises are defined by the presence of compulsions. However, compul- the results of a decade of research by the authors dedicated to sive behaviors are observed in many other psychiatric disorders, exploring the neuropsychological underpinnings of the OCRDs, particularly those involving deficient impulse control. For exam- as examples of compulsive disorders, from the perspective of ple, much of the behavior associated with disorders of eating, diagnosis, evidence-based treatments, candidate neuro-psycho- substance addiction, and “behavioral addiction,” such as patho- logical endophenotypes, and associated neural circuitry. The logical gambling or problematic internet usage (Ioannidis et al., research builds upon previous and ongoing research by other 2016), is theorized to shift over the course of time from reward- groups and, as it has progressed, has generated testable mod- driven impulsive (rapid, reckless) to compulsive activity (Everitt els of compulsivity as a biologically relevant trans-diagnostic and Robbins, 2005; Robbins et al., 2012). These disorders share a domain that could be expected to advance diagnostic classifi- profound experience of “lack of control,” thought to derive from cation and identify new avenues for treatment, including novel the dysfunctional inhibition of thoughts and behaviors naturally psychological, pharmacological, and somatic treatment targets prone to excess, for example, grooming, eating, purging, gam- for these disabling and intransigent disorders. bling, and checking. As poorly understood lifespan disorders, they are difficult to treat and responsible for considerable psy- The Obsessive-Compulsive and Related Disorders chiatric (depression, suicide) and somatic morbidity and cost to The DSM-5 OCRD cluster, comprising obsessive–compulsive dis- the individual and society as a whole (Hollander et al., 2016). order (OCD), body dysmorphic disorder (BDD), hoarding disor - Regrettably, the development of new treatments in psychia- der, hair-pulling disorder, and skin-picking disorder, represents try is slowing, related, at least in part, to difficulties translating some of the most costly, functionally disabling, and treatment- positive results from experiments using nonhuman illness mod- resistant brain disorders. By gathering together diagnoses previ- els to the clinical setting. These difficulties align with growing ously listed in the DSM-IV under Anxiety Disorders, Somatoform concern about the scientific utility of the existing diagnostic sys- Disorders, and Impulse-Control Disorders Not Elsewhere tems (ICD-10, World Health Organisation 1992, DSM-5, APA 2013) Classified, this new classification aims to advance the scien- that tend to define psychiatric disorders according to symptoms tific study of the disorders as well as to improve their clinical and syndromes and give less prominence to neuropsychological recognition and management. The disorders commonly occur substrates. It is thought likely that the considerable biological together and yet are surprisingly poorly recognized, as individu- heterogeneity that exists within the current taxonomy is ham- als are often not forthcoming about their symptoms (e.g., due pering identification of the underpinning mechanisms that may to a sense of shame, or lack of knowledge that these problems serve as new therapeutic targets. In response, the EU Roadmap constitute recognized mental disorders). As a result, there is for Mental Health Research in Europe (Haro et al., 2014) and the usually a considerable time-lag, in the case of OCD, amounting US National Institute of Mental Health, Research Domain Criteria to approximately 15 years, before the correct diagnosis is made (https://www.nimh.nih.gov/research-priorities/rdoc; Insel et  al., and the correct treatments initiated. The duration of untreated 2010) have called for new ways of classifying psychopathology to illness represents one of the principal factors determining clini- better support treatment development based on dimensions of cal and health outcomes (Dell’Osso et al., 2013), emphasizing the observable behavior with established biological validity, irrespec- importance of early detection, especially for child and adoles- tive of diagnosis. Identifying the pathophysiological mechanisms cent onset OCD (Fineberg et  al., 2013a). It is to be hoped that underpinning compulsivity as a trans-diagnostic, neuropsycho- by introducing this new classification, clinicians would be more logical domain would therefore be expected to advance the search likely to enquire about and detect the other disorders. It is fully for new treatment targets and support innovation in developing expected that the forthcoming ICD revision will adopt a simi- evidence-based treatments (Fineberg et al 2013a). lar approach and may even include additional new diagnoses Many different compulsive disorders are found clustered among the OCRD grouping, such as olfactory reference syn- within the same individual (comorbidity) or within the families drome (Marras et al., 2016). of affected individuals, implying that vulnerability to these dis- OCRDs are generally thought to be highly heritable (hoarding orders is mediated via shared pathophysiological mechanisms disorder, Iervolino et  al., 2009; OCD, Nestadt et  al., 2010; BDD, (Fineberg et  al., 2014). The investigation of endophenotypes Monzani et  al., 2012) lifespan disorders (reviewed in Steketee, (intermediate phenotypes) that lie closer than do the expressed 2011; APA 2013), though episodic forms of OCD, hair pulling, and behaviors (phenotypes) to the genetic and environmental ori- skin picking are seen. They are characterized by the irresistible gins of compulsive disorders (Gottesman and Gould, 2003; urge to perform distressing and time-consuming compulsive Chamberlain and Menzies, 2009), such as changes in cognitive acts. Of these disorders, OCD has been subject to most study performance, or structural and functional brain imaging abnor - and is arguably the most well understood. OCD affects approxi- malities, is expected to provide a clearer understanding of the mately 3% of the general population, though only a fraction biological processes underpinning these disorders. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 44 | International Journal of Neuropsychopharmacology, 2018 of affected individuals present for treatment. Of considerable attain symmetry, the other involving behavioral disinhibition) interest, subthreshold OCD is found to be extremely common as possible trans-diagnostic phenotypes of compulsive behavior. and such cases share a similar age of onset and symptom tra- jectory as OCD, suggesting a natural continuum of compulsive Evidence-Based Treatment of OCD and Related behavior exists affecting as many as 20% of the general popula- Disorders tion (Fineberg et al., 2013b). Figure 1 summarizes the evidence-based treatment of the Patients with OCD show difficulty in flexibly shifting atten- tional focus away from distressing intrusive, perseverative OCRDs based on a systematic review (Grant et al., 2014a). Apart from some studies of OCD and BDD, the pharmacotherapies thoughts (obsessions) and behaviors (compulsions) (Fineberg et  al., 2010, 2014). Washing, checking, ordering, and arranging were almost exclusively tested in small un-replicated trials, and the psychotherapies were not rigorously tested against a compulsions are extremely common. Whereas traditional learn- ing-based psychological models of OCD posit harm avoidance as matched control of fair comparison. Randomized controlled treatment trials of adequate size and power to enable the detec- the major reinforcer of compulsive behaviors, some symptoms of OCD, especially those concerned with ordering and arranging tion of predictive outcome markers are urgently needed to drive forward the clinical management of these disorders on an indi- to achieve symmetry, appear to reflect a need to make the envir - onment “feel right.” Growing evidence suggests these symptoms vidualized basis (Sachdev et al., 2017). OCD typically responds to pharmacological treatment with represent a separate OCD subgroup, in which compulsions are driven by the urge to avoid an unpleasant “not just right feel- serotonin reuptake inhibitors (SRIs; clomipramine and selective SRIs, SSRIs) according to a dose-response relationship (higher ing.” The “not just right feeling” has been found to be associated with an earlier age of OCD onset and the presence of sensory doses needed for better clinical response) or to SSRIs combined with antipsychotic agents, and to cognitive behavior ther- processing difficulties (Hellriegel et  al., 2016), implicating the involvement of neuro-developmental mechanisms akin to aut- apy (CBT) involving exposure and response prevention (ERP) (Fineberg et al., 2015). Antipsychotics represent first-line treat- ism spectrum disorder (ASD) in its etiology. Hoarding disorder is a separate, poorly understood, and ment for Tourette’s syndrome and adjunctive antipsychotic may be preferentially effective in OCD with comorbid tics (Bloch et al., highly treatment refractory OCRD that involves the compulsive acquisition of new items and difficulty discarding owned items. 2006). BDD has been studied less intensively than OCD but also shows a similar treatment response (Veale et al., 2014; Rashid et These hoarding behaviors can also be viewed as an expres- sion of the need to make the environment “feel right.” Typical al., 2015; Phillips et al., 2016), though it remains less clear as to whether higher SSRI dosages and adjunctive antipsychotic are responses when asking individuals what they would think/feel if we threw out a “treasured item,” which may be an old sweet of value (reviewed in Reghunandanan et al., 2015c). The com- pulsions associated with ASD also respond to SSRI, though the paper, bus ticket, etc. are “it feels like I am missing part of me, it does not feel right” (Frost and Steketee, 2010). Hoarding compul- increased risk of SSRI-induced adverse effects in the autistic population, such as behavioral activation and agitation, warrant sions are also commonly found in patients with OCD as well as those with neurodevelopmental disorders such as ASD. In young care in dosage titration and subject selection (Kolevzon et al., 2006). Hoarding behavior has been mainly studied in the con- people with OCD, hoarding is associated with prominent execu- tive function deficits (Park et al., 2016). Hair-pulling disorder and text of comorbid OCD and may respond to SSRI or venlafaxine (Saxena and Sumner, 2014), but as yet no effective pharmaco- skin-picking disorder, on the other hand, are defined by more obviously disinhibited behavior, in the form of repetitive, body- logical treatment has been established for primary hoarding dis- order. CBT, even when delivered intensively over long periods, focused grooming habits that can be considered as either pre- dominantly impulsive or compulsive, depending on the nature has so far been found to produce only limited improvement in hoarding behavior (Uhm et al., 2016). In hair-pulling disorder the of the symptoms expressed (Chamberlain et al., 2007). Other phenotypic signs of an altered neurodevelopmental data supporting the efficacy of SSRI and clomipramine are also not strong. Unlike OCD, but similar to impulse control disorders, trajectory are also commonly observed in patients with OCRDs, such as traits or symptoms of tic disorder, ASD, and attention SSRIs appeared to have a rapid onset of effect which was not sustained over time (Rothbart et al., 2013). Habit reversal ther - deficit hyperactivity disorder. These comorbid traits and diag- noses appear to cluster in the same patient or within their fam- apy, rather than ERP, has emerged as the psychological therapy of choice (McGuire et al., 2014). Other data from single rand- ily members, hinting that shared, heritable neuro-behavioral mechanisms contribute to the expression of many compulsive omized controlled trials in hair-pulling disorder suggest that olanzapine (an antipsychotic agent) (Van Ameringen et al., 2010) disorders (de Vries et al., 2016; Wikramanayake et al., 2017). Cases of tic-related OCD tend to have a male predominance and n-acetyl cysteine (an amino acid compound) (Grant et al., 2009) could be effective. Naltrexone, an opiate antagonist, pro- (similar to ASD), an earlier age of onset, and a higher proportion of OCD symptoms related to symmetry, “not just-right experi- duced substantial benefits in a small open-label study of chil- dren with hair pulling disorder (De Sousa, 2008), but the drug ences,” and forbidden thoughts compared with non-tic-related OCD (Prado et al., 2008). Additionally, tic-related OCD shows a was not effective in a double-blind placebo-controlled study. However, those in this study with a family history of addiction more favorable response to adjunctive treatment with dopa- mine antagonist drugs (Bloch et al., 2006). In response to the showed a greater (but not statistically significant) decrease in the urge to hair-pull (Grant et al., 2014b). Skin picking disorder emerging evidence, the DSM-5 has highlighted the presence of tic as the first neuro-behavioral specifier of a clinically relevant has been barely studied to date, but as with hair-pulling disorder, shows some response to SSRI and n-acetyl cysteine (reviewed in OCD subtype. Studies in patients with Tourette’s syndrome indi- cate a complex genetic relationship exists between tic disorder, Reghunandanan et al., 2015c). Approximately 40% of OCD patients fail to respond to stand- OCD, and attention deficit hyperactivity disorder. One such recent study (Darrow et al., 2016) identified two independent, ard forms of therapy (Fineberg et al., 2015). Of great interest, a wide range of pharmacological compounds have been tested in heritable, symptom-based factors (one involving the urge to Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Fineberg et al. | 45 Disorder Rx Psychotherapy Other OCD SSRI CBT with ERP Cingulotomy Clomipramine CBT+family therapy Capsulotomy Adjuncveanpsychoc ACT Deep brain (haloperidol, risperidone, smulaon queapine, olanzapine, rTMS aripiprazole) BDD SSRI CBT with ERP Clomipramine Hoarding Disorder SSRI (in comorbid OCD) CBT for hoarding venlafaxine Hair-pulling Disorder Clomipramine Habit reversal therapy N-Acetyl Cysteine ACT Olanzapine Dialeccal BT Stress Reducon Skin picking Disorder SSRI Habit reversal therapy N-Acetyl Cysteine ACT-enhanced BT Figure 1. Evidence-based treatments for OCRDS. Adapted from Grant J, Chamberlain S, Odlaug B, Clinical Guide to OCRDs, Oxford, 2014a. Treatments with robust evi- dence of efficacy derived from randomized controlled trials of fair comparison are highlighted in bold black type. ACT, acceptance and commitment therapy; BDD, body dysmorphic disorder; BT ,behavior therapy; CBT, cognitive behavior therapy; ERP, exposure and response prevention; OCD, obsessive compulsive disorder; rTMS r , epeti- tive transcranial magnetic stimulation; Rx, Medication; SSRI, selective serotonin reuptake inhibitor. treatment-resistant OCD and some have been found to be effect- pathological gambling), impulse control disorders (e.g., inter - ive in small-sized trials, implicating a multiplicity of potential mittent explosive disorder), or even neurodevelopmental disor - treatment targets and mechanisms (see Figure 2) ders (e.g. ASD), challenging their classification within the OCRDs Thus, notwithstanding the limitations of the study data, grouping. Alternatively, by taking a dimensional (impulsive- some compulsive disorders (e.g., OCD, BDD) exhibit a strik- compulsive-habit) approach to the psychopharmacology of the ingly similar treatment response to SRIs, suggesting that the OCRDs, the emerging evidence may instead be interpreted to underpinning neural mechanisms may overlap significantly, support the inclusion of some of these other disorders into an and possibly also with those relating to anxiety and affec- expanded OCRDs grouping (Sachdev et al., 2017). tive disorders. In contrast, hair pulling and skin picking dis- orders, which are also characterized by prominent impulse Neuropsychological Endophenotypes control and addictive symptomatology, respond better to treat- ment with drugs acting on dopamine, glutamate, opioid, and Psychiatric symptoms and cognitive deficits can be conceptual- noradrenergic systems, that is, potentially more like impulse- ized as disordered structure, connectivity, and function in large- control disorders or even behavioral addictions (e.g. Grant et scale neural networks. A series of evolutionarily well-conserved, al., 2014b), whereas those with SRI-resistant OCD respond to parallel, cortico-striato-thalamo-cortical (CSTC) circuits are similar agents in combination with SSRI, and OCD with promi- believed to underpin the expression of compulsive behaviors nent motor symptoms (tics, habits) may respond preferentially (Alexander et al., 1986; Cummings et al., 1993; Groenewegen and to adjunctive dopamine antagonists, known to modulate the Uylings 2000). These circuits include direct (positive feedback) cortico-striatal motor circuitry involved in Tourette’s syndrome and indirect (negative feedback) pathways, projecting from spe- and animal models of excessive habit behavior (Fineberg et al., cific cortical areas to the corresponding subregions of the stri- 2014; Furlong et al., 2014). atum and thalamus with recurrent projections to the cortex. The pharmacological treatment response may be of par- They are involved in diverse computational activities, includ- ticular value for parsing psychiatric disorders and defining ing reward processing, action selection, habit formation, and the boundaries of diagnostic groups, as it depends on under- motor control (Arnsten et  al., 2011; Robbins et  al., 2012). They pinning biological mechanisms. As the treatment trial data for play an important role in recognizing behaviorally significant the OCRDs accrues, it is possible that for some disorders more stimuli (and in error detection) and in regulating goal-directed convincing similarities will be found with disorders classified responses (Lovinger, 2010) and may therefore be particularly elsewhere in the DSM, such as the behavioral addictions (e.g., important for OCRDs. The anatomical overlap and functional Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 46 | International Journal of Neuropsychopharmacology, 2018 Compound Study Outcome Insel et al., 1983 D-amphetamine> placebo D-amphetamine Joffe et al., 1991 D-amphetamine> placebo (single dose) Methylphenidate =placebo Ketamine Rodriguez et al., 2013 Ketamine > placebo (IV; single dose) Bloch et al., 2012 (open-label) No responders at 3 days MirtazapineKoran et al., 2005a Mirtazapine> placebo (double-blinded disconnuaon) Memanne Ghaleiha et al., 2013 Memanne >placebo Haghighi et al., 2013 Memanne >placebo LamotrigineBruno et al., 2012 Lamotrigine> placebo Khalkhali et al., 2016 Lamotrigine> placebo N-acetyl cysteine Afshar et al., 2012 N-acetyl cysteine >placebo Sarris et al., 2015 N-acetyl cysteine= placebo Paydary et al., 2016 N-acetyl cysteine >placebo Costa et al, 2017 N-acetyl cysteine= placebo Topiramate Berlin et al., 2010 Topiramate > placebo (compulsions only) Mowla et al., 2010 Topiramate >placebo Afshar et al., 2014 Topiramate = placebo Morphine Koran et al., 2005bMorphine> placebo (once weekly) Figure 2. SSRI-Resistant OCD: Small sized randomized controlled trials showing efficacy vs. placebo. interplay between these circuits may explain why compulsive clusters such as hoarding (Saxena et al., 2004; Mataix-Cols behavior occurs in so many psychiatric syndromes. et al., 2005). The use of sophisticated cognitive and affective paradigms has generated new heuristics regarding the role of these circuits (Fitzgerald et al., 2004; Remijnse et al., 2006); Historical Perspectives for example, during implicit learning, OCD subjects failed to Early indications that the compulsive behaviors seen in OCD and show an expected increase in striatal activity and instead acti- other compulsive disorders may be mediated by CSTC circuits vated temporal cortex regions (Rauch et al., 2001). The obser- (reviewed in Reghunandanan et al., 2015a) included research vation that some behavioral challenges, such as exposure to showing an association between postencephalitis Parkinsonian, OCD cues, induce over-activation of the orbitofrontal cortex obsessive-compulsive symptoms and striatal lesions (Cheyette on functional imaging and others induce underactivation (e.g. and Cummings, 1995). OCD symptoms were also found to occur Chamberlain et al., 2008) may be explained by functional seg- in a range of other neurological disorders involving striatal regation within the orbitofrontal cortex. pathology, including Tourette’s syndrome, Sydenham’s chorea, Pediatric imaging research has also supported the involve- Huntington’s disorder, and Parkinson’s disorder (Pitman et al., ment of CTSC circuits in OCD (reviewed in Reghunandanan 1987; Rapoport, 1989; Stein et al., 1994). OCD patients have sub- et al., 2015a) and potentially offers the promise of being sequently been found to demonstrate abnormalities in a broad able to determine the evolution of brain abnormalities over series of measures used in neuropsychiatric (e.g., neurological time (Rosenberg and Keshavan, 1998, Rosenberg et al., 2011). soft signs, olfactory identification, evoked potentials, intra-corti- Abnormal structure or function in other brain regions such cal inhibition) and neuropsychological (e.g., executive function) as the temporal lobe structures involved in memory and fear research (Stein et al., 1994; Purcell et al., 1998a). These abnor- processing (Hugo et al., 1999; Zungu-Dirwayi, 1999, Szeszko et malities have consistently implicated CSTC dysfunction and al., 1999) and the supra marginal gyrus and the parietal lobe impaired control of the inhibition of thoughts and behaviors involved in the initiation and flexible control of instrumental (reviewed in Morein-Zamir et al., 2010). Some evidence has sug- behavior (Chamberlain et al., 2008; Meunier et al., 2012) have gested that they are relatively specific to disorders character - less commonly been found in OCD. However, recent meta- ized by compulsive behaviors (Purcell et al., 1998b; Phillips et and mega-analyses of structural imaging data collected from al., 2010). research sites worldwide found distinct patterns of subcorti- Advances in brain imaging have provided persuasive neuro- cal abnormalities in pediatric and adult OCD patients. The anatomical data for OCD (Rauch and Baxter, 1998; Graybiel and hippocampus as well as the pallidum seemed to be of impor- Rauch, 2000; Whiteside et al., 2004; Mataix-Cols and van den tance in adult OCD, whereas the thalamus was involved in Heuvel, 2006; Menzies et al., 2007; Milad and Rauch, 2012) as pediatric OCD (Boedhoe et al., 2017). well as Tourette’s syndrome (Groenewegen et al., 2003), tricho- Both successful SRI pharmacotherapy and behavioral ther - tillomania (Chamberlain et al., 2009), impulse control disorders apy have been shown in OCD to normalize activity in CSTC in Parkinson’s disease (van den Heuvel et al., 2010), and addict- circuits (Baxter et al., 1992). Baseline structure or activity may ive disorders (Everitt and Robbins, 2005). Functional imaging in differentially predict response to pharmacotherapy and psy- OCD has demonstrated increased activity in CSTC circuits con- chotherapy (Brody et al., 1998; Hoexter et al., 2013) suggesting necting the orbitofrontal cortex, cingulate cortex, and striatum, that different treatment modalities exert their clinical effects both at rest and especially during exposure to feared stimuli via different neuro-mechanisms (Reghunandanan et al., 2015a). (reviewed in Reghunandanan et al., 2015a). Somewhat different Neurosurgical interruption of CSTC circuits may also reduce circuits may be involved in mediating different OCD symptom OCD symptoms as well as decrease striatal volume (Rauch, 2000). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 AUGMENTATION MONOTHERAPY Fineberg et al. | 47 Magnetic resonance spectroscopy has demonstrated altera- excessive fronto-striatal connectivity within that circuit tions in glutamate metabolites in CSTC circuits (Rosenberg et (Bourne et al., 2012). The degree of such normalization corre- al., 2004; Whiteside et al., 2006; Yucel et al., 2007), in some cases lated with reduced severity of symptoms (Figee et al., 2013). normalizing after successful treatment with an SSRI (Rosenberg et al., 2000). Evidence from the relatively few positron emission tomography (PET) ligand studies so far performed in OCD have Neurocognitive Models of OCRDS identified abnormal binding of the serotonin transporter in cortical and subcortical areas (Reimold et al., 2007; Matsumoto Neurocognitive changes are likely to be of great value for study- et al., 2010; Hesse et al., 2011) and of the striatal postsynaptic ing the neurobiology of psychiatric disorders, as they are theo- dopamine D2 receptor (Moresco et al., 2007; Perani et al., 2008; retically more directly linked to brain structure and function Denys et al., 2013), which normalized after treatment with SSRI than are the more complex higher-level phenotypes such as (Moresco et al., 2007). compulsive symptoms (Fineberg et al., 2014). They are also more Techniques combining gene variants and brain imaging tractable to exploration across animal species (Dalley et al., 2011) have been used to enhance the imaging findings. Several gene and are invaluable for clinicians and patients, providing a richer variants have been found to be associated with structural understanding of the phenotype. Of the available instruments, and functional alteration in CSTC circuits relevant to OCRDs computerized cognitive tests have several advantages over pen (reviewed in Reghunandanan et al., 2015a). For example, in and paper assessment. To date, a number of tasks derived from patients with OCD, genetic variation in the serotonin trans- the Cambridge Neuropsychological Test Automated Battery porter was demonstrated to be associated with reduced orbito- (CANTAB), which includes tests that are adaptable for transla- frontal cortex volume as measured by magnetic resonance tional work in animals and for application during brain imag- imaging (MRI) (Atmaca et al., 2011; Hesse, 2011) and the avail- ing, have shown considerable utility in fractionating cognitive ability of the serotonin transporter in the putamen, nucleus processes in OCRDS and in localizing neural and neurochemical accumbens, and hypothalamus as measured by PET (Hesse et substrates. al., 2011). Growing evidence from human and animal research using Thus, in OCRDs, distributed network perturbation appears tests such as the CANTAB suggests that the neurocognitive focused around the prefrontal cortex, caudate, putamen, and mechanisms mediating behavioral inhibition (motor inhibition, associated neurocircuitry. In OCD, convergent evidence points cognitive inflexibility) and habit formation (shift from goal- to deficient top-down inhibitory control in the prefrontal cortex directed to habitual responding) variably contribute toward vul- nodes within this circuitry, coupled with the hijacking of flex- nerability to compulsive activity in a broad range of compulsive ible, contingency-dependent instrumental behavior in favor of disorders (reviewed in Fineberg et al., 2014). Moreover, some of excess habit generation mediated by dysfunction within the these deficits can be found in unaffected healthy relatives of dorsal striatum (reviewed in Fineberg et al., 2014; Gillan et al., OCD probands, suggesting they represent vulnerability or trait 2016a). Abnormal activation in the dorsal striatum, especially markers of compulsivity that also exist in nonpatient groups. the head of the caudate nucleus and the putamen, is well rep- licated in the OCD literature (reviewed in Reghunandanan et Motor Inhibition al., 2015a, 2015b), implicating the cognitive fronto-striatal loop Multiple tiers of evidence, ranging from functional magnetic communicating with the dorsolateral prefrontal cortex driving resonance imaging (fMRI) of individuals with focal frontal action selection and the motor loops driving goal-directed and lobe lesions to animal research, have demonstrated that the habitual responses (Gillan et al., 2014). This neuroanatomical inhibitory control of motor acts is sub-served by a neural net- model goes some way to explain the link between compulsive work linking the right inferior frontal gyrus with its subcortical acts and harm-related thoughts and activities. Involvement of (including subthalamic) connections (Rubia et al., 2003). Motor the putamen may be particularly relevant for the development of inhibition can be reliably tested using the stop-signal reaction sensorimotor symptom such as tics. However, imaging research time (SSRT) task (Aron et al., 2005). Pharmacological manipula- suggests that a wider range of CTSC circuits are involved in OCD, tion in rodents and humans suggests that motor response inhi- including systems responsible for reward processing more usu- bition, as indexed by the SSRT, falls under the neuro-modulatory ally associated with addiction (Klanker et al., 2013). influence of the norepinephrine system (Chamberlain et al., Surgical disconnection of this circuitry via stereotactic cap- 2006b, 2007a, 2013). In contrast, serotonin appears not to be cen- sulotomy, cingulotomy, or limbic leucotomy has been used to trally involved in this particular measure of impulsivity (Clark treat severe, intractable OCD for several decades, with some et al., 2005a; Chamberlain et al., 2006b; reviewed in Fineberg et evidence of success. A double-blind, sham-controlled trial has al., 2014). Paradoxically, compared with the SSRIs, there is only recently produced limited evidence of the efficacy and tol- weak evidence to suggest that drugs acting to increase norepi- erability of ventral capsulotomy using gamma radio-surgery nephrine in the synaptic cleft, such as the SNRIs venlafaxine (Lopes et al., 2014, 2015; Batistuzzo et al., 2015). Promising and duloxetine (Hollander et al., 2003; Dell’Osso et al., 2008; results from a small number of treatment studies using inva- Dougherty et al., 2015; Mowla et al., 2016), are beneficial in OCD. sive (deep brain stimulation) or noninvasive (transcranial In a series of experiments using the SSRT (Chamberlain magnetic stimulation, transcranial direct current stimulation) et al., 2006a; Odlaug et al., 2011), evidence of significant impair - methods of neuro-modulation to target either cortical (orbito- ment in motor inhibition, compared with healthy controls, was frontal cortex, presupplementary motor area [pre-SMA]) or found in separate groups of patients with OCD, hair-pulling, and subcortical (nucleus accumbens, subthalamic nucleus) nodes gambling disorder. However, this deficit was not seen in a study or white matter tracts within this frontal-striatal circuitry of community respondents with obsessive compulsive person- (reviewed in Senço et al., 2015) indicate new treatment pos- ality traits but without OCD (Fineberg et  al., 2015), suggesting sibilities for refractory obsessive-compulsive disorders. There that this form of inhibitory failure represents a concomitant of is experimental evidence that in patients with OCD, deep compulsive motor acts. In the case of OCD, SSRT performance brain stimulation targeted to the nucleus accumbens reduced was also highly significantly impaired in unaffected first-degree Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 48 | International Journal of Neuropsychopharmacology, 2018 relatives (Chamberlain et  al., 2007b). In a MRI study of OCD Obsessive-compulsive disorders may be differen ated using tests of families that included unaffected first-degree relatives (Menzies inhibitory failure, though considerable intra-class heterogeneity exists et al., 2007), reduced cortical grey matter volume, coupled with increased basal ganglia grey matter volume, was found to cor - relate with SSRT indices of increased motor disinhibition. This SPD OCPD study produced some of the earliest evidence of a structural BDD imbalance in inhibitory cortico-striatal circuitry as a neuro- HPD COGNITIVE MOTOR cognitive endophenotype of motor impulsivity in OCD. A more OCD INHIBITION INFLEXIBILITY recent fMRI study demonstrated trait-dependent compensatory Schizo Hoarding D hyperactivity in the pre-SMA during the performance of the -OCD SSRT in both medication-free patients with OCD and unaffected siblings vs healthy controls, representing another neurocogni- tive endophenotype of motor impulsivity, in this case possibly Figure 3. Motor Inhibition, Cognitive Inflexibility and OC Spectrum Dis- related to inefficient neural processing within the pre-SMA in orders. BDD, body-dysmorphic disorder; HPD, hair-pulling disorder; OCD, those vulnerable to OCD (de Wit et al., 2012). obsessive-compulsive disorder; OCPD, obsessive compulsive personality disorder; schizo-OCD, schizophrenia with OCD; SPD, skin-picking disorder. Cognitive Inflexibility The intradimensional-extradimensional (ID-ED) shift task not only in patients with OCD but also in their unaffected, never- examines different components of attentional flexibility, includ- treated relatives (Rejminse et al., 2006; Chamberlain et al., 2008). ing reversal learning, set formation, and inhibition, as well as Reversal-learning–related hypofunction, therefore, appears to shifting attention between stimulus dimensions (ED shift). be another candidate endophenotype for compulsivity that Studies have demonstrated that ED shift is impaired in OCD exists in people at increased genetic risk of OCD. and additionally in the unaffected first-degree relatives of OCD The identification of cognitive endophenotypes, such as subjects (Chamberlain et al., 2006a, 2007b; Vaghi et al., 2016), those reflecting failures in motor inhibition and cognitive flex- suggesting that this aspect of cognitive inflexibility represents ibility, opens new perspectives for the development of bio- an endophenotype for OCD-related compulsivity. Moreover, markers that may be objectively quantified and used to parse ED shift impairment has been identified in patients with other compulsive disorders into more biologically homogeneous obsessive-compulsive spectrum disorders, including obsessive- groups and that may even enable the development of personal- compulsive personality disorder (Fineberg et al., 2015), schizo- ized forms of treatment tailored to the individual (Figure 3). For phrenia with OCD (Patel et al., 2010), and BDD (Jefferies-Sewell et example, a small-sized, randomized, placebo-controlled trial in al., 2016). In a study of OCD hoarders compared with compulsive patients with skin picking disorder found that whereas lamo- hoarders without OCD, significant EDS changes versus healthy trigine was not efficacious in the group as a whole, benefit was controls were found in the OCD hoarders only, suggesting that seen in a subset of patients who exhibited relatively impaired the comorbid group was associated with greater cognitive cognitive flexibility on the EDS (Grant et al., 2010). Results such inflexibility (Morein-Zamir et al., 2014). Interestingly, another as these highlight the need for randomized controlled studies of study found that hair-pulling disorder was not associated with adequate power to prospectively examine the role of cognitive EDS impairment, though OCD was, suggesting that cognitive endophenotypes as predictors of treatment response across the inflexibility is not an essential component of repetitive acts of full spectrum of compulsive disorders. grooming (Chamberlain et al., 2006a). According to a recent fMRI analysis, compared with healthy Habit Learning controls, patients with OCD when tested in a resting state, irre- Compulsions are characterized by the persistence of activities spective of treatment status, showed reduced functional con- that become disconnected from the prevailing environmental nectivity in circuits linking the dorsal caudate nucleus and its contingencies and lack an obvious relationship to the overall anatomical cortical projections (Vaghi et  al., 2017). In addition, goal of the activity. In OCD, many patients are fully aware that reduced connectivity between the left dorsal caudate and the their compulsive behaviors bear little to no relation to desirable ventrolateral prefrontal cortex, an area of cortex known to be outcomes, yet despite this knowledge, they continue to per - associated with EDS in healthy controls (Rogers et  al., 2000), form them. They often describe their compulsions as unwanted was associated with reduced OCD-related EDS performance. habits. The reduced functional connectivity within this circuitry may According to associative learning theories of instrumen- account for the deficits in shifting attentional focus away from tal behavior (Balleine and Dickinson, 1998; de Wit et al., 2009), inappropriate intrusive thoughts and rituals, resulting in the actions are supported by at least 2 separate neural systems: a perseverative behavior seen in OCD and acting as a potential goal-directed system and a habitual system. When controlled biomarker of OCD. by the goal-directed system, actions are purposeful inasmuch Perseverating on a behavior that was once rewarded, but as they are flexibly performed to obtain desired goals or avoid is later associated with harmful consequences, may reflect a undesired events. In contrast, habitual behaviors are consid- lack of contingency-related cognitive flexibility. Exerting flexibil- ered lower order behaviors as they are performed as a routine ity in learning and unlearning behavior based on (probabilistic) response to specific environmental triggers and are insensi- contingencies (probabilistic reversal-learning) may be particu- tive to changes in environmental contingency (i.e., whether the larly relevant for the development of compulsive tendencies action is contextually appropriate) or the outcome value of the (Fineberg et al., 2014). Contingency-related flexibility is depend- behavior (i.e., whether the goal is actually desirable). After mul- ent on serotonin systems (Clarke et al., 2005b) and has been tiple repetitions, the habit system begins to render purposeful linked to orbito-frontal cortex (OFC) function (Rubia et al., 2003). behavior rigid and automatic (Adams et al., 1981, 1982), allowing Reduced activation of the OFC, lateral PFC, and parietal cortex simple acts to be conducted without effort. Exaggerated habit was observed using task-related fMRI during reversal learning, formation is consistent with the ego-dystonic stimulus-driven Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Fineberg et al. | 49 aspects of compulsivity. Compulsivity may thus arise at least in provide compelling support for the hypothesis that compulsions part from a shift from goal-directed action to habit, rendering in OCD result from a shift from goal-directed to habitual behav- behavior insensitive to its outcome or to the prevailing environ- ioral control and are underpinned by changes in neural activity mental contingencies. focused around the vmPFC, caudate nucleus, and the associated The caudate nucleus is both pivotally involved in OCD, fronto-striatal neural circuitry. as well as in the dynamic regulation of goal-directed contin- gency learning, under the prevailing influence of the ventro- Safety Signaling medial prefrontal cortex (vmPFC), which tracks the current The vmPFC plays a complex role in fear learning and safety- value of outcomes. In contrast, habitual acts involve the pos- signaling and is closely involved in integrating the evalu- terior lateral putamen, where stimulus-response associations ative processing of environmental cues with flexible behavior. are stored (Balleine and O’doherty, 2010; Gillan et al., 2011). In Abnormal vmPFC activation has been implicated in anxiety a recent fMRI study of OCD patients (Banca et al., 2015), the disorders (Schiller et  al., 2008; Cha et  al., 2014,) as well as in experimental provocation of autobiographical compulsions in impaired fear retention in OCD (Milad et al., 2013). Dysfunctional OCD patients was shown to reduce neural activation in brain processing within the vmPFC therefore represents a plausible regions implicated in goal-directed behavioral control (vmPFC, mechanism by which explicit contingency knowledge related to caudate nucleus) with concordant increased activation in safety and harm is undermined, leading to the failure to flex- regions implicated in habit learning (pre-SMA, putamen). This ibly update fear responses and the persistence of rigid, habitual finding contrasts with previous evidence of generalized fronto- compulsive activity. Further studies in OCD patients are there- striato-limbic hyperactivation during OCD symptom evocation fore under way to clarify the neuro-psychological relationship and provocation. This is likely due to differences in task nature between fear and anxiety processing in the vmPFC on the one and design. The cited study used a highly ecological symptom hand and cognitive flexibility in the caudate nucleus on the provocation paradigm, which overcame some of the limitations other. A  recent neuroimaging study of Pavlovian fear reversal of previous studies, as well as, for the first time, subject-driven found that OCD patients failed to flexibly update fear responses, feedback that enabled the authors to specifically address the as measured by skin conductance changes, despite normal ini- link between symptom provocation and compulsive urges to tial fear conditioning. This inability to update threat estimation track the motor component of OCD. By contrast, the hyperac- was significantly correlated with vmPFC hyperactivation during tivation of caudate and medial prefrontal cortex found in pre- early fear learning. The findings suggest that there is an absence vious studies could represent OCD-related changes in other of vmPFC safety signaling in OCD that potentially undermines cognitive domains such as imagery or autobiographical memory explicit contingency knowledge and that may go some way to recollection, which are also processed in the medial prefrontal explain the link between cognitive inflexibility, fear, and anx- cortex (Lin WJ et al., 2015). iety processing in compulsive disorders such as OCD (Apergis- Stronger support for a shift toward habitual responding is Schoute et al., 2017). derived from the following series of studies that investigated the extent to which patients with OCD showed a bias towards per- Compulsive-Obsessive Disorder forming stimulus-response habits and away from goal-directed In the shock avoidance studies by Gillan et al. (2014, 2015), post- activities. In the first of these studies (Gillan et  al., 2011), sub- hoc explanations for continuing to respond to the devalued jects were trained to respond to cues to press computer keys to stimulus (e.g., “why did you press?”) were described as irrational win valuable points on a computer game. Next, some of the keys threat beliefs by many of the OCD patients (e.g., “I thought were devalued, that is, they were no longer linked to a valuable I might still be shocked”). Like obsessions, these beliefs were dir- outcome and subjects were told not to press them when cued ectly contradictory to the patients’ explicit knowledge of threat to do so. Yet, the OCD patients continued to habitually press in and their ratings of shock expectancy. Thus, in OCD subjects response to the cue, even after the keys had ceased to be linked faced with aversive situations, dysfunctional activation of the to a reward. vmPFC and dorsal striatum may disrupt normal goal-directed The next study attempted to more closely model the devel- behavior, leading to the generation of harm-avoidance habits opment of compulsions as behaviors designed to avoid harmful that readily become compulsive or urge-driven and that may consequences (as opposed to gain appetitive outcomes), using a go on to create ego-dystonic, irrational fears (obsessions) with shock-avoidance task (Gillan et al., 2014). Subjects were trained the effect of perpetuating the compulsive behavior. According to lever-press in response to a computer signal to avoid a mildly to this compulsive-obsessive disorder model, the compulsive painful electric shock indicated by the signal. After excessive behaviors of OCD play a key role in ensuring the persistence of training on the task, the electric wire was obviously discon- the obsessions. nected and the subjects instructed not to press in response to Consistent with this model, behavioral therapy using expos- the signal. As predicted, however, patients with OCD continued ure and response prevention (ERP), representing the standard to lever-press to the devalued stimulus that explicitly no longer psychological therapy for OCD (www. NICE.org.uk), requires predicted a shock and did so significantly more than a matched patients to undergo symptom provocation via exposure to rele- healthy control group (Gillan et al., 2014). In a subsequent study, vant stimuli or situations in order to learn to resist the urge this habitual shock-avoidance behavior was directly related to perform the compulsions. ERP has been found not only to to fMRI evidence of hyperactivity in both the vmPFC, during produce a reduction in compulsive responding, but also con- the initial acquisition of the goal-directed avoidance behav- currently causes the urge to respond and the associated obses- ior, and in the caudate, during the performance of the habit- sive thoughts to attenuate (Foa et al., 2005). Our data suggest ual avoidance behaviors (Gillan et al., 2015). In addition, more that suppressing compulsions, for example using ERP, should OCD patients than controls reported experiencing a premonitory remain a key therapeutic intervention in OCRDs and hint that urge to perform the shock-avoidance habits, the intensity of habit reversal therapies (Morris et al., 2013) that are designed to which correlated with the performance of the habits and with break habitual associations between exposure-related cues and the strength of the fMRI caudate hyperactivity. These findings Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 50 | International Journal of Neuropsychopharmacology, 2018 Neurocognitive Definition Task Neural system Neurochemistry Compulsive disorders showing abnormalitiesin Domain this domain compared to healthycontrols Motorinhibition pre-potent motor stop signal reaction rightinferior frontal cortex , norepinephrine OCD(and st unaffected1 disinhibition time task SMAand subcortical connections, includingsub- degree relatives), thalamic nucleus BDD, hair-pulling disorder, hoarding disorder, skin picking disorder, gambling disorder, binge-eating disorder inability to adapt reversal learning orbitofrontal cortex and Serotonin, OCD(and Contingencyrelated st unaffected1 cognitiveinflexibility behavior after tasks subcorticalconnections degree relatives), negative feedback Dopamine? pathological gambling Attentionalinflexibility inability to switch extra-dimensional Ventro-lateral PFC-humans. Dopamine OCD, attentionbetween attentionalset- stimuli shifting Lateral PFC -primates BDD, (CANTAB) andsubcortical connections OCDwith schizophrenia, OCPD, Anorexia nervosa, Bingeeating disorder Inflexible fear learning Inflexible fear Pavlovianfear VMPFC, caudate,insula, anterior ?OCD learning and reversal cingulatecortex inadequate safety signalling Lack of sensitivity Habitformation Fronto-striatalcircuits: Dopamine, OCD, Habitlearning to goals, taskstesting contingenciesor appetitive or Habitactivity involves Serotonin? Binge-eating outcomes of actions avoidancehabit connectionsbetween SMA and disorder, learning under posteriorputamen outcome Methamphetamine devaluation. Goal-directedactivityinvolves or cocaineabuse connectionsbetween VMPFC Two-step andcaudate sequential discrimination task; model-based(goal directed)versus model free (habitual) decision making. Figure 4. Subdividing compulsive disorders according to neurocognitive domains: task performance, neural and neurochemical correlates. Abbreviations: CANTAB, Cambridge Neuropsychological Test Automated Battery; OCPD, obsessive compulsive personality disorder; PFC, prefrontal cortex; SMA, supplementary motor area; VMPFC, ventromedial prefrontal cortex; ?, findings not assured. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Fineberg et al. | 51 compulsive responses and that are currently used to treat hair- with intrusive thought, anxious-depression, and social with- pulling disorder (Rothbart et al., 2013) may also have value in drawal. Critically, they found that when the individual disorders OCD, for example by augmenting the clinical response to ERP. (OCD, eating disorder, impulse control disorder, addiction) were replaced with the compulsive factor, the deficits in goal-directed control were captured even more strongly. Moreover, this asso- Disorders of Compulsivity: A Common Bias toward ciation was highly specific when compared with the other non- Learning Habits? compulsive dimensions of psychopathology. These data indicate A number of computational modelling techniques (e.g., the that deficits in goal-directed control, conferring vulnerability for two-step sequential discrimination task; Daw et al., 2011) have developing rigid habits, may have a specific role in driving the been developed to infer the prevailing balance between goal- compulsive behaviors that characterize diverse disorders such directed and habitual behavioral control by assessing a person’s as OCD, eating disorder, substance abuse, and addiction. decision-making tendencies (respectively, model-based versus model-free). These questionnaires and computational tasks Integrating Neuropsychological Models with have the added advantage of being readily disseminated on-line Treatment Models and therefore available to test very large numbers of subjects. In one of the earliest studies that applied this methodology to Based on these and other emerging findings, it is possible to compulsivity, Voon et al. (2015a) tested a trans-diagnostic group draw inferences about the neuropsychological mechanisms of subjects with diagnoses involving both natural reward (binge underpinning the response to standard treatments in dis- eating disorder), artificial reward (methamphetamine/cocaine orders such as OCD (Gillan et al., 2016a). Increased stress is abuse), and OCD and compared them with healthy controls. The known to induce a tendency to form habits (Schwabe and Wolf, results showed a common bias across all these disorders away 2009). It has therefore been suggested that SSRIs may act in from model-based (goal-directed) learning. In addition, the habit OCD by restraining anxiety and reducing the effects of punish- formation bias was associated with lower grey matter volumes ment, thereby helping the OCD patient to switch from habitual in the caudate and medial orbitofrontal cortex on structural MRI. towards goal-directed behavior and indirectly attenuating the The findings suggested that dysfunction in a neurocompu- need to perform compulsions (Morein-Zamir et al., 2013). This tational mechanism favoring model-free habit learning may effect of SSRI could also enhance the capacity to benefit from underlie the repetitive behaviors that ultimately dominate in CBT with ERP (Gillan et al., 2016a). The finding from a non-ran- diverse disorders involving compulsion. In a further study (Voon domized study that goal-directed learning under both reward et al., 2015b) that compared performance on the two-step task and punishment conditions was enhanced in OCD patients under conditions of reward and loss, OCD subjects compared receiving SSRI (Palminteri et al., 2012) provides some support with healthy volunteers were less goal orientated (model-based) for this hypothesis. Further support is derived from more recent and more habitual (model-free) to reward outcomes with a shift findings in healthy volunteers that acute tryptophan deple- towards greater model-based and lower habitual choices to loss tion, which reduces serotonin transmission, induced a shift (punishment) outcomes. These results highlight the import- from goal-directed to habitual responding on a slips-of-action ance of motivation for learning processes in OCD and suggest test and also had a deleterious effect on model-based learning that distinct clinical strategies based on reward valence may be (Worbe et al., 2015, 2016). warranted. However, if the mechanism of effect of SSRI in OCD Most recently, Gillan et al. (2016b) applied computational depended on anxiety reduction, benzodiazepines and other modelling to investigate whether a dimensional approach could anxiolytics would also be expected to show evidence of effi- better delineate the clinical manifestations of goal-directed cacy, which they do not. Moreover, SSRIs are at their most learning deficits using large-scale online assessment of psy- efficacious in OCD at dosages higher than is typically recom- chiatric symptoms and neurocognitive performance in two mended for anxiety disorders (Fineberg et al., 2013c; Skapinakis independent general population samples. Nearly 2000 people et al., 2016). An alternative hypothesis, therefore, proposes completed the online self-report questionnaires measuring that SSRIs exert a therapeutic effect in OCD by bolstering goal- decision-making preferences as well as symptoms of various directed behavior through direct pharmacological actions in mental health conditions. As expected, people demonstrating those areas of cortex implicated in safety signaling and goal- reduced goal-directed control on the two-step task (Daw et al., directed control, including the vmPFC and medial orbitofrontal 2011) also reported higher rates of compulsive symptomatology cortex (El Mansari and Blier, 2006; Gillan et al., 2015; Voon et related to OCD and also eating disorder, impulse control dis- al 2015a). El Mansari and Blier (2006) reviewed the effects on order, and addiction symptoms, further demonstrating the gen- 5-HT release and the adaptive changes in pre- and postsynaptic eralizability of the deficits across multiple compulsive disorders. 5-HT receptor sensitivity induced by SRI treatment in rodent By leveraging an online methodology to collect such a large brain structures involved in OCD, including analogues of the dataset, Gillan et al. (2016b) were also able to deal with a key OFC. The time course of increased 5-HT release and terminal limitation of standard case-control research, the question of 5-HT1D desensitization aligned with the course of the thera- specificity. While the demonstration of a degree of generaliz- peutic response to SRI in OCD. In addition, consistent with the ability of cognitive deficits across compulsive disorders that are dose-dependent therapeutic effect of SRIs, a greater dose of SRI similarly characterized by a loss of control over behavior, alco- induced greater reuptake inhibition, which played an essential hol addiction, eating disorders, and impulsivity is of interest, role in this phenomenon. The authors further hypothesized without establishing the specificity of this deficit to this class that the therapeutic effect of SRI-enhanced 5-HT release in the of symptoms (and not depressive symptoms, for example), the OFC is mediated by the activation of postsynaptic 5-HT2-like findings are limited. By carrying out a factor analysis on their receptors. This cortical region is among the most consistently dataset, Gillan and colleagues identified that the self-report psy- implicated in OCD (Whiteside et al., 2004) and shares overlap- chopathological data could be neatly fitted into three separate ping functional connectivity abnormalities with those seen in transdiagnostic symptom dimensions: compulsive behavior addicted individuals at rest (Meunier et al., 2012). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 52 | International Journal of Neuropsychopharmacology, 2018 Antipsychotics are used to treat stereotyped or self-injurious predicted by a spectrum of neuropsychological mechanisms, behavior in patients with ASD. It has been proposed that antip- including, inter alia, impaired motor inhibition, cognitive inflex- sychotics may also work in OCD by reducing habitual or stereo- ibility (attentional set-shift, reversal learning), and an imbal- typed behavior patterns. The anti-OCD effect of antipsychotic ance in goal-directed vs habit learning. In OCD, abnormal safety agents, when co-administered with SSRI, has been shown to signaling may undermine accurate safety learning, resulting in positively correlate with the drugs’ inherent dopamine D2 and inflexible threat beliefs, with important implications for expo- D3 receptor antagonist affinities (Ducasse et al., 2014). However, sure-based therapies that rely on robust safety memories and whereas studies in rodents have identified a link between dopa- future treatment development (Apergis-Schoute et al., 2017). mine in the dorsal striatum and the flexible modulation of Avoidance habits, acting via disrupted goal-directed learn- learnt behavior (Lovinger et al., 2010; Furlong et al., 2014), stud- ing, represent a plausible model of chronic OCD-related com- ies of dopamine receptor agonists and antagonists in human pulsivity. Furthermore, emerging evidence implicates disrupted models of compulsive behavior have produced ambiguous find- goal-directed learning in an extended group of DSM disorders ings (reviewed in Gillan et al., 2016a). characterized by compulsive behaviors and intrusive thoughts, ERP for OCD involves repeated exposure to the fear-inducing and maps with specificity onto a trans-diagnostic compulsive stimuli that would ordinarily trigger a compulsive response, and symptom-dimension. Distributed network perturbation asso- resistance to the urge to perform the compulsion, so that the ciated with these cognitive changes, affecting the prefrontal urge eventually dissipates. However, ERP usually involves weeks cortex (vmPFC, lateral PFC), the dorsal striatum (caudate), and of practice, few people manage to drop all their compulsions, the associated neuro-circuitry modulating emotional, cognitive, and about one-half of those with the condition are not helped and motor control, has been identified in OCD. Networked stud- at all (Reghunandanan et al., 2015b). The finding that, in OCD, ies investigating multiple disorders under the same conditions, patients may fail to flexibly update threat perception through head-to-head, are needed to determine the extent to which faulty vmPFC safety signaling (Apergis-Schoute et al., 2017) may these changes overlap with or differentiate other disorders explain some of the difficulties that many experience in extin- of compulsive behavior. Empirical evidence suggests that the guishing OCD-related fears and offers exciting new treatment psychopathology of OCRDs becomes more habitual over time. heuristics. The failure to recognize when a feared situation has Mega-analysis in OCD suggests that illness-related structural become safe may explain why people with OCD find ERP so dif- brain changes differ in pediatric and adult cases. Longitudinal ficult and the treatment takes so long to work. Clinicians may studies are now needed to explore the effect of duration of therefore find these results helpful in their discussions with untreated disorder on the mediating neurobiology. These find- their patients, who could be persuaded of the importance of ings would have the potential to inform (1) the development sticking with the therapy rather than giving up prematurely. of biomarkers to enable the detection of compulsive disorder This may even explain why co-administration of SSRI with ERP at the earliest opportunity, crucially, in children, adolescents, is found to be helpful. In addition, the new findings indicate the and young adults, before it becomes entrenched, as well as (2) need to explore new methods of strengthening attention to safe the development of new treatments with novel mechanisms situations during ERP to enhance fear-extinction, for example, of action designed to strengthen goal-directed behavior and through the use of psychopharmacological, cognitive, or neuro- top-down cognitive strategies for controlling urges with better modulation strategies. efficacy and tolerability. Agreement on a standardized set of Another way in which the efficacy of ERP for OCD can be validated clinical measures of compulsivity that could be used explained is via the systematic breaking of habitual (stimulus- trans-diagnostically would represent a rational next step. response) associations between exposure-related cues and compulsive responses, achieved through repeated response-pre- vention exercises (Gillan et al., 2016). Brain-imaging measures Acknowledgments of hyperactivity in the caudate nucleus of OCD patients were T.W.R.  and colleagues (A.A.-S., P.B.) acknowledge financial found to correlate both with goal-directed deficits and subjective support for studies on OCD from the Wellcome Trust (grant urges to respond habitually (Gillan et al., 2014). In other studies, 104631/Z/14/Z). M.M.V.  is supported by a Pinsent-Darwin caudate abnormalities were found to be remediated when OCD Studentship in Mental Pathology and a Cambridge Home and patients respond to ERP (Baxter et al., 1992; Whiteside et al., 2012). European Union Scholarship Scheme studentship. C.M.G.  is These results suggest ERP may exert a direct effect on caudate supported by a fellowship from MQ. Dr Chamberlain’s involve- hyperactivity. Abstinence in addiction, which results in a reduc- ment in this work was funded by a Wellcome Trust Fellowship tion in craving, may also work by breaking stimulus-response (110049/Z/15/Z). associations between cues and drug-taking behavior. However, both ERP and abstinence are experienced as aversive and drop- out rates are high, reflecting the need to develop more clinic- Statement of Interest ally acceptable ways to deliver this form of treatment. Moreover, as the habitual behaviors are strengthened with repetition In the past several years, Dr Fineberg has received research sup- (Tricomi et al., 2009), OCD and addictions become even more dif- port from Lundbeck, Glaxo-SmithKline, European College of ficult to treat over time, emphasizing the importance of detec- Neuropsychopharmacology (ECNP), Servier, Cephalon, Astra tion and intervention at the earliest stage (Fineberg et al., 2013a; Zeneca, Medical Research Council (UK), National Institute Gillan et al., 2016a). for Health Research, Wellcome Foundation, University of Hertfordshire, EU (FP7), and Shire. Dr Fineberg has received hon- oraria for lectures at scientific meetings from Abbott, Otsuka, Conclusions Lundbeck, Servier, Astra Zeneca, Jazz pharmaceuticals, Bristol Myers Squibb, UK College of Mental Health Pharmacists, and The data presented serve to highlight the potential of a dimen- sional, biologically grounded approach to psychiatry research. British Association for Psychopharmacology (BAP). Dr Fineberg has received financial support to attend scientific meetings from They suggest that vulnerability to compulsive activity can be Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Fineberg et al. | 53 RANZCP, Shire, Janssen, Lundbeck, Servier, Novartis, Bristol Myers Batistuzzo MC, Hoexter MQ, Taub A, Gentil AF, Cesar RC, Joaquim Squibb, Cephalon, International College of Obsessive-Compulsive MA, D’Alcante CC, McLaughlin NC, Canteras MM, Shavitt RG, Spectrum Disorders, International Society for behavioral Savage CR, Greenberg BD, Norén G, Miguel EC, Lopes AC (2015) Addiction, CINP, IFMAD, ECNP, BAP, World Health Organization, and Visuospatial memory improvement after gamma ventral Royal College of Psychiatrists. Dr Fineberg has received financial capsulotomy in treatment refractory obsessive-compulsive royalties for publications from Oxford University Press and pay- disorder patients. Neuropsychopharmacology 40:1837–45. ment for editorial duties from Taylor and Francis. Dr Chamberlain Baxter LR Jr, Schwartz JM, Bergman KS, Szuba MP, Guze BH, consults for Cambridge Cognition and Shire. Dr Trevor Robbins Mazziotta JC, Alazraki A, Selin CE, Ferng HK, Munford P, et al. has recently consulted for Cambridge Cognition, Mundipharma, (1992) Caudate glucose metabolite changes with both drug Lundbeck, and Otsuka and has received royalties from Cambridge and behavior therapy for obsessive–compulsive disorder. Cognition for CANTAB, and a research grant from Lundbeck, as Arch Gen Psychiatry 49:681–9. well as editorial honoraria from Springer Verlag and Elsevier. Dr Berlin HA, Koran LM, Jenike MA, Shapira NA, Chaplin W, Pallanti Barbara Sahakian consults for Cambridge Cognition, Peak, and S, Hollander E (2011) Double-blind, placebo-controlled trial of Mundipharma and holds a grant from the Wallitt Foundation. topiramate augmentation in treatment-resistant obsessive- She has in the recent past consulted for Lundbeck, Servier, and compulsive disorder. J Clin Psychiatry 72:716–721. Otsuka and received grants from Peak and Janssen/JandJ. Bloch MH, Landeros-Weisenberger A, Kelmendi B, Coric V, Bracken MB, Leckman JF (2006) A systematic review: anti- psychotic augmentation with treatment refractory obses- References sive-compulsive disorder. Mol Psychiatry 11:622–632. Adams C (1982) Variations in the sensitivity of instrumental Bloch MH, Wasylink S, Landeros-Weisenberger A, Panza KE, Bill- responding to reinforcer devaluation. Q J Exp Psychol 34B:77– ingslea E, Leckman JF, Krystal JH, Bhagwagar Z, Sanacora G, 98. 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Abstract

Compulsions are repetitive, stereotyped thoughts and behaviors designed to reduce harm. Growing evidence suggests that the neurocognitive mechanisms mediating behavioral inhibition (motor inhibition, cognitive inflexibility) reversal learning and habit formation (shift from goal-directed to habitual responding) contribute toward compulsive activity in a broad range of disorders. In obsessive compulsive disorder, distributed network perturbation appears focused around the prefrontal cortex, caudate, putamen, and associated neuro-circuitry. Obsessive compulsive disorder-related attentional set-shifting deficits correlated with reduced resting state functional connectivity between the dorsal caudate and the ventrolateral prefrontal cortex on neuroimaging. In contrast, experimental provocation of obsessive compulsive disorder symptoms reduced neural activation in brain regions implicated in goal-directed behavioral control (ventromedial prefrontal cortex, caudate) with concordant increased activation in regions implicated in habit learning (presupplementary motor area, putamen). The ventromedial prefrontal cortex plays a multifaceted role, integrating affective evaluative processes, flexible behavior, and fear learning. Findings from a neuroimaging study of Pavlovian fear reversal, in which obsessive compulsive disorder patients failed to flexibly update fear responses despite normal initial fear conditioning, suggest there is an absence of ventromedial prefrontal cortex safety signaling in obsessive compulsive disorder, which potentially undermines explicit Received: April 27, 2017; Revised: August 23, 2017; Accepted: September 18, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is 42 properly cited. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Fineberg et al. | 43 International Journal of Neuropsychopharmacology (2018) 21(1): 42–58 contingency knowledge and may help to explain the link between cognitive inflexibility, fear, and anxiety processing in doi:10.1093/ijnp/pyx088 compulsive disorders such as obsessive compulsive disorder. Advance Access Publication: September 23, 2017 Review Keywords: cognitive domains, neural circuitry, and treatment Introduction Compulsions are stereotyped behaviors, performed according Based on emerging data from the neurosciences, this nar- to rigid rules and designed to reduce or avoid unpleasant con- rative review, which was first delivered as a plenary lecture sequences (Chamberlain et al., 2009). The newly created DSM-5 at the 2016 Annual Congress of the International College of Obsessive Compulsive and Related Disorders (OCRDs) (APA 2013) Neuropsychopharmacology (Fineberg et  al., 2016), appraises are defined by the presence of compulsions. However, compul- the results of a decade of research by the authors dedicated to sive behaviors are observed in many other psychiatric disorders, exploring the neuropsychological underpinnings of the OCRDs, particularly those involving deficient impulse control. For exam- as examples of compulsive disorders, from the perspective of ple, much of the behavior associated with disorders of eating, diagnosis, evidence-based treatments, candidate neuro-psycho- substance addiction, and “behavioral addiction,” such as patho- logical endophenotypes, and associated neural circuitry. The logical gambling or problematic internet usage (Ioannidis et al., research builds upon previous and ongoing research by other 2016), is theorized to shift over the course of time from reward- groups and, as it has progressed, has generated testable mod- driven impulsive (rapid, reckless) to compulsive activity (Everitt els of compulsivity as a biologically relevant trans-diagnostic and Robbins, 2005; Robbins et al., 2012). These disorders share a domain that could be expected to advance diagnostic classifi- profound experience of “lack of control,” thought to derive from cation and identify new avenues for treatment, including novel the dysfunctional inhibition of thoughts and behaviors naturally psychological, pharmacological, and somatic treatment targets prone to excess, for example, grooming, eating, purging, gam- for these disabling and intransigent disorders. bling, and checking. As poorly understood lifespan disorders, they are difficult to treat and responsible for considerable psy- The Obsessive-Compulsive and Related Disorders chiatric (depression, suicide) and somatic morbidity and cost to The DSM-5 OCRD cluster, comprising obsessive–compulsive dis- the individual and society as a whole (Hollander et al., 2016). order (OCD), body dysmorphic disorder (BDD), hoarding disor - Regrettably, the development of new treatments in psychia- der, hair-pulling disorder, and skin-picking disorder, represents try is slowing, related, at least in part, to difficulties translating some of the most costly, functionally disabling, and treatment- positive results from experiments using nonhuman illness mod- resistant brain disorders. By gathering together diagnoses previ- els to the clinical setting. These difficulties align with growing ously listed in the DSM-IV under Anxiety Disorders, Somatoform concern about the scientific utility of the existing diagnostic sys- Disorders, and Impulse-Control Disorders Not Elsewhere tems (ICD-10, World Health Organisation 1992, DSM-5, APA 2013) Classified, this new classification aims to advance the scien- that tend to define psychiatric disorders according to symptoms tific study of the disorders as well as to improve their clinical and syndromes and give less prominence to neuropsychological recognition and management. The disorders commonly occur substrates. It is thought likely that the considerable biological together and yet are surprisingly poorly recognized, as individu- heterogeneity that exists within the current taxonomy is ham- als are often not forthcoming about their symptoms (e.g., due pering identification of the underpinning mechanisms that may to a sense of shame, or lack of knowledge that these problems serve as new therapeutic targets. In response, the EU Roadmap constitute recognized mental disorders). As a result, there is for Mental Health Research in Europe (Haro et al., 2014) and the usually a considerable time-lag, in the case of OCD, amounting US National Institute of Mental Health, Research Domain Criteria to approximately 15 years, before the correct diagnosis is made (https://www.nimh.nih.gov/research-priorities/rdoc; Insel et  al., and the correct treatments initiated. The duration of untreated 2010) have called for new ways of classifying psychopathology to illness represents one of the principal factors determining clini- better support treatment development based on dimensions of cal and health outcomes (Dell’Osso et al., 2013), emphasizing the observable behavior with established biological validity, irrespec- importance of early detection, especially for child and adoles- tive of diagnosis. Identifying the pathophysiological mechanisms cent onset OCD (Fineberg et  al., 2013a). It is to be hoped that underpinning compulsivity as a trans-diagnostic, neuropsycho- by introducing this new classification, clinicians would be more logical domain would therefore be expected to advance the search likely to enquire about and detect the other disorders. It is fully for new treatment targets and support innovation in developing expected that the forthcoming ICD revision will adopt a simi- evidence-based treatments (Fineberg et al 2013a). lar approach and may even include additional new diagnoses Many different compulsive disorders are found clustered among the OCRD grouping, such as olfactory reference syn- within the same individual (comorbidity) or within the families drome (Marras et al., 2016). of affected individuals, implying that vulnerability to these dis- OCRDs are generally thought to be highly heritable (hoarding orders is mediated via shared pathophysiological mechanisms disorder, Iervolino et  al., 2009; OCD, Nestadt et  al., 2010; BDD, (Fineberg et  al., 2014). The investigation of endophenotypes Monzani et  al., 2012) lifespan disorders (reviewed in Steketee, (intermediate phenotypes) that lie closer than do the expressed 2011; APA 2013), though episodic forms of OCD, hair pulling, and behaviors (phenotypes) to the genetic and environmental ori- skin picking are seen. They are characterized by the irresistible gins of compulsive disorders (Gottesman and Gould, 2003; urge to perform distressing and time-consuming compulsive Chamberlain and Menzies, 2009), such as changes in cognitive acts. Of these disorders, OCD has been subject to most study performance, or structural and functional brain imaging abnor - and is arguably the most well understood. OCD affects approxi- malities, is expected to provide a clearer understanding of the mately 3% of the general population, though only a fraction biological processes underpinning these disorders. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 44 | International Journal of Neuropsychopharmacology, 2018 of affected individuals present for treatment. Of considerable attain symmetry, the other involving behavioral disinhibition) interest, subthreshold OCD is found to be extremely common as possible trans-diagnostic phenotypes of compulsive behavior. and such cases share a similar age of onset and symptom tra- jectory as OCD, suggesting a natural continuum of compulsive Evidence-Based Treatment of OCD and Related behavior exists affecting as many as 20% of the general popula- Disorders tion (Fineberg et al., 2013b). Figure 1 summarizes the evidence-based treatment of the Patients with OCD show difficulty in flexibly shifting atten- tional focus away from distressing intrusive, perseverative OCRDs based on a systematic review (Grant et al., 2014a). Apart from some studies of OCD and BDD, the pharmacotherapies thoughts (obsessions) and behaviors (compulsions) (Fineberg et  al., 2010, 2014). Washing, checking, ordering, and arranging were almost exclusively tested in small un-replicated trials, and the psychotherapies were not rigorously tested against a compulsions are extremely common. Whereas traditional learn- ing-based psychological models of OCD posit harm avoidance as matched control of fair comparison. Randomized controlled treatment trials of adequate size and power to enable the detec- the major reinforcer of compulsive behaviors, some symptoms of OCD, especially those concerned with ordering and arranging tion of predictive outcome markers are urgently needed to drive forward the clinical management of these disorders on an indi- to achieve symmetry, appear to reflect a need to make the envir - onment “feel right.” Growing evidence suggests these symptoms vidualized basis (Sachdev et al., 2017). OCD typically responds to pharmacological treatment with represent a separate OCD subgroup, in which compulsions are driven by the urge to avoid an unpleasant “not just right feel- serotonin reuptake inhibitors (SRIs; clomipramine and selective SRIs, SSRIs) according to a dose-response relationship (higher ing.” The “not just right feeling” has been found to be associated with an earlier age of OCD onset and the presence of sensory doses needed for better clinical response) or to SSRIs combined with antipsychotic agents, and to cognitive behavior ther- processing difficulties (Hellriegel et  al., 2016), implicating the involvement of neuro-developmental mechanisms akin to aut- apy (CBT) involving exposure and response prevention (ERP) (Fineberg et al., 2015). Antipsychotics represent first-line treat- ism spectrum disorder (ASD) in its etiology. Hoarding disorder is a separate, poorly understood, and ment for Tourette’s syndrome and adjunctive antipsychotic may be preferentially effective in OCD with comorbid tics (Bloch et al., highly treatment refractory OCRD that involves the compulsive acquisition of new items and difficulty discarding owned items. 2006). BDD has been studied less intensively than OCD but also shows a similar treatment response (Veale et al., 2014; Rashid et These hoarding behaviors can also be viewed as an expres- sion of the need to make the environment “feel right.” Typical al., 2015; Phillips et al., 2016), though it remains less clear as to whether higher SSRI dosages and adjunctive antipsychotic are responses when asking individuals what they would think/feel if we threw out a “treasured item,” which may be an old sweet of value (reviewed in Reghunandanan et al., 2015c). The com- pulsions associated with ASD also respond to SSRI, though the paper, bus ticket, etc. are “it feels like I am missing part of me, it does not feel right” (Frost and Steketee, 2010). Hoarding compul- increased risk of SSRI-induced adverse effects in the autistic population, such as behavioral activation and agitation, warrant sions are also commonly found in patients with OCD as well as those with neurodevelopmental disorders such as ASD. In young care in dosage titration and subject selection (Kolevzon et al., 2006). Hoarding behavior has been mainly studied in the con- people with OCD, hoarding is associated with prominent execu- tive function deficits (Park et al., 2016). Hair-pulling disorder and text of comorbid OCD and may respond to SSRI or venlafaxine (Saxena and Sumner, 2014), but as yet no effective pharmaco- skin-picking disorder, on the other hand, are defined by more obviously disinhibited behavior, in the form of repetitive, body- logical treatment has been established for primary hoarding dis- order. CBT, even when delivered intensively over long periods, focused grooming habits that can be considered as either pre- dominantly impulsive or compulsive, depending on the nature has so far been found to produce only limited improvement in hoarding behavior (Uhm et al., 2016). In hair-pulling disorder the of the symptoms expressed (Chamberlain et al., 2007). Other phenotypic signs of an altered neurodevelopmental data supporting the efficacy of SSRI and clomipramine are also not strong. Unlike OCD, but similar to impulse control disorders, trajectory are also commonly observed in patients with OCRDs, such as traits or symptoms of tic disorder, ASD, and attention SSRIs appeared to have a rapid onset of effect which was not sustained over time (Rothbart et al., 2013). Habit reversal ther - deficit hyperactivity disorder. These comorbid traits and diag- noses appear to cluster in the same patient or within their fam- apy, rather than ERP, has emerged as the psychological therapy of choice (McGuire et al., 2014). Other data from single rand- ily members, hinting that shared, heritable neuro-behavioral mechanisms contribute to the expression of many compulsive omized controlled trials in hair-pulling disorder suggest that olanzapine (an antipsychotic agent) (Van Ameringen et al., 2010) disorders (de Vries et al., 2016; Wikramanayake et al., 2017). Cases of tic-related OCD tend to have a male predominance and n-acetyl cysteine (an amino acid compound) (Grant et al., 2009) could be effective. Naltrexone, an opiate antagonist, pro- (similar to ASD), an earlier age of onset, and a higher proportion of OCD symptoms related to symmetry, “not just-right experi- duced substantial benefits in a small open-label study of chil- dren with hair pulling disorder (De Sousa, 2008), but the drug ences,” and forbidden thoughts compared with non-tic-related OCD (Prado et al., 2008). Additionally, tic-related OCD shows a was not effective in a double-blind placebo-controlled study. However, those in this study with a family history of addiction more favorable response to adjunctive treatment with dopa- mine antagonist drugs (Bloch et al., 2006). In response to the showed a greater (but not statistically significant) decrease in the urge to hair-pull (Grant et al., 2014b). Skin picking disorder emerging evidence, the DSM-5 has highlighted the presence of tic as the first neuro-behavioral specifier of a clinically relevant has been barely studied to date, but as with hair-pulling disorder, shows some response to SSRI and n-acetyl cysteine (reviewed in OCD subtype. Studies in patients with Tourette’s syndrome indi- cate a complex genetic relationship exists between tic disorder, Reghunandanan et al., 2015c). Approximately 40% of OCD patients fail to respond to stand- OCD, and attention deficit hyperactivity disorder. One such recent study (Darrow et al., 2016) identified two independent, ard forms of therapy (Fineberg et al., 2015). Of great interest, a wide range of pharmacological compounds have been tested in heritable, symptom-based factors (one involving the urge to Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Fineberg et al. | 45 Disorder Rx Psychotherapy Other OCD SSRI CBT with ERP Cingulotomy Clomipramine CBT+family therapy Capsulotomy Adjuncveanpsychoc ACT Deep brain (haloperidol, risperidone, smulaon queapine, olanzapine, rTMS aripiprazole) BDD SSRI CBT with ERP Clomipramine Hoarding Disorder SSRI (in comorbid OCD) CBT for hoarding venlafaxine Hair-pulling Disorder Clomipramine Habit reversal therapy N-Acetyl Cysteine ACT Olanzapine Dialeccal BT Stress Reducon Skin picking Disorder SSRI Habit reversal therapy N-Acetyl Cysteine ACT-enhanced BT Figure 1. Evidence-based treatments for OCRDS. Adapted from Grant J, Chamberlain S, Odlaug B, Clinical Guide to OCRDs, Oxford, 2014a. Treatments with robust evi- dence of efficacy derived from randomized controlled trials of fair comparison are highlighted in bold black type. ACT, acceptance and commitment therapy; BDD, body dysmorphic disorder; BT ,behavior therapy; CBT, cognitive behavior therapy; ERP, exposure and response prevention; OCD, obsessive compulsive disorder; rTMS r , epeti- tive transcranial magnetic stimulation; Rx, Medication; SSRI, selective serotonin reuptake inhibitor. treatment-resistant OCD and some have been found to be effect- pathological gambling), impulse control disorders (e.g., inter - ive in small-sized trials, implicating a multiplicity of potential mittent explosive disorder), or even neurodevelopmental disor - treatment targets and mechanisms (see Figure 2) ders (e.g. ASD), challenging their classification within the OCRDs Thus, notwithstanding the limitations of the study data, grouping. Alternatively, by taking a dimensional (impulsive- some compulsive disorders (e.g., OCD, BDD) exhibit a strik- compulsive-habit) approach to the psychopharmacology of the ingly similar treatment response to SRIs, suggesting that the OCRDs, the emerging evidence may instead be interpreted to underpinning neural mechanisms may overlap significantly, support the inclusion of some of these other disorders into an and possibly also with those relating to anxiety and affec- expanded OCRDs grouping (Sachdev et al., 2017). tive disorders. In contrast, hair pulling and skin picking dis- orders, which are also characterized by prominent impulse Neuropsychological Endophenotypes control and addictive symptomatology, respond better to treat- ment with drugs acting on dopamine, glutamate, opioid, and Psychiatric symptoms and cognitive deficits can be conceptual- noradrenergic systems, that is, potentially more like impulse- ized as disordered structure, connectivity, and function in large- control disorders or even behavioral addictions (e.g. Grant et scale neural networks. A series of evolutionarily well-conserved, al., 2014b), whereas those with SRI-resistant OCD respond to parallel, cortico-striato-thalamo-cortical (CSTC) circuits are similar agents in combination with SSRI, and OCD with promi- believed to underpin the expression of compulsive behaviors nent motor symptoms (tics, habits) may respond preferentially (Alexander et al., 1986; Cummings et al., 1993; Groenewegen and to adjunctive dopamine antagonists, known to modulate the Uylings 2000). These circuits include direct (positive feedback) cortico-striatal motor circuitry involved in Tourette’s syndrome and indirect (negative feedback) pathways, projecting from spe- and animal models of excessive habit behavior (Fineberg et al., cific cortical areas to the corresponding subregions of the stri- 2014; Furlong et al., 2014). atum and thalamus with recurrent projections to the cortex. The pharmacological treatment response may be of par- They are involved in diverse computational activities, includ- ticular value for parsing psychiatric disorders and defining ing reward processing, action selection, habit formation, and the boundaries of diagnostic groups, as it depends on under- motor control (Arnsten et  al., 2011; Robbins et  al., 2012). They pinning biological mechanisms. As the treatment trial data for play an important role in recognizing behaviorally significant the OCRDs accrues, it is possible that for some disorders more stimuli (and in error detection) and in regulating goal-directed convincing similarities will be found with disorders classified responses (Lovinger, 2010) and may therefore be particularly elsewhere in the DSM, such as the behavioral addictions (e.g., important for OCRDs. The anatomical overlap and functional Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 46 | International Journal of Neuropsychopharmacology, 2018 Compound Study Outcome Insel et al., 1983 D-amphetamine> placebo D-amphetamine Joffe et al., 1991 D-amphetamine> placebo (single dose) Methylphenidate =placebo Ketamine Rodriguez et al., 2013 Ketamine > placebo (IV; single dose) Bloch et al., 2012 (open-label) No responders at 3 days MirtazapineKoran et al., 2005a Mirtazapine> placebo (double-blinded disconnuaon) Memanne Ghaleiha et al., 2013 Memanne >placebo Haghighi et al., 2013 Memanne >placebo LamotrigineBruno et al., 2012 Lamotrigine> placebo Khalkhali et al., 2016 Lamotrigine> placebo N-acetyl cysteine Afshar et al., 2012 N-acetyl cysteine >placebo Sarris et al., 2015 N-acetyl cysteine= placebo Paydary et al., 2016 N-acetyl cysteine >placebo Costa et al, 2017 N-acetyl cysteine= placebo Topiramate Berlin et al., 2010 Topiramate > placebo (compulsions only) Mowla et al., 2010 Topiramate >placebo Afshar et al., 2014 Topiramate = placebo Morphine Koran et al., 2005bMorphine> placebo (once weekly) Figure 2. SSRI-Resistant OCD: Small sized randomized controlled trials showing efficacy vs. placebo. interplay between these circuits may explain why compulsive clusters such as hoarding (Saxena et al., 2004; Mataix-Cols behavior occurs in so many psychiatric syndromes. et al., 2005). The use of sophisticated cognitive and affective paradigms has generated new heuristics regarding the role of these circuits (Fitzgerald et al., 2004; Remijnse et al., 2006); Historical Perspectives for example, during implicit learning, OCD subjects failed to Early indications that the compulsive behaviors seen in OCD and show an expected increase in striatal activity and instead acti- other compulsive disorders may be mediated by CSTC circuits vated temporal cortex regions (Rauch et al., 2001). The obser- (reviewed in Reghunandanan et al., 2015a) included research vation that some behavioral challenges, such as exposure to showing an association between postencephalitis Parkinsonian, OCD cues, induce over-activation of the orbitofrontal cortex obsessive-compulsive symptoms and striatal lesions (Cheyette on functional imaging and others induce underactivation (e.g. and Cummings, 1995). OCD symptoms were also found to occur Chamberlain et al., 2008) may be explained by functional seg- in a range of other neurological disorders involving striatal regation within the orbitofrontal cortex. pathology, including Tourette’s syndrome, Sydenham’s chorea, Pediatric imaging research has also supported the involve- Huntington’s disorder, and Parkinson’s disorder (Pitman et al., ment of CTSC circuits in OCD (reviewed in Reghunandanan 1987; Rapoport, 1989; Stein et al., 1994). OCD patients have sub- et al., 2015a) and potentially offers the promise of being sequently been found to demonstrate abnormalities in a broad able to determine the evolution of brain abnormalities over series of measures used in neuropsychiatric (e.g., neurological time (Rosenberg and Keshavan, 1998, Rosenberg et al., 2011). soft signs, olfactory identification, evoked potentials, intra-corti- Abnormal structure or function in other brain regions such cal inhibition) and neuropsychological (e.g., executive function) as the temporal lobe structures involved in memory and fear research (Stein et al., 1994; Purcell et al., 1998a). These abnor- processing (Hugo et al., 1999; Zungu-Dirwayi, 1999, Szeszko et malities have consistently implicated CSTC dysfunction and al., 1999) and the supra marginal gyrus and the parietal lobe impaired control of the inhibition of thoughts and behaviors involved in the initiation and flexible control of instrumental (reviewed in Morein-Zamir et al., 2010). Some evidence has sug- behavior (Chamberlain et al., 2008; Meunier et al., 2012) have gested that they are relatively specific to disorders character - less commonly been found in OCD. However, recent meta- ized by compulsive behaviors (Purcell et al., 1998b; Phillips et and mega-analyses of structural imaging data collected from al., 2010). research sites worldwide found distinct patterns of subcorti- Advances in brain imaging have provided persuasive neuro- cal abnormalities in pediatric and adult OCD patients. The anatomical data for OCD (Rauch and Baxter, 1998; Graybiel and hippocampus as well as the pallidum seemed to be of impor- Rauch, 2000; Whiteside et al., 2004; Mataix-Cols and van den tance in adult OCD, whereas the thalamus was involved in Heuvel, 2006; Menzies et al., 2007; Milad and Rauch, 2012) as pediatric OCD (Boedhoe et al., 2017). well as Tourette’s syndrome (Groenewegen et al., 2003), tricho- Both successful SRI pharmacotherapy and behavioral ther - tillomania (Chamberlain et al., 2009), impulse control disorders apy have been shown in OCD to normalize activity in CSTC in Parkinson’s disease (van den Heuvel et al., 2010), and addict- circuits (Baxter et al., 1992). Baseline structure or activity may ive disorders (Everitt and Robbins, 2005). Functional imaging in differentially predict response to pharmacotherapy and psy- OCD has demonstrated increased activity in CSTC circuits con- chotherapy (Brody et al., 1998; Hoexter et al., 2013) suggesting necting the orbitofrontal cortex, cingulate cortex, and striatum, that different treatment modalities exert their clinical effects both at rest and especially during exposure to feared stimuli via different neuro-mechanisms (Reghunandanan et al., 2015a). (reviewed in Reghunandanan et al., 2015a). Somewhat different Neurosurgical interruption of CSTC circuits may also reduce circuits may be involved in mediating different OCD symptom OCD symptoms as well as decrease striatal volume (Rauch, 2000). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 AUGMENTATION MONOTHERAPY Fineberg et al. | 47 Magnetic resonance spectroscopy has demonstrated altera- excessive fronto-striatal connectivity within that circuit tions in glutamate metabolites in CSTC circuits (Rosenberg et (Bourne et al., 2012). The degree of such normalization corre- al., 2004; Whiteside et al., 2006; Yucel et al., 2007), in some cases lated with reduced severity of symptoms (Figee et al., 2013). normalizing after successful treatment with an SSRI (Rosenberg et al., 2000). Evidence from the relatively few positron emission tomography (PET) ligand studies so far performed in OCD have Neurocognitive Models of OCRDS identified abnormal binding of the serotonin transporter in cortical and subcortical areas (Reimold et al., 2007; Matsumoto Neurocognitive changes are likely to be of great value for study- et al., 2010; Hesse et al., 2011) and of the striatal postsynaptic ing the neurobiology of psychiatric disorders, as they are theo- dopamine D2 receptor (Moresco et al., 2007; Perani et al., 2008; retically more directly linked to brain structure and function Denys et al., 2013), which normalized after treatment with SSRI than are the more complex higher-level phenotypes such as (Moresco et al., 2007). compulsive symptoms (Fineberg et al., 2014). They are also more Techniques combining gene variants and brain imaging tractable to exploration across animal species (Dalley et al., 2011) have been used to enhance the imaging findings. Several gene and are invaluable for clinicians and patients, providing a richer variants have been found to be associated with structural understanding of the phenotype. Of the available instruments, and functional alteration in CSTC circuits relevant to OCRDs computerized cognitive tests have several advantages over pen (reviewed in Reghunandanan et al., 2015a). For example, in and paper assessment. To date, a number of tasks derived from patients with OCD, genetic variation in the serotonin trans- the Cambridge Neuropsychological Test Automated Battery porter was demonstrated to be associated with reduced orbito- (CANTAB), which includes tests that are adaptable for transla- frontal cortex volume as measured by magnetic resonance tional work in animals and for application during brain imag- imaging (MRI) (Atmaca et al., 2011; Hesse, 2011) and the avail- ing, have shown considerable utility in fractionating cognitive ability of the serotonin transporter in the putamen, nucleus processes in OCRDS and in localizing neural and neurochemical accumbens, and hypothalamus as measured by PET (Hesse et substrates. al., 2011). Growing evidence from human and animal research using Thus, in OCRDs, distributed network perturbation appears tests such as the CANTAB suggests that the neurocognitive focused around the prefrontal cortex, caudate, putamen, and mechanisms mediating behavioral inhibition (motor inhibition, associated neurocircuitry. In OCD, convergent evidence points cognitive inflexibility) and habit formation (shift from goal- to deficient top-down inhibitory control in the prefrontal cortex directed to habitual responding) variably contribute toward vul- nodes within this circuitry, coupled with the hijacking of flex- nerability to compulsive activity in a broad range of compulsive ible, contingency-dependent instrumental behavior in favor of disorders (reviewed in Fineberg et al., 2014). Moreover, some of excess habit generation mediated by dysfunction within the these deficits can be found in unaffected healthy relatives of dorsal striatum (reviewed in Fineberg et al., 2014; Gillan et al., OCD probands, suggesting they represent vulnerability or trait 2016a). Abnormal activation in the dorsal striatum, especially markers of compulsivity that also exist in nonpatient groups. the head of the caudate nucleus and the putamen, is well rep- licated in the OCD literature (reviewed in Reghunandanan et Motor Inhibition al., 2015a, 2015b), implicating the cognitive fronto-striatal loop Multiple tiers of evidence, ranging from functional magnetic communicating with the dorsolateral prefrontal cortex driving resonance imaging (fMRI) of individuals with focal frontal action selection and the motor loops driving goal-directed and lobe lesions to animal research, have demonstrated that the habitual responses (Gillan et al., 2014). This neuroanatomical inhibitory control of motor acts is sub-served by a neural net- model goes some way to explain the link between compulsive work linking the right inferior frontal gyrus with its subcortical acts and harm-related thoughts and activities. Involvement of (including subthalamic) connections (Rubia et al., 2003). Motor the putamen may be particularly relevant for the development of inhibition can be reliably tested using the stop-signal reaction sensorimotor symptom such as tics. However, imaging research time (SSRT) task (Aron et al., 2005). Pharmacological manipula- suggests that a wider range of CTSC circuits are involved in OCD, tion in rodents and humans suggests that motor response inhi- including systems responsible for reward processing more usu- bition, as indexed by the SSRT, falls under the neuro-modulatory ally associated with addiction (Klanker et al., 2013). influence of the norepinephrine system (Chamberlain et al., Surgical disconnection of this circuitry via stereotactic cap- 2006b, 2007a, 2013). In contrast, serotonin appears not to be cen- sulotomy, cingulotomy, or limbic leucotomy has been used to trally involved in this particular measure of impulsivity (Clark treat severe, intractable OCD for several decades, with some et al., 2005a; Chamberlain et al., 2006b; reviewed in Fineberg et evidence of success. A double-blind, sham-controlled trial has al., 2014). Paradoxically, compared with the SSRIs, there is only recently produced limited evidence of the efficacy and tol- weak evidence to suggest that drugs acting to increase norepi- erability of ventral capsulotomy using gamma radio-surgery nephrine in the synaptic cleft, such as the SNRIs venlafaxine (Lopes et al., 2014, 2015; Batistuzzo et al., 2015). Promising and duloxetine (Hollander et al., 2003; Dell’Osso et al., 2008; results from a small number of treatment studies using inva- Dougherty et al., 2015; Mowla et al., 2016), are beneficial in OCD. sive (deep brain stimulation) or noninvasive (transcranial In a series of experiments using the SSRT (Chamberlain magnetic stimulation, transcranial direct current stimulation) et al., 2006a; Odlaug et al., 2011), evidence of significant impair - methods of neuro-modulation to target either cortical (orbito- ment in motor inhibition, compared with healthy controls, was frontal cortex, presupplementary motor area [pre-SMA]) or found in separate groups of patients with OCD, hair-pulling, and subcortical (nucleus accumbens, subthalamic nucleus) nodes gambling disorder. However, this deficit was not seen in a study or white matter tracts within this frontal-striatal circuitry of community respondents with obsessive compulsive person- (reviewed in Senço et al., 2015) indicate new treatment pos- ality traits but without OCD (Fineberg et  al., 2015), suggesting sibilities for refractory obsessive-compulsive disorders. There that this form of inhibitory failure represents a concomitant of is experimental evidence that in patients with OCD, deep compulsive motor acts. In the case of OCD, SSRT performance brain stimulation targeted to the nucleus accumbens reduced was also highly significantly impaired in unaffected first-degree Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 48 | International Journal of Neuropsychopharmacology, 2018 relatives (Chamberlain et  al., 2007b). In a MRI study of OCD Obsessive-compulsive disorders may be differen ated using tests of families that included unaffected first-degree relatives (Menzies inhibitory failure, though considerable intra-class heterogeneity exists et al., 2007), reduced cortical grey matter volume, coupled with increased basal ganglia grey matter volume, was found to cor - relate with SSRT indices of increased motor disinhibition. This SPD OCPD study produced some of the earliest evidence of a structural BDD imbalance in inhibitory cortico-striatal circuitry as a neuro- HPD COGNITIVE MOTOR cognitive endophenotype of motor impulsivity in OCD. A more OCD INHIBITION INFLEXIBILITY recent fMRI study demonstrated trait-dependent compensatory Schizo Hoarding D hyperactivity in the pre-SMA during the performance of the -OCD SSRT in both medication-free patients with OCD and unaffected siblings vs healthy controls, representing another neurocogni- tive endophenotype of motor impulsivity, in this case possibly Figure 3. Motor Inhibition, Cognitive Inflexibility and OC Spectrum Dis- related to inefficient neural processing within the pre-SMA in orders. BDD, body-dysmorphic disorder; HPD, hair-pulling disorder; OCD, those vulnerable to OCD (de Wit et al., 2012). obsessive-compulsive disorder; OCPD, obsessive compulsive personality disorder; schizo-OCD, schizophrenia with OCD; SPD, skin-picking disorder. Cognitive Inflexibility The intradimensional-extradimensional (ID-ED) shift task not only in patients with OCD but also in their unaffected, never- examines different components of attentional flexibility, includ- treated relatives (Rejminse et al., 2006; Chamberlain et al., 2008). ing reversal learning, set formation, and inhibition, as well as Reversal-learning–related hypofunction, therefore, appears to shifting attention between stimulus dimensions (ED shift). be another candidate endophenotype for compulsivity that Studies have demonstrated that ED shift is impaired in OCD exists in people at increased genetic risk of OCD. and additionally in the unaffected first-degree relatives of OCD The identification of cognitive endophenotypes, such as subjects (Chamberlain et al., 2006a, 2007b; Vaghi et al., 2016), those reflecting failures in motor inhibition and cognitive flex- suggesting that this aspect of cognitive inflexibility represents ibility, opens new perspectives for the development of bio- an endophenotype for OCD-related compulsivity. Moreover, markers that may be objectively quantified and used to parse ED shift impairment has been identified in patients with other compulsive disorders into more biologically homogeneous obsessive-compulsive spectrum disorders, including obsessive- groups and that may even enable the development of personal- compulsive personality disorder (Fineberg et al., 2015), schizo- ized forms of treatment tailored to the individual (Figure 3). For phrenia with OCD (Patel et al., 2010), and BDD (Jefferies-Sewell et example, a small-sized, randomized, placebo-controlled trial in al., 2016). In a study of OCD hoarders compared with compulsive patients with skin picking disorder found that whereas lamo- hoarders without OCD, significant EDS changes versus healthy trigine was not efficacious in the group as a whole, benefit was controls were found in the OCD hoarders only, suggesting that seen in a subset of patients who exhibited relatively impaired the comorbid group was associated with greater cognitive cognitive flexibility on the EDS (Grant et al., 2010). Results such inflexibility (Morein-Zamir et al., 2014). Interestingly, another as these highlight the need for randomized controlled studies of study found that hair-pulling disorder was not associated with adequate power to prospectively examine the role of cognitive EDS impairment, though OCD was, suggesting that cognitive endophenotypes as predictors of treatment response across the inflexibility is not an essential component of repetitive acts of full spectrum of compulsive disorders. grooming (Chamberlain et al., 2006a). According to a recent fMRI analysis, compared with healthy Habit Learning controls, patients with OCD when tested in a resting state, irre- Compulsions are characterized by the persistence of activities spective of treatment status, showed reduced functional con- that become disconnected from the prevailing environmental nectivity in circuits linking the dorsal caudate nucleus and its contingencies and lack an obvious relationship to the overall anatomical cortical projections (Vaghi et  al., 2017). In addition, goal of the activity. In OCD, many patients are fully aware that reduced connectivity between the left dorsal caudate and the their compulsive behaviors bear little to no relation to desirable ventrolateral prefrontal cortex, an area of cortex known to be outcomes, yet despite this knowledge, they continue to per - associated with EDS in healthy controls (Rogers et  al., 2000), form them. They often describe their compulsions as unwanted was associated with reduced OCD-related EDS performance. habits. The reduced functional connectivity within this circuitry may According to associative learning theories of instrumen- account for the deficits in shifting attentional focus away from tal behavior (Balleine and Dickinson, 1998; de Wit et al., 2009), inappropriate intrusive thoughts and rituals, resulting in the actions are supported by at least 2 separate neural systems: a perseverative behavior seen in OCD and acting as a potential goal-directed system and a habitual system. When controlled biomarker of OCD. by the goal-directed system, actions are purposeful inasmuch Perseverating on a behavior that was once rewarded, but as they are flexibly performed to obtain desired goals or avoid is later associated with harmful consequences, may reflect a undesired events. In contrast, habitual behaviors are consid- lack of contingency-related cognitive flexibility. Exerting flexibil- ered lower order behaviors as they are performed as a routine ity in learning and unlearning behavior based on (probabilistic) response to specific environmental triggers and are insensi- contingencies (probabilistic reversal-learning) may be particu- tive to changes in environmental contingency (i.e., whether the larly relevant for the development of compulsive tendencies action is contextually appropriate) or the outcome value of the (Fineberg et al., 2014). Contingency-related flexibility is depend- behavior (i.e., whether the goal is actually desirable). After mul- ent on serotonin systems (Clarke et al., 2005b) and has been tiple repetitions, the habit system begins to render purposeful linked to orbito-frontal cortex (OFC) function (Rubia et al., 2003). behavior rigid and automatic (Adams et al., 1981, 1982), allowing Reduced activation of the OFC, lateral PFC, and parietal cortex simple acts to be conducted without effort. Exaggerated habit was observed using task-related fMRI during reversal learning, formation is consistent with the ego-dystonic stimulus-driven Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Fineberg et al. | 49 aspects of compulsivity. Compulsivity may thus arise at least in provide compelling support for the hypothesis that compulsions part from a shift from goal-directed action to habit, rendering in OCD result from a shift from goal-directed to habitual behav- behavior insensitive to its outcome or to the prevailing environ- ioral control and are underpinned by changes in neural activity mental contingencies. focused around the vmPFC, caudate nucleus, and the associated The caudate nucleus is both pivotally involved in OCD, fronto-striatal neural circuitry. as well as in the dynamic regulation of goal-directed contin- gency learning, under the prevailing influence of the ventro- Safety Signaling medial prefrontal cortex (vmPFC), which tracks the current The vmPFC plays a complex role in fear learning and safety- value of outcomes. In contrast, habitual acts involve the pos- signaling and is closely involved in integrating the evalu- terior lateral putamen, where stimulus-response associations ative processing of environmental cues with flexible behavior. are stored (Balleine and O’doherty, 2010; Gillan et al., 2011). In Abnormal vmPFC activation has been implicated in anxiety a recent fMRI study of OCD patients (Banca et al., 2015), the disorders (Schiller et  al., 2008; Cha et  al., 2014,) as well as in experimental provocation of autobiographical compulsions in impaired fear retention in OCD (Milad et al., 2013). Dysfunctional OCD patients was shown to reduce neural activation in brain processing within the vmPFC therefore represents a plausible regions implicated in goal-directed behavioral control (vmPFC, mechanism by which explicit contingency knowledge related to caudate nucleus) with concordant increased activation in safety and harm is undermined, leading to the failure to flex- regions implicated in habit learning (pre-SMA, putamen). This ibly update fear responses and the persistence of rigid, habitual finding contrasts with previous evidence of generalized fronto- compulsive activity. Further studies in OCD patients are there- striato-limbic hyperactivation during OCD symptom evocation fore under way to clarify the neuro-psychological relationship and provocation. This is likely due to differences in task nature between fear and anxiety processing in the vmPFC on the one and design. The cited study used a highly ecological symptom hand and cognitive flexibility in the caudate nucleus on the provocation paradigm, which overcame some of the limitations other. A  recent neuroimaging study of Pavlovian fear reversal of previous studies, as well as, for the first time, subject-driven found that OCD patients failed to flexibly update fear responses, feedback that enabled the authors to specifically address the as measured by skin conductance changes, despite normal ini- link between symptom provocation and compulsive urges to tial fear conditioning. This inability to update threat estimation track the motor component of OCD. By contrast, the hyperac- was significantly correlated with vmPFC hyperactivation during tivation of caudate and medial prefrontal cortex found in pre- early fear learning. The findings suggest that there is an absence vious studies could represent OCD-related changes in other of vmPFC safety signaling in OCD that potentially undermines cognitive domains such as imagery or autobiographical memory explicit contingency knowledge and that may go some way to recollection, which are also processed in the medial prefrontal explain the link between cognitive inflexibility, fear, and anx- cortex (Lin WJ et al., 2015). iety processing in compulsive disorders such as OCD (Apergis- Stronger support for a shift toward habitual responding is Schoute et al., 2017). derived from the following series of studies that investigated the extent to which patients with OCD showed a bias towards per- Compulsive-Obsessive Disorder forming stimulus-response habits and away from goal-directed In the shock avoidance studies by Gillan et al. (2014, 2015), post- activities. In the first of these studies (Gillan et  al., 2011), sub- hoc explanations for continuing to respond to the devalued jects were trained to respond to cues to press computer keys to stimulus (e.g., “why did you press?”) were described as irrational win valuable points on a computer game. Next, some of the keys threat beliefs by many of the OCD patients (e.g., “I thought were devalued, that is, they were no longer linked to a valuable I might still be shocked”). Like obsessions, these beliefs were dir- outcome and subjects were told not to press them when cued ectly contradictory to the patients’ explicit knowledge of threat to do so. Yet, the OCD patients continued to habitually press in and their ratings of shock expectancy. Thus, in OCD subjects response to the cue, even after the keys had ceased to be linked faced with aversive situations, dysfunctional activation of the to a reward. vmPFC and dorsal striatum may disrupt normal goal-directed The next study attempted to more closely model the devel- behavior, leading to the generation of harm-avoidance habits opment of compulsions as behaviors designed to avoid harmful that readily become compulsive or urge-driven and that may consequences (as opposed to gain appetitive outcomes), using a go on to create ego-dystonic, irrational fears (obsessions) with shock-avoidance task (Gillan et al., 2014). Subjects were trained the effect of perpetuating the compulsive behavior. According to lever-press in response to a computer signal to avoid a mildly to this compulsive-obsessive disorder model, the compulsive painful electric shock indicated by the signal. After excessive behaviors of OCD play a key role in ensuring the persistence of training on the task, the electric wire was obviously discon- the obsessions. nected and the subjects instructed not to press in response to Consistent with this model, behavioral therapy using expos- the signal. As predicted, however, patients with OCD continued ure and response prevention (ERP), representing the standard to lever-press to the devalued stimulus that explicitly no longer psychological therapy for OCD (www. NICE.org.uk), requires predicted a shock and did so significantly more than a matched patients to undergo symptom provocation via exposure to rele- healthy control group (Gillan et al., 2014). In a subsequent study, vant stimuli or situations in order to learn to resist the urge this habitual shock-avoidance behavior was directly related to perform the compulsions. ERP has been found not only to to fMRI evidence of hyperactivity in both the vmPFC, during produce a reduction in compulsive responding, but also con- the initial acquisition of the goal-directed avoidance behav- currently causes the urge to respond and the associated obses- ior, and in the caudate, during the performance of the habit- sive thoughts to attenuate (Foa et al., 2005). Our data suggest ual avoidance behaviors (Gillan et al., 2015). In addition, more that suppressing compulsions, for example using ERP, should OCD patients than controls reported experiencing a premonitory remain a key therapeutic intervention in OCRDs and hint that urge to perform the shock-avoidance habits, the intensity of habit reversal therapies (Morris et al., 2013) that are designed to which correlated with the performance of the habits and with break habitual associations between exposure-related cues and the strength of the fMRI caudate hyperactivity. These findings Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 50 | International Journal of Neuropsychopharmacology, 2018 Neurocognitive Definition Task Neural system Neurochemistry Compulsive disorders showing abnormalitiesin Domain this domain compared to healthycontrols Motorinhibition pre-potent motor stop signal reaction rightinferior frontal cortex , norepinephrine OCD(and st unaffected1 disinhibition time task SMAand subcortical connections, includingsub- degree relatives), thalamic nucleus BDD, hair-pulling disorder, hoarding disorder, skin picking disorder, gambling disorder, binge-eating disorder inability to adapt reversal learning orbitofrontal cortex and Serotonin, OCD(and Contingencyrelated st unaffected1 cognitiveinflexibility behavior after tasks subcorticalconnections degree relatives), negative feedback Dopamine? pathological gambling Attentionalinflexibility inability to switch extra-dimensional Ventro-lateral PFC-humans. Dopamine OCD, attentionbetween attentionalset- stimuli shifting Lateral PFC -primates BDD, (CANTAB) andsubcortical connections OCDwith schizophrenia, OCPD, Anorexia nervosa, Bingeeating disorder Inflexible fear learning Inflexible fear Pavlovianfear VMPFC, caudate,insula, anterior ?OCD learning and reversal cingulatecortex inadequate safety signalling Lack of sensitivity Habitformation Fronto-striatalcircuits: Dopamine, OCD, Habitlearning to goals, taskstesting contingenciesor appetitive or Habitactivity involves Serotonin? Binge-eating outcomes of actions avoidancehabit connectionsbetween SMA and disorder, learning under posteriorputamen outcome Methamphetamine devaluation. Goal-directedactivityinvolves or cocaineabuse connectionsbetween VMPFC Two-step andcaudate sequential discrimination task; model-based(goal directed)versus model free (habitual) decision making. Figure 4. Subdividing compulsive disorders according to neurocognitive domains: task performance, neural and neurochemical correlates. Abbreviations: CANTAB, Cambridge Neuropsychological Test Automated Battery; OCPD, obsessive compulsive personality disorder; PFC, prefrontal cortex; SMA, supplementary motor area; VMPFC, ventromedial prefrontal cortex; ?, findings not assured. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Fineberg et al. | 51 compulsive responses and that are currently used to treat hair- with intrusive thought, anxious-depression, and social with- pulling disorder (Rothbart et al., 2013) may also have value in drawal. Critically, they found that when the individual disorders OCD, for example by augmenting the clinical response to ERP. (OCD, eating disorder, impulse control disorder, addiction) were replaced with the compulsive factor, the deficits in goal-directed control were captured even more strongly. Moreover, this asso- Disorders of Compulsivity: A Common Bias toward ciation was highly specific when compared with the other non- Learning Habits? compulsive dimensions of psychopathology. These data indicate A number of computational modelling techniques (e.g., the that deficits in goal-directed control, conferring vulnerability for two-step sequential discrimination task; Daw et al., 2011) have developing rigid habits, may have a specific role in driving the been developed to infer the prevailing balance between goal- compulsive behaviors that characterize diverse disorders such directed and habitual behavioral control by assessing a person’s as OCD, eating disorder, substance abuse, and addiction. decision-making tendencies (respectively, model-based versus model-free). These questionnaires and computational tasks Integrating Neuropsychological Models with have the added advantage of being readily disseminated on-line Treatment Models and therefore available to test very large numbers of subjects. In one of the earliest studies that applied this methodology to Based on these and other emerging findings, it is possible to compulsivity, Voon et al. (2015a) tested a trans-diagnostic group draw inferences about the neuropsychological mechanisms of subjects with diagnoses involving both natural reward (binge underpinning the response to standard treatments in dis- eating disorder), artificial reward (methamphetamine/cocaine orders such as OCD (Gillan et al., 2016a). Increased stress is abuse), and OCD and compared them with healthy controls. The known to induce a tendency to form habits (Schwabe and Wolf, results showed a common bias across all these disorders away 2009). It has therefore been suggested that SSRIs may act in from model-based (goal-directed) learning. In addition, the habit OCD by restraining anxiety and reducing the effects of punish- formation bias was associated with lower grey matter volumes ment, thereby helping the OCD patient to switch from habitual in the caudate and medial orbitofrontal cortex on structural MRI. towards goal-directed behavior and indirectly attenuating the The findings suggested that dysfunction in a neurocompu- need to perform compulsions (Morein-Zamir et al., 2013). This tational mechanism favoring model-free habit learning may effect of SSRI could also enhance the capacity to benefit from underlie the repetitive behaviors that ultimately dominate in CBT with ERP (Gillan et al., 2016a). The finding from a non-ran- diverse disorders involving compulsion. In a further study (Voon domized study that goal-directed learning under both reward et al., 2015b) that compared performance on the two-step task and punishment conditions was enhanced in OCD patients under conditions of reward and loss, OCD subjects compared receiving SSRI (Palminteri et al., 2012) provides some support with healthy volunteers were less goal orientated (model-based) for this hypothesis. Further support is derived from more recent and more habitual (model-free) to reward outcomes with a shift findings in healthy volunteers that acute tryptophan deple- towards greater model-based and lower habitual choices to loss tion, which reduces serotonin transmission, induced a shift (punishment) outcomes. These results highlight the import- from goal-directed to habitual responding on a slips-of-action ance of motivation for learning processes in OCD and suggest test and also had a deleterious effect on model-based learning that distinct clinical strategies based on reward valence may be (Worbe et al., 2015, 2016). warranted. However, if the mechanism of effect of SSRI in OCD Most recently, Gillan et al. (2016b) applied computational depended on anxiety reduction, benzodiazepines and other modelling to investigate whether a dimensional approach could anxiolytics would also be expected to show evidence of effi- better delineate the clinical manifestations of goal-directed cacy, which they do not. Moreover, SSRIs are at their most learning deficits using large-scale online assessment of psy- efficacious in OCD at dosages higher than is typically recom- chiatric symptoms and neurocognitive performance in two mended for anxiety disorders (Fineberg et al., 2013c; Skapinakis independent general population samples. Nearly 2000 people et al., 2016). An alternative hypothesis, therefore, proposes completed the online self-report questionnaires measuring that SSRIs exert a therapeutic effect in OCD by bolstering goal- decision-making preferences as well as symptoms of various directed behavior through direct pharmacological actions in mental health conditions. As expected, people demonstrating those areas of cortex implicated in safety signaling and goal- reduced goal-directed control on the two-step task (Daw et al., directed control, including the vmPFC and medial orbitofrontal 2011) also reported higher rates of compulsive symptomatology cortex (El Mansari and Blier, 2006; Gillan et al., 2015; Voon et related to OCD and also eating disorder, impulse control dis- al 2015a). El Mansari and Blier (2006) reviewed the effects on order, and addiction symptoms, further demonstrating the gen- 5-HT release and the adaptive changes in pre- and postsynaptic eralizability of the deficits across multiple compulsive disorders. 5-HT receptor sensitivity induced by SRI treatment in rodent By leveraging an online methodology to collect such a large brain structures involved in OCD, including analogues of the dataset, Gillan et al. (2016b) were also able to deal with a key OFC. The time course of increased 5-HT release and terminal limitation of standard case-control research, the question of 5-HT1D desensitization aligned with the course of the thera- specificity. While the demonstration of a degree of generaliz- peutic response to SRI in OCD. In addition, consistent with the ability of cognitive deficits across compulsive disorders that are dose-dependent therapeutic effect of SRIs, a greater dose of SRI similarly characterized by a loss of control over behavior, alco- induced greater reuptake inhibition, which played an essential hol addiction, eating disorders, and impulsivity is of interest, role in this phenomenon. The authors further hypothesized without establishing the specificity of this deficit to this class that the therapeutic effect of SRI-enhanced 5-HT release in the of symptoms (and not depressive symptoms, for example), the OFC is mediated by the activation of postsynaptic 5-HT2-like findings are limited. By carrying out a factor analysis on their receptors. This cortical region is among the most consistently dataset, Gillan and colleagues identified that the self-report psy- implicated in OCD (Whiteside et al., 2004) and shares overlap- chopathological data could be neatly fitted into three separate ping functional connectivity abnormalities with those seen in transdiagnostic symptom dimensions: compulsive behavior addicted individuals at rest (Meunier et al., 2012). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 52 | International Journal of Neuropsychopharmacology, 2018 Antipsychotics are used to treat stereotyped or self-injurious predicted by a spectrum of neuropsychological mechanisms, behavior in patients with ASD. It has been proposed that antip- including, inter alia, impaired motor inhibition, cognitive inflex- sychotics may also work in OCD by reducing habitual or stereo- ibility (attentional set-shift, reversal learning), and an imbal- typed behavior patterns. The anti-OCD effect of antipsychotic ance in goal-directed vs habit learning. In OCD, abnormal safety agents, when co-administered with SSRI, has been shown to signaling may undermine accurate safety learning, resulting in positively correlate with the drugs’ inherent dopamine D2 and inflexible threat beliefs, with important implications for expo- D3 receptor antagonist affinities (Ducasse et al., 2014). However, sure-based therapies that rely on robust safety memories and whereas studies in rodents have identified a link between dopa- future treatment development (Apergis-Schoute et al., 2017). mine in the dorsal striatum and the flexible modulation of Avoidance habits, acting via disrupted goal-directed learn- learnt behavior (Lovinger et al., 2010; Furlong et al., 2014), stud- ing, represent a plausible model of chronic OCD-related com- ies of dopamine receptor agonists and antagonists in human pulsivity. Furthermore, emerging evidence implicates disrupted models of compulsive behavior have produced ambiguous find- goal-directed learning in an extended group of DSM disorders ings (reviewed in Gillan et al., 2016a). characterized by compulsive behaviors and intrusive thoughts, ERP for OCD involves repeated exposure to the fear-inducing and maps with specificity onto a trans-diagnostic compulsive stimuli that would ordinarily trigger a compulsive response, and symptom-dimension. Distributed network perturbation asso- resistance to the urge to perform the compulsion, so that the ciated with these cognitive changes, affecting the prefrontal urge eventually dissipates. However, ERP usually involves weeks cortex (vmPFC, lateral PFC), the dorsal striatum (caudate), and of practice, few people manage to drop all their compulsions, the associated neuro-circuitry modulating emotional, cognitive, and about one-half of those with the condition are not helped and motor control, has been identified in OCD. Networked stud- at all (Reghunandanan et al., 2015b). The finding that, in OCD, ies investigating multiple disorders under the same conditions, patients may fail to flexibly update threat perception through head-to-head, are needed to determine the extent to which faulty vmPFC safety signaling (Apergis-Schoute et al., 2017) may these changes overlap with or differentiate other disorders explain some of the difficulties that many experience in extin- of compulsive behavior. Empirical evidence suggests that the guishing OCD-related fears and offers exciting new treatment psychopathology of OCRDs becomes more habitual over time. heuristics. The failure to recognize when a feared situation has Mega-analysis in OCD suggests that illness-related structural become safe may explain why people with OCD find ERP so dif- brain changes differ in pediatric and adult cases. Longitudinal ficult and the treatment takes so long to work. Clinicians may studies are now needed to explore the effect of duration of therefore find these results helpful in their discussions with untreated disorder on the mediating neurobiology. These find- their patients, who could be persuaded of the importance of ings would have the potential to inform (1) the development sticking with the therapy rather than giving up prematurely. of biomarkers to enable the detection of compulsive disorder This may even explain why co-administration of SSRI with ERP at the earliest opportunity, crucially, in children, adolescents, is found to be helpful. In addition, the new findings indicate the and young adults, before it becomes entrenched, as well as (2) need to explore new methods of strengthening attention to safe the development of new treatments with novel mechanisms situations during ERP to enhance fear-extinction, for example, of action designed to strengthen goal-directed behavior and through the use of psychopharmacological, cognitive, or neuro- top-down cognitive strategies for controlling urges with better modulation strategies. efficacy and tolerability. Agreement on a standardized set of Another way in which the efficacy of ERP for OCD can be validated clinical measures of compulsivity that could be used explained is via the systematic breaking of habitual (stimulus- trans-diagnostically would represent a rational next step. response) associations between exposure-related cues and compulsive responses, achieved through repeated response-pre- vention exercises (Gillan et al., 2016). Brain-imaging measures Acknowledgments of hyperactivity in the caudate nucleus of OCD patients were T.W.R.  and colleagues (A.A.-S., P.B.) acknowledge financial found to correlate both with goal-directed deficits and subjective support for studies on OCD from the Wellcome Trust (grant urges to respond habitually (Gillan et al., 2014). In other studies, 104631/Z/14/Z). M.M.V.  is supported by a Pinsent-Darwin caudate abnormalities were found to be remediated when OCD Studentship in Mental Pathology and a Cambridge Home and patients respond to ERP (Baxter et al., 1992; Whiteside et al., 2012). European Union Scholarship Scheme studentship. C.M.G.  is These results suggest ERP may exert a direct effect on caudate supported by a fellowship from MQ. Dr Chamberlain’s involve- hyperactivity. Abstinence in addiction, which results in a reduc- ment in this work was funded by a Wellcome Trust Fellowship tion in craving, may also work by breaking stimulus-response (110049/Z/15/Z). associations between cues and drug-taking behavior. However, both ERP and abstinence are experienced as aversive and drop- out rates are high, reflecting the need to develop more clinic- Statement of Interest ally acceptable ways to deliver this form of treatment. Moreover, as the habitual behaviors are strengthened with repetition In the past several years, Dr Fineberg has received research sup- (Tricomi et al., 2009), OCD and addictions become even more dif- port from Lundbeck, Glaxo-SmithKline, European College of ficult to treat over time, emphasizing the importance of detec- Neuropsychopharmacology (ECNP), Servier, Cephalon, Astra tion and intervention at the earliest stage (Fineberg et al., 2013a; Zeneca, Medical Research Council (UK), National Institute Gillan et al., 2016a). for Health Research, Wellcome Foundation, University of Hertfordshire, EU (FP7), and Shire. Dr Fineberg has received hon- oraria for lectures at scientific meetings from Abbott, Otsuka, Conclusions Lundbeck, Servier, Astra Zeneca, Jazz pharmaceuticals, Bristol Myers Squibb, UK College of Mental Health Pharmacists, and The data presented serve to highlight the potential of a dimen- sional, biologically grounded approach to psychiatry research. British Association for Psychopharmacology (BAP). Dr Fineberg has received financial support to attend scientific meetings from They suggest that vulnerability to compulsive activity can be Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/42/4210641 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Fineberg et al. | 53 RANZCP, Shire, Janssen, Lundbeck, Servier, Novartis, Bristol Myers Batistuzzo MC, Hoexter MQ, Taub A, Gentil AF, Cesar RC, Joaquim Squibb, Cephalon, International College of Obsessive-Compulsive MA, D’Alcante CC, McLaughlin NC, Canteras MM, Shavitt RG, Spectrum Disorders, International Society for behavioral Savage CR, Greenberg BD, Norén G, Miguel EC, Lopes AC (2015) Addiction, CINP, IFMAD, ECNP, BAP, World Health Organization, and Visuospatial memory improvement after gamma ventral Royal College of Psychiatrists. Dr Fineberg has received financial capsulotomy in treatment refractory obsessive-compulsive royalties for publications from Oxford University Press and pay- disorder patients. Neuropsychopharmacology 40:1837–45. ment for editorial duties from Taylor and Francis. Dr Chamberlain Baxter LR Jr, Schwartz JM, Bergman KS, Szuba MP, Guze BH, consults for Cambridge Cognition and Shire. Dr Trevor Robbins Mazziotta JC, Alazraki A, Selin CE, Ferng HK, Munford P, et al. has recently consulted for Cambridge Cognition, Mundipharma, (1992) Caudate glucose metabolite changes with both drug Lundbeck, and Otsuka and has received royalties from Cambridge and behavior therapy for obsessive–compulsive disorder. Cognition for CANTAB, and a research grant from Lundbeck, as Arch Gen Psychiatry 49:681–9. well as editorial honoraria from Springer Verlag and Elsevier. Dr Berlin HA, Koran LM, Jenike MA, Shapira NA, Chaplin W, Pallanti Barbara Sahakian consults for Cambridge Cognition, Peak, and S, Hollander E (2011) Double-blind, placebo-controlled trial of Mundipharma and holds a grant from the Wallitt Foundation. topiramate augmentation in treatment-resistant obsessive- She has in the recent past consulted for Lundbeck, Servier, and compulsive disorder. J Clin Psychiatry 72:716–721. Otsuka and received grants from Peak and Janssen/JandJ. Bloch MH, Landeros-Weisenberger A, Kelmendi B, Coric V, Bracken MB, Leckman JF (2006) A systematic review: anti- psychotic augmentation with treatment refractory obses- References sive-compulsive disorder. Mol Psychiatry 11:622–632. Adams C (1982) Variations in the sensitivity of instrumental Bloch MH, Wasylink S, Landeros-Weisenberger A, Panza KE, Bill- responding to reinforcer devaluation. Q J Exp Psychol 34B:77– ingslea E, Leckman JF, Krystal JH, Bhagwagar Z, Sanacora G, 98. 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