Outlining new frontiers for the comprehension of obsessive-compulsive disorder: a review of its relationship with fear and anxiety

Abstracts

A ansiedade é um componente importante da psicopatologia do transtorno obsessivo-compulsivo (TOC). Até o momento, a maioria das intervenções que provaram ser eficazes para o tratamento de TOC é semelhante àquelas desenvolvidas para outros transtornos de ansiedade. No entanto, estudos que investigaram a neurobiologia do TOC chegaram a conclusões que nem sempre são compatíveis com aquelas anteriormente associadas aos demais transtornos de ansiedade. OBJETIVOS: Neste artigo, revisamos o grau de sobreposição entre as características do TOC e a fenomenologia e fisiopatologia dos demais transtornos de ansiedade com o intuito de dar suporte ao racional que orienta a pesquisa nesse campo. RESULTADOS: Alguns dados sobre os neurocircuitos envolvidos na manifestação dos transtornos de ansiedade foram obtidos a partir do estudo de modelos animais de ansiedade, e da neuroimagem estrutural e funcional em humanos. Esses trabalhos sugerem que no TOC, além da disfunção das vias corticoestriatais, o funcionamento do circuito amigdalocortical, essencial para a apresentação da resposta de medo e processos de extinção dessa resposta, também pode estar prejudicado. CONCLUSÃO: É provável que a ansiedade seja uma dimensão relevante do TOC, com impacto em outras características desse transtorno. Consequentemente, estudos futuros podem se beneficiar da investigação dos fenômenos de medo e ansiedade e de suas relações com os tipos de obsessões e compulsões, idade de início do TOC, comorbidades e padrões de resposta ao tratamento.

transtornos obsessivo-compulsivos; transtornos da ansiedade; medo; transtorno do estresse; pós-traumático; neuroimagem; epidemiologia; tratamento

ARTICLE

Outlining new frontiers for the comprehension of obsessive-compulsive disorder: a review of its relationship with fear and anxiety

Juliana Belo Diniz^I; Euripedes Constantino Miguel^I; Amanda Ribeiro de Oliveira^II,III; Adriano Edgar Reimer^II,III; Marcus Lira Brandão^II,III; Maria Alice de Mathis^I; Marcelo Camargo Batistuzzo^I; Daniel Lucas Conceição Costa^I; Marcelo Queiroz Hoexter^I,IV

^IDepartment & Institute of Psychiatry, Hospital das Clínicas, Universidade de São Paulo, Medical School, São Paulo, Brazil

^IILaboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

^IIIInstitute of Neuroscience and Behavior, Ribeirão Preto, Brazil

^IVInterdisciplinary Laboratory of Clinical Neuroscience (LiNC), Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil

^{Corresponding author}

ABSTRACT

Anxiety is an important component of the psychopathology of the obsessive-compulsive disorder (OCD). So far, most interventions that have proven to be effective for treating OCD are similar to those developed for other anxiety disorders. However, neurobiological studies of OCD came to conclusions that are not always compatible with those previously associated with other anxiety disorders.

OBJECTIVES: The aim of this study is to review the degree of overlap between OCD and other anxiety disorders phenomenology and pathophysiology to support the rationale that guides research in this field.

RESULTS: Clues about the neurocircuits involved in the manifestation of anxiety disorders have been obtained through the study of animal anxiety models, and structural and functional neuroimaging in humans. These investigations suggest that in OCD, in addition to dysfunction in cortico-striatal pathways, the functioning of an alternative neurocircuitry, which involves amygdalo-cortical interactions and participates in fear conditioning and extinction processes, may be impaired.

CONCLUSION: It is likely that anxiety is a relevant dimension of OCD that impacts on other features of this disorder. Therefore, future studies may benefit from the investigation of the expression of fear and anxiety by OCD patients according to their type of obsessions and compulsions, age of OCD onset, comorbidities, and patterns of treatment response.

Descriptors: obsessive-compulsive disorder; anxiety disorders; fear; stress disorders, post-traumatic; neuroimaging; epidemiology; treatment.

Introduction

The future of the diagnostic classification systems of psychiatric disorders (DSM and ICD) has been a matter of debate in recent literature.¹ Several authors participating in the DSM-5 task force have built the argument in favor of obsessive-compulsive disorder (OCD) as the core diagnosis of a new group within the anxiety disorders umbrella, known as obsessive-compulsive spectrum disorders.^2,3 More recently, the grouping of disorders for both future DSM-5 and ICD-11 (also known as their meta-structures) has been thoroughly reviewed, and additional questions have been raised regarding not only the relationship between OCD and anxiety disorders, but also its relationship to post-traumatic stress (currently classified as an anxiety disorder) and the until now independent group of dissociative disorders.⁴

It has been pointed previously that the grouping of disorders in the future classifications might have several implications to research, diagnosis, and management of psychiatric disorders. Disorders grouped together presume greater familial aggregation and co-occurrence, similar psychopathology or etiological bases, as well as sharing the main pharmacological or psychotherapeutic treatments.⁴ As an effort to contribute to this discussion and to bring it to new audiences, we review the main findings in recent literature regarding several aspects of the relationship between OCD and other anxiety disorders from the field of psychopathology, also including a broad selection of methods encompassing human and animal research that investigated the neurobiology of fear and anxiety. Our goal is to investigate the degree of overlap between OCD and other anxiety disorders phenomenology and pathophysiology to support the rational for future research in the area.

OCD classification as an anxiety disorder

Psychopathology

In the DSM IV-TR criteria for OCD, anxiety is mentioned once in the description of obsessions: "Recurrent and persistent thoughts, impulses, or images that are experienced as intrusive and inappropriate, causing anxiety or distress" (transcribed from DSM IV-TR manual). The choice of using the conjunction "or" in that sentence leaves the ground open for interpreting that anxiety may not be a symptom required for the diagnosis of OCD. But is that really the case? Moreover, even if anxiety was proven to be a symptom required for OCD diagnosis, another important question to be answered would be: Is anxiety a core symptom of OCD or irrelevant epiphenomena?

The definition of anxiety itself is complex because it includes physiological responses (such as increased sweating, elevated heart rate, tremor, hyperventilation etc.) and cognitive experiences (such as repetitive thoughts about a fearful situation or imagining catastrophic events that might happen in the future). Some authors differentiate fear from anxiety based on their temporal relation to the fearful situation. While anxiety is the anticipation of a future threat, fear is the response to the present threat. However, fear and anxiety share the same physical and mental symptoms.⁵

Most OCD patients report that they perform repetitive rituals to alleviate the uncomfortable feelings resulting from increased anxiety. Nonetheless, after analyzing the verbal reports of subjective sensations preceding patients' compulsive rituals, some authors⁶ reported that other feelings (besides increased anxiety) can be part of the discomfort preceding OCD repetitive behaviors. Such subjective feelings have been named sensory phenomena, a term that encompasses localized tactile and muscle-skeletal sensations; "just-right" perceptions associated to sensory stimuli, such as visual, tactile, or auditory; "just-right" feelings not associated with any triggering stimuli; feelings of incompleteness; energy; and an urge.^6,7

Sensory phenomena have been associated with the need of perfection⁸ and the presence of comorbid tic disorders.⁶ Miguel et al.⁹ tried to differentiate OCD patients with and without Tourette Syndrome (TS) - a severe variant of tic disorders - based on the presence of obsessions, autonomic anxiety, and sensory phenomena. They found that OCD patients without TS had a higher frequency of cognitive phenomena (obsessions) and autonomic anxiety preceding their repetitive behaviors, while OCD patients with Tourette syndrome had a higher frequency of sensory phenomena. Less studied, the finding of higher autonomic anxiety preceding compulsions in OCD patients without tics was neither replicated nor investigated in other studies. To make this issue more complex, some patients report the cognitive component of anxiety in the absence of autonomic symptoms. Therefore, the relevance of sensory phenomena (in comparison with increased anxiety) as the trigger of compulsions has not yet been established, and the question if anxiety is always present in OCD remains unanswered.

The discomfort alleviated by compulsions may also appear as a feeling of "disgust". This feeling is characteristic of OCD with contamination fears and cleaning rituals, but it is present in other anxiety disorders such as post traumatic stress disorder (PTSD)¹⁰ and specific phobia.¹¹ Disgust, however, cannot be disentangled from anxiety (the higher the disgust the worse the anxiety).¹² So, once more, it is unclear if compulsions can be maintained without increased anxiety.

The role of anxiety in the maintenance of compulsive behavior will be better explored in the treatment response section of this review. Briefly, for a significant part of OCD patients, the treatment based on anxiety reduction and habituation is reasonably effective in reducing OC symptoms.¹³ In summary, for a significant proportion of patients, anxiety plays a major role in OCD psychopathology. It is unclear if there is a subgroup of patients who do not have anxiety as the main cause of the discomfort preceding compulsive behavior. Given the current evidence, the classification of OCD as an anxiety disorder based on psychopathology seems reasonable, as well as the continuing investigation of mechanisms involving fear and anxiety in OCD patients.

Epidemiology

Comorbid disorders are the rule rather than the exception in OCD and it is estimated that OCD is accompanied by at least one additional psychiatric condition in 32-90% of the patients.^14-19 As a group, anxiety disorders are the most frequent comorbid conditions in OCD.^16,18-20

Social anxiety disorder (SAD) is a frequent condition in OCD patients and some studies describe it as the most prevalent comorbidity among the anxiety disorders.^17,21,22 Epidemiological studies have described the prevalence of SAD in OCD ranging from 15% to 43.5%,^18,19,21,23 whereas in clinical samples the reported prevalence rates were: 14%,²⁴ 15.6%,¹⁶ 21.8%,²⁵ 23.4%,^22,26 26%,^27,28 36.2%,²⁹ and 42%.³⁰

Rasmussen et al.³¹ studied 44 OCD patients and found high rates of comorbidity with other anxiety disorders. Simple phobia was the most frequent condition (27%), followed by SAD (18%), separation anxiety disorder (18%), panic disorder (14%) and agoraphobia (9%). Eisen et al.²² found the following rates of comorbidity in a prospective study: simple phobia (20.8%), generalized anxiety disorder (19.5%), and panic disorder (11.7%). Rasmussen et al.²⁸ studied 100 patients with a primary diagnosis of OCD and observed that 22% of them had comorbid simple phobia and 12% panic disorder. In a British epidemiological survey.¹⁸ the most frequent OCD comorbidity was depressive episode (36.8%), followed by GAD (31.4%), agoraphobia or panic disorder (22.1%), SAD (17.3%), and specific phobia (15.1%).

Although relatively more frequent in OCD patients than in the general population, other anxiety disorders may have an independent clinical course. In addition, at least some OCD patients may not experience an additional anxiety disorder during their life span. Therefore, it is adequate to classify OCD as a disorder and not as a symptom of other anxiety disorders. On the other hand, comorbidity patterns point toward a close association between OCD and other anxiety disorders, specially social phobia and GAD.

Neurobiology

The neurobiology of OCD and other anxiety disorders is not fully understood. Clues about the neurocircuits involved in the manifestation of anxiety symptoms have been obtained through the study of animal models of anxiety and structural and functional neuroimaging in humans. The findings that resulted from the use of such methodologies are described below.

Animal models of anxiety

Because OCD is a heterogeneous and extremely complex disorder, different animal models are used in an attempt to better understand the distinct aspects and subtypes of OCD. Due to the cognitive nature of obsessions, they are not directly accessible in animals, but since the cognitive and motor manifestations of OCD are intimately linked, modeling compulsive behaviors is a common approach for an OCD animal model. However, the manifestation of compulsive behaviors is consistent with the presence of some degree of generalized anxiety and, thereby, it is not easy to distinguish among anxiety, obsession, and other forms of distress. Ethological animal models of OCD include repetitive or stereotyped behaviors and instinctive motor behaviors that occur during periods of conflict or stress.^32-34 On the other hand, in pharmacological animal models of OCD certain drug treatments may induce behavioral alterations that resemble the behavioral aspects of this disorder.^32-34 In this section, we briefly describe some ethological and pharmacological animal models of OCD.

Stereotypy models

In animals, motor stereotypy, represented by a wide range of invariant and repetitive behaviors, can be induced through pharmacological manipulation or may occur spontaneously. Grooming has been considered the most common type of stereotyped behavior recorded in animals in the context of the study of the neurobiology of OCD. The acral-lick dermatitis, a grooming disorder characterized by excessive licking or biting of extremities, is related to cleaning rituals observed in OCD and responds to treatment with serotonin reuptake inhibitors (SRIs).^35,36 Also, the plucking of fur or whiskers from cage mates or the animal itself is a common form of an abnormal, repetitive behavior that has similarity with hair pulling in humans (trichotillomania), which is found in OCD.^37,38 Pharmacologically, investigations have focused on the influence of the serotonergic and dopaminergic systems in the expression of these behaviors.

Pharmacologically-induced attenuation in spontaneous alternation behavior

Spontaneous alternation behavior refers to the natural tendency of rats to sequentially and successively explore novel places. In this model, food deprived rats are allowed to run in a T-maze in which both goal-boxes are baited with flavored milk. The mean number of choices made until an alternation occurs is the critical measure. The reduction of spontaneous alternation has been proposed as a model of the perseverative symptoms and indecisiveness seen in OCD^39,40 and it is prevented by chronic treatment with fluoxetine.⁴⁰

Quinpirole-induced compulsive checking behavior

In the experiment first proposed by Szechtman et al.⁴¹, after about 10 repeated injections (spaced at 3-4 day intervals) of the D₂/D₃ dopaminergic agonist quinpirole, rats became sensitized to the drug, reaching a high level of activity in the open-field. Quinpirole-induced behavior has the form of compulsive checking, one of the most distinctive behaviors in OCD patients.^42,43 Compulsive checking is present if a rat returns to a particular locale excessively often and rapidly with rare visits to other places; in addition, quinpirole-treated rats perform a characteristic set of ritual-like motor acts.^41,44 Clomipramine, which is used in the pharmacotherapy of OCD, attenuates the development of quinpirole-induced compulsive checking behavior.⁴¹

Hypergrooming induced by administration of oxytocin in the central nucleus of amygdala

A possible relationship between oxytocin and OCD was suggested since high levels of this neuropeptide were found in the cerebrospinal fluid of patients with OCD.^45,46 In rodents, administration of oxytocin in the central nucleus of amygdala (CeA) induces hypergrooming and it has been suggested as a model of OCD.⁴⁷ In the oxytocin model, rats receive an injection of oxytocin in the CeA and are placed in an openfield for the quantification of grooming behaviors. As a displacement behavior that occurs in situations in which the animal experiences conflict or indecision,^48,49 grooming must act, probably through oxytocin, as a counter mechanism to overlap increased anxiety.

Food restriction-induced hyperactivity

In the food restriction-induced hyperactivity model, rats fed only once a day and given access to a running wheel begin to run excessively and eat less.^50,51 Although food restriction-induced hyperactivity has long been considered an animal model of anorexia nervosa,^52,53 it also has features analogous to OCD; for example, fluoxetine attenuates food restriction-induced hyperactivity, whereas imipramine, which is ineffective for treatment of OCD, does not affect the development of the syndrome.⁵¹

The signal attenuation model

The signal attenuation model has been developed based on the theoretical proposal that compulsions result from a deficit in the signaling associated with the performance of goal-directed responses.^33,34 In this model, the goal-directed behavior is lever-pressing for food. The effects of signal attenuation on lever-pressing responses are assessed under extinction conditions (i.e., pressing the lever results in the presentation of a conditioned stimulus but no reward is delivered). The effects of non-reward are clearly seen in the form of excessive lever-presses, suggested as a measure of compulsive behavior.⁵⁴ Excessive lever pressing is attenuated by SRIs, whereas tricyclic antidepressants, anxiolytics and antipsychotics had no effect.^54-56

Marble burying test

Rodents use bedding material to bury either noxious or harmless objects. In this model, burying of glass marbles by laboratory rodents begins as an appropriate activity but, after frustrated investigation of the nonreactive stimulus object, the behavior persists as a compulsive stereotypy.^57,58 Because the duration and extent of burying were reduced by a variety of anxiolytic drugs, this model was originally suggested as a screening test for anxiolytic activity.^57-60 The finding that burying was reduced by SRIs raised the possibility that this behavior may also be related to OCD.^57-59

From the knowledge obtained with animal models of obsessive-compulsive behavior, it becomes clear that establishing conditions that would enable the differentiation between the action of anxiolytic and anti-compulsive drugs is a critical issue. Accordingly, it is challenging to find an animal model of OCD that avoids the ambiguity frequently seen in the current animal models of anxiety. To disclose particularities in the different forms of fear based on ethological, pharmacological and genetic parameters would be the best approach for addressing certain questions like the development and/or test of new treatments for OCD.

Functional and Structural Neuroimaging in Humans

The classical dominant neurocircuitry model of OCD points to the involvement of cortico-striatal pathways that mainly interconnect the orbitofrontal and anterior cingulate cortices, striatum and thalamus.^61,62 Functional neuroimaging studies performed in patients with OCD, at rest and during symptom provocation, have demonstrated elevated regional brain activity within these regions that attenuates after successful treatment with both selective SRIs and CBT.⁶² Likewise, a growing number of short-term longitudinal structural neuroimaging investigations have documented regional gray matter volume changes within cortico-striatal pathways in OCD patients, especially after medication.⁶¹ However, progresses in the field of neurosciences and brain imaging investigations have now suggested that the cortico-striatal model of OCD is not sufficient to explain such a complex and heterogeneous disorder.⁶³ As aforementioned in this review, the classification of OCD as an anxiety disorder seems pertinent, as a significant proportion of patients experiences extreme levels of anxiety. In these patients, beyond a dysfunction in cortico-striatal pathways, the functioning of an alternative neurocircuitry, that involves amygdalo-cortical interactions and participates in fear conditioning and extinction processes, may be impaired.⁶⁴ Moreover, recent anatomical investigations have shown that the cortico-striatal loops are much more integrated to other brain nodes than it was considered in the past.⁶⁵ For example, medial portions of the orbitofrontal cortex, a key cortical node within the cortico-striatal loop and extensively implicated in OCD,⁶⁶ have connections to several brain regions that mediate fear and anxiety, such as the amygdale.⁶⁷

Convergent data from animal models and human studies indicate that the amygdala plays a central role in threat appraisal and expression of conditioned fear responses, in which exacerbated amygdala activation leads to inappropriate or excessive fear manifestation.⁶⁴ On the other hand, particular cortical regions, such as the ventromedial prefrontal and medial orbitofrontal cortices, by inhibiting amygdala hyperresponsiveness, are implicated in fear extinction.⁶⁸ In addition, the hippocampus also modulates amygdala responsiveness by providing contextual information of a given situation.⁶⁹ Thus, the neurobiology of anxiety disorders may involve a deficient prefrontal top-down inhibition over exaggerated amygdala responses to emotional salient situations.⁷⁰

Evidences of amygdala hyperactivation leading to increased fear response to specific threat-related stimuli have been reported in patients with PTSD,⁷¹ panic disorder,⁷² SAD, specific phobia,⁷³ GAD,⁷⁴ and OCD.⁷⁵ However, despite some similarities, OCD may differ from other anxiety disorders. The connectivity between the amygdala and the prefrontal cortex, which is usually diminished in other anxiety disorders, is increased in OCD patients compared to controls.⁷⁶ Moreover, when submitted to nonspecific threat-related stimuli, instead of hyperactivation, OCD patients present hyporesponsivity of the amygdala.⁷⁷ Lastly, the pattern of elevated regional brain activity within orbitofrontal and anterior cingulate cortices, striatum and thalamus extensively observed in OCD patients⁶² is not found in other anxiety disorders. Therefore, although the fear response seems to be increased in OCD patients, the mechanisms responsible for this increase might be different from the ones responsible for the exaggerated fear response observed in other anxiety disorders.

Electrophysiological studies in humans

Electrophysiology encompasses a myriad of techniques aimed at measuring physiological responses (such as palmar sweating, heart rate variability, and muscular activity) that are associated with emotional mechanisms (such as fear and anxiety). In this section, we will review the main findings based on the observation of alteration in the galvanic skin conductance response (related to aforementioned palmar sweating), heart rate, and muscular activity consequential to fear in OCD and other anxiety disorders. The studies included in this review have investigated the magnitude of the muscular reflexes triggered by fear (e.g. acoustic startle) or one pattern of fear acquisition known as classical conditioning. Although other mechanisms of fear acquisition have been previously postulated (for a more comprehensive review see Hofmann⁷⁸), classical conditioning has provided the best experimental conditions. It is easily translated into findings from animal models (as its effects can be observed irrespectively of the underlying cognitive processes involved), and the fear response is acquired by most individuals regardless of their previous contacts with the stimulus presented or with characteristics of their innate fear responses. It is important to mention that this experimental condition does not account for factors such as predictability and uncontrollability of the aversive events; these factors have been shown to be highly associated with the presentation of the fear response in animal models.⁷⁹ The lack of studies that evaluated other types of fear acquisition in OCD and the relative abundance of studies of classical conditioning in anxiety disorders was the main reason that guided this decision.

The acoustic startle (also known as auditory startle) is a reflex elicited by sudden loud tones that is characterized by increases in skin conductance, heart rate and contraction of muscles such as the orbicular muscles that are responsible for the blinking movements. The muscular activity measured by the electromyogram is commonly used to determine the startle magnitude. The magnitude of the fear response (acoustic startle) was greater in patients with panic disorder,⁸⁰ PTSD,⁸¹ SAD,⁸² and GAD⁸³ than in healthy subjects. In OCD, results are still inconsistent^84,85 but point toward a trend of larger unconditioned responses when compared to healthy controls. In one study, the fear response presented by OCD patients exposed to loud tones was characterized by larger than expected increases in heart rate while alterations in skin conductance and electromyogram showed similar patterns to controls.⁸⁵

The classical conditioning was first described in animals and corresponds to the effect of presenting an innately aversive stimulus (the unconditioned stimulus, e.g. an electric shock) right after a neutral stimulus (the conditioned stimulus, e.g. a blue square figure or a mild sound). This procedure causes the previously neutral stimulus to elicit the fear response in the absence of the unconditioned stimulus. The fear response can be extinguished after repetitive presentations of the conditioned stimulus not followed by the unconditioned one. However, the fear response can resurge after being extinguished and this process is called failure of extinction recall.⁸⁶ The fear response produces a sensible increase in the galvanic skin response (associated with palmar sweating)⁸⁷ and in the heart rate.⁸⁸ Therefore, variability in skin conductance and heart rate are commonly used as methods to estimate the magnitude of the fear conditioned response. As mentioned earlier, the learning of the conditioned fear response as well as that of extinction is associated with the activation of the amygdala (among other brain regions), whereas the ability to recall extinction involves the activation of the medial prefrontal cortex. The hippocampus also plays a key role in this conditioned fear circuit.⁶⁹

Although classical conditioning probably does not explain most of acquired fears, it has been shown to be involved in the etiology of symptoms in specific phobias,⁸⁹ SAD,^90,91 panic disorder⁹² and PTSD.⁹³ In panic disorder, one small study (n = 39 panic disorder patients and 33 healthy subjects) has found a pattern suggestive of resistance to extinction of the conditioned fear in patients compared to controls.⁹² In SAD, on the other hand, one study (n = 20 SAD patients and 18 healthy subjects) has found that patients responded with fear to aversive facial expressions and showed conditioned fear to stimulus paired with the aversive facial expressions while in controls, such phenomena were not observed.⁹¹ However, the most consistent finding regarding fear conditioning in anxiety disorders is the failure to recall extinction found to be much more prevalent among PTSD patients than healthy subjects.^93,94 One study (n = 39 patients with OCD and 21 healthy subjects), has explored the effects of fear conditioning in OCD.⁹⁵ In that study, however, authors chose to look at the responses promoted by fear conditioning and extinction through their effect on the auditory evoked potentials instead of looking at skin conductance and heart rate variability. The suppression of the auditory evoked potentials is a measure of sensory gating (this concept will be better discussed in the following sections of this review) and has been shown to be altered in a broad range of disorders such as schizophrenia and different anxiety disorders. In the study by Nanbu et al.,⁹⁵ the sensory gating of OCD patients was altered in both the conditioning and extinction phases of the experiment, while in healthy subjects the altered sensory gating was evident during conditioning but recovered to baseline levels during extinction. These results suggest that although a dysfunction in the ability to extinguish a conditioned fear may not be present in OCD, the sensory gating alterations produced by conditioning do not go back to normal with extinction, as is the case in healthy subjects.

Future studies are warranted to replicate the findings mentioned above. The preliminary results obtained so far corroborate the hypothesis that fear conditioning may be a valid model to be used in the investigation of mechanisms related to fear acquisition and extinction in OCD, at least for a subgroup of patients. However, more elaborate methodology may be required if traditional methods yield negative results.

Sensorimotor gating

Sensorimotor gating corresponds to the ability of the brain to inhibit an unconditioned motor response in the presence of the stimulus that usually elicits that response. Classically, this gating ability is tested trough the presentation of a weak stimulus (the prepulse) preceding the full stimulus that has been previously shown to elicit the motor response (startle) in the individual being tested. The prepulse inhibition (PPI) effect is not prone to extinction or habituation and remains stable even after multiple testing. Moreover, it is observed in all mammals and therefore it can be studied across species.⁹⁶

Initially, PPI was shown to be altered in patients with schizophrenia (the presentation of the weak stimulus was not able to inhibit the startle response more often than in healthy subjects). However, more recently it was found to be altered in other neuropsychiatric disorders as well, such as panic disorder.^97,98 PTSD,⁹⁹ OCD,^100,101 and Tourette's Syndrome (TS) alone¹⁰² or comorbid with attention deficit and hyperactivity disorder (ADHD),¹⁰³ among others.⁹⁶ In OCD, Ahmari et al.¹⁰¹ performed an exploratory analysis of their results (n = 22 OCD patients and 22 healthy subjects) and suggested that patients with comorbid tics are the ones with lower levels of PPI. Negative findings have also been reported for PTSD^81,104 and OCD,¹⁰⁵ but the inconsistencies may be explained by methodological issues.⁹⁶

In animal models, the disruption of PPI has been shown to be the consequence of pharmacological interventions interfering with dopaminergic, serotonergic or glutamatergic pathways.¹⁰⁶ In addition, it has been related to lesions in the limbic cortex, striatum, pallidum or pontine tegmentum.¹⁰⁷ Therefore, the findings of unspecific disruption of PPI in different neuropsychiatric conditions may be actually the effect of completely independent mechanisms that lead to the dysfunction of the corticostriatum-thalamo-cortical circuit.

Neuropsychological studies in humans

The findings from neuropsychological studies suggest that OCD patients present specific cognitive impairments when compared to healthy subjects. The visuospatial abilities and executive functions (mainly inhibitory control and cognitive flexibility) seem to be the most impaired functions in OCD.¹⁰⁸ Such cognitive alterations can even precede the onset of the disorder¹⁰⁹ and also be present in unaffected relatives of OCD patients.¹¹⁰ In this section, we will review the findings from neuropsychological studies that compared OCD patients with other anxiety disorders as an attempt to elucidate the specificities of cognitive dysfunction in OCD.

A few studies compared the performance of patients with OCD, panic disorder and healthy controls. Using the Cambridge Neuropsychological Test Automated Battery (CANTAB), Purcell et al.¹¹¹ found that while panic disorder patients did not differ from controls regarding executive functions, OCD patients presented significant deficits of executive functions (initiation of tasks) and motor abilities (processing speed). Using a different methodology, Clayton et al.¹¹² found specific deficits in attentional inhibition of OCD patients on psychometric attention tests (Test of Everyday Attention - TEA), compared with panic disorder patients and controls. Boldrini et al.¹¹³ also reported specific deficits in OCD in verbal fluency using the test Controlled Oral Word Association (COWA), in visual performance tasks such as the Corsi Block Task and the Rey-Osterrieth Complex Figure Test (RCFT), and in set shifting using the Wisconsin Card Sorting Test (WCST) when compared to panic disorder patients. In this later study, both groups presented deficits in spatial learning compared to healthy controls. In the study by Bannon et al.,¹¹⁴ no differences between groups were evident regarding planning, verbal fluency or working memory, but OCD patients had worse performance in tests measuring cognitive flexibility (WCST) and inhibitory control (assessed by Stroop and Go-Nogo tasks).

Regarding neuropsychological performance, OCD patients have shown deficits that are more evident than the ones shown by panic disorder patients. The comparison with other anxiety disorders (SAD, GAD and PTSD) has not been investigated so far. In general, anxiety disorders do not seem to share any specific patterns of dysfunction except for the one described as attentional bias that will be reviewed below.

Attentional Bias

The preferential allocation of attentional resources toward threatening as compared with neutral stimuli is known as attentional bias,¹¹⁵ which is significantly increased in anxious individuals compared with healthy subjects.¹¹⁶ The measurement of attentional bias across disorders varies greatly, as paradigms use different types of stimuli and indirect evaluations of attention. Stimuli can be words, images or faces that are threat specific (related to the main condition being investigated) or not.¹¹⁶ The reaction time to perform a specific task is the most common indirect measure of attention¹¹⁶ (as is the case for emotional Stroop test and dot probe paradigms) but other measures based on eye movement¹¹⁷ have also been used.

Most anxiety disorders have been associated with attentional bias, including: specific phobia,^118,119 SAD,^120,121 GAD,¹²² PTSD,¹²³ and panic disorder.¹²⁴ In OCD, both positive^115,125 and negative^126,127 findings have been reported. Contrasting with what has been found in other anxiety disorders, unspecific attentional bias was shown not to be prominent in OCD patients compared with healthy subjects.¹²⁷ Specific bias has been associated with OCD in a few studies.¹¹⁵ In a small study (n = 23 OCD subjects with contamination fears and 5 subjects without OCD or contamination fears), Cisler et al.¹¹⁵ found that OCD patients had slower reactions after the presentation of pictures representing disgust and unspecific fear compared to controls. The authors interpreted that this was a sign of difficulty in disengaging attention from both specific and unspecific threatening stimuli. In a larger study (n = 48 OCD patients), Sizino da Victoria et al.¹²⁸ found that within the OCD population the reaction to specific stimuli was associated with the severity of that symptom dimension in the subject being tested. In addition to this specificity of reaction, if any attentional bias is present in OCD, it might be related to specific subtypes. Therefore, further studies exploring attentional bias toward personally salient stimuli in subgroups of OCD patients are still warranted.

Treatment response

Psychopharmacology

Anxiety disorders, including OCD, share similarities regarding pharmacological treatment, although prognosis and length of treatment may vary for each disorder. Most anxiety disorder patients experience a progressive reduction of their symptoms with the continuous use of SRIs and immediate symptomatic relief with benzodiazepines.¹²⁹ Specific phobia is the exception to the indication of SRIs. OCD has a specificity related to the preferential response to antidepressants that are potent SRIs. Antidepressants with other mechanisms of action may be effective for the treatment of other anxiety disorders (such as imipramine for panic disorder^130,131 and GAD¹³² and amitriptyline for PTSD¹³³), but none has been shown to be effective for OCD treatment when used in monotherapy.¹³⁴

Serotonin neurotransmission has been associated with the regulation of emotion including effects related to the response to stressful situations, sleep-wake cycle, sexual activity, and vulnerability to depressive symptoms.^135,136 However, it is unknown if the dysfunction of serotonergic neurotransmission is the starting point of the etiological mechanisms that lead to anxiety disorders or the results of the interaction with other neurotransmission systems. Indeed, drugs acting in other neurotransmitters have been shown to be affective in the treatment of anxiety disorders. Alterations in the serotonergic pathways (either as the primary dysfunction or as a secondary consequence of other systems' dysfunction) play a major role in the mechanisms related to the maintenance of anxiety in most anxiety disorders including OCD.¹³⁷

Psychotherapy

Regarding psychotherapy, most evidence based manualized treatments target specific anxiety symptoms. For example, prolonged exposure is specifically directed to the treatment of PTSD,¹³⁸ techniques of exposure therapy and cognitive restructuring were developed for specific phobia¹³⁹ and SAD,¹⁴⁰ and relaxation and breathing retraining are mainly used in panic disorder.¹⁴¹ In OCD, exposure with response prevention (alone or in combination with cognitive techniques) is the intervention that was most studied and most frequently proven effective.¹⁴² Nonetheless, many of the behavioral and cognitive techniques used in the treatment of anxiety disorders are based on the same principal of fear habituation through stimulus exposure.¹⁴³

Exposure therapy was designed based on the observation that a conditioned fear response could be extinguished with the repeated presentation of the conditioned stimulus not followed by the innately aversive stimulus (also explained in the Electrophysiology section). Therefore, it was postulated that exposure to the frightening stimulus would lead to habituation (in other words, the extinction of the putatively conditioned fear response).¹⁴³ Anxiety disorders differ mostly in the characterization of the frightening stimulus. The stimulus can be: height, closed places, snakes, dogs, spiders etc., in specific phobia; public speaking or any social interaction, in social anxiety; physical alterations such as tachycardia, in panic disorder; places that are hard to escape from, in agoraphobia; and variable according to symptoms content in OCD (e.g. public restrooms in patients with contamination fears). In addition to the different type of stimulus, OCD requires that exposure is followed by response prevention; otherwise, the performance of a ritual will lead to a temporary reduction in anxiety that hampers the habituation process. Despite these peculiarities regarding OCD exposure therapy, as well as other anxiety disorders, OCD may improve with the habituation to the fearful stimulus suggesting that fear condition may participate in the etiology of obsessive fears.¹⁴⁴

Conclusions and directions for future research

Anxiety is an important aspect of OCD with bases on its psychopathological presentation and, so far, most interventions that have been proved effective for treating OCD are similar to the ones developed for other anxiety disorders, such as SAD, GAD, panic, and PTSD. However, the study of the neurobiology of OCD has led to conclusions that are not always compatible with what has been previously associated with other anxiety disorders. For instance, an animal model of OCD has been developed with the injection of oxytocin (a hormone with anxiolytic properties) in the amygdala. In addition, OCD patients may not show increased response or lack of control over unspecific fear, such as SAD and GAD patients show, or may present with dysfunction of executive functions that are not at all impaired in patients with panic disorder. Moreover, OCD patients show a variety of patterns of activation obtained trough functional neuroimaging that not always resemble the classical amygdala activation described in PTSD, panic, and SAD. On the other hand, the pattern involving the orbital frontal cortex found in OCD may be related to the type of OCD symptoms and may not explain the alterations seen in all OCD patients.

The classical neurobiological model that suggests a dysregulation of the cortico-striatal circuits in OCD may be unsatisfactory to explain such a complex and heterogeneous disorder. Recent evidence that implicate an alternative neurocircuitry, which mediates fear responses and anxiety through the interaction between the ventro-medial prefrontal cortex, the medial orbital-frontal cortex and amygdala in the pathophysiology of OCD, may contribute to the development of new treatment approaches directed at fear habituation and extinction.

The investigation of the role of fear and anxiety in OCD may also elucidate the bases for such disparities. But more importantly, it may elucidate the disparities regarding symptom presentation and treatment response seen among OCD patients. It is likely that anxiety is a relevant dimension of OCD that may impact other patients' characteristics. Therefore, future studies should investigate the manifestation of fear and anxiety in association with heterogeneous characteristics of OCD, such as the type of obsessions and compulsions, the age at onset, comorbid diagnosis, and patterns of treatment response. Likewise, studies should investigate whether abnormalities in the ventro-medial pre-frontal cortex, the medial orbital-frontal cortex, and amygdala circuitry in different subtypes of OCD are warranted.

References

1. Stein D. Psychobiology of anxiety disorders and obsessivecompulsive spectrum disorders. CNS Spectr. 2008;13(9Suppl14):23-8.

2. Hollander E, Braun A, Simeon D. Should OCD leave the anxiety disorders in DSM-V? The case for obsessive compulsive-related disorders. Depress Anxiety. 2008;25(4):317-29.

3. Phillips KA, Stein DJ, Rauch SL, Hollander E, Fallon BA, Barsky A, Fineberg N, Mataix-Cols D, Ferrão YA, Saxena S, Wilhelm S, Kelly MM, Clark LA, Pinto A, Bienvenu OJ, Farrow J, Leckman J. Should an obsessive-compulsive spectrum grouping of disorders be included in DSM-V? Depress Anxiety. 2010;27(6):528-55.

4. Stein DJ, Craske MG, Friedman MJ, Phillips KA. Meta-structure issues for the DSM-5: how do anxiety disorders, obsessivecompulsive and related disorders, post-traumatic disorders, and dissociative disorders fit together? Curr Psychiatry Rep. 2011;13(4):248-50.

5. Griffin JB. Anxiety. In: Walker HK, Hall, WD, Hurst, JW (editors). Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworth Publishers, a division of Reed Publishing; 1990.

6. Miguel EC, do Rosário-Campos MC, Prado HS, do Valle R, Rauch SL, Coffey BJ, Baer L, Savage CR, O'Sullivan RL, Jenike MA, Leckman JF. Sensory phenomena in obsessivecompulsive disorder and Tourette's disorder. J Clin Psychiatry. 2000;61(2):150-6;quiz7.

7. Prado HS, Rosário MC, Lee J, Hounie AG, Shavitt RG, Miguel EC. Sensory phenomena in obsessive-compulsive disorder and tic disorders: a review of the literature. CNS Spectr. 2008;13(5):425-32.

8. Lee JC, Prado HS, Diniz JB, Borcato S, da Silva CB, Hounie AG, Miguel EC, Leckman JF, do Rosário MC. Perfectionism and sensory phenomena: phenotypic components of obsessivecompulsive disorder. Compr Psychiatry. 2009;50(5):431-6.

9. Miguel E, Baer L, Coffey B, Rauch S, Savage C, O'Sullivan R, Phillips K, Moretti C, J Leckman JF, Jenike MA. Phenomenological differences appearing with repetitive behaviours in obsessivecompulsive disorder and Gilles de la Tourette's syndrome. Br J Psychiatry. 1997;170:140-5.

10. Engelhard IM, Olatunji BO, de Jong PJ. Disgust and the development of posttraumatic stress among soldiers deployed to Afghanistan. J Anxiety Disord. 2011;25(1):58-63.

11. Davey GC. Disgust: the disease-avoidance emotion and its dysfunctions. Philos Trans R Soc Lond B Biol Sci. 2011;366(1583):3453-65.

12. Davey GC, Macdonald BA, Brierley L. The effect of disgust on anxiety ratings to fear-relevant, disgust-relevant and fearirrelevant stimuli. J Anxiety Disord. 2008;22(8):1347-54.

13. Neziroglu F, Henricksen J, Yaryura-Tobias J. Psychotherapy of obsessive-compulsive disorder and spectrum: established facts and advances, 1995-2005. Psychiatr Clin North Am. 2006;29(2):585-604.

14. Pigott TA, L'Heureux F, Dubbert B, Bernstein S, Murphy DL. Obsessive compulsive disorder: comorbid conditions. J Clin Psychiatry. 1994;55(Suppl):15-27; discussion 8-32.

15. Yaryura-Tobias JA, Grunes MS, Todaro J, McKay D, Neziroglu FA, Stockman R. Nosological insertion of axis I disorders in the etiology of obsessive-compulsive disorder. J Anxiety Disord. 2000;14(1):19-30.

16. Tükel R, Polat A, Ozdemir O, Aksüt D, Türksoy N. Comorbid conditions in obsessive-compulsive disorder. Compr Psychiatry. 2002;43(3):204-9.

17. Denys D, Tenney N, van Megen HJ, de Geus F, Westenberg HG. Axis I and II comorbidity in a large sample of patients with obsessive-compulsive disorder. J Affect Disord. 2004;80(2-3):155-62.

18. Torres AR, Prince MJ, Bebbington PE, Bhugra D, Brugha TS, Farrell M, Jenkins R, Lewis G, Meltzer H, Singleton N. Obsessive-compulsive disorder: prevalence, comorbidity, impact, and help-seeking in the British National Psychiatric Morbidity Survey of 2000. Am J Psychiatry. 2006;163(11):1978-85.

19. Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15(1):53-63.

20. Weissman MM, Bland RC, Canino GJ, Greenwald S, Hwu HG, Lee CK, Newman SC, Oakley-Browne MA, Rubio-Stipec M, Wickramaratne PJ et al. The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group. J Clin Psychiatry. 1994;55(Suppl):5-10.

21. Douglass HM, Moffitt TE, Dar R, McGee R, Silva P. Obsessive-compulsive disorder in a birth cohort of 18-year-olds: prevalence and predictors. J Am Acad Child Adolesc Psychiatry. 1995;34(11):1424-31.

22. Eisen JL, Goodman WK, Keller MB, Warshaw MG, DeMarco LM, Luce DD, Rasmussen SA. Patterns of remission and relapse in obsessive-compulsive disorder: a 2-year prospective study. J Clin Psychiatry. 1999;60(5):346-51;quiz 52.

23. Grabe HJ, Meyer C, Hapke U, Rumpf HJ, Freyberger HJ, Dilling H, John U. Lifetime-comorbidity of obsessive-compulsive disorder and subclinical obsessive-compulsive disorder in Northern Germany. Eur Arch Psychiatry Clin Neurosci. 2001;251(3):130-5.

24. Austin LS, Lydiard RB, Fossey MD, Zealberg JJ, Laraia MT, Ballenger JC. Panic and phobic disorders in patients with obsessive compulsive disorder. J Clin Psychiatry. 1990;51(11):456-8.

25. Brakoulias V, Starcevic V, Sammut P, Berle D, Milicevic D, Moses K, Hannan A. Obsessive-compulsive spectrum disorders: a comorbidity and family history perspective. Australas Psychiatry. 2011;19(2):151-5.

26. LaSalle VH, Cromer KR, Nelson KN, Kazuba D, Justement L, Murphy DL. Diagnostic interview assessed neuropsychiatric disorder comorbidity in 334 individuals with obsessivecompulsive disorder. Depress Anxiety. 2004;19(3):163-73.

27. Rasmussen SA, Eisen JL. Clinical and epidemiologic findings of significance to neuropharmacologic trials in OCD. Psychopharmacol Bull. 1988;24(3):466-70.

28. Rasmussen SA, Eisen JL. The epidemiology and clinical features of obsessive compulsive disorder. Psychiatr Clin North Am. 1992;15(4):743-58.

29. Masi G, Millepiedi S, Mucci M, Bertini N, Pfanner C, Arcangeli F. Comorbidity of obsessive-compulsive disorder and attentiondeficit/ hyperactivity disorder in referred children and adolescents. Compr Psychiatry. 2006;47(1):42-7.

30. Crino RC, Andrews G. Obsessive-compulsive disorder and axis I comorbidity. Journal of Anxiety Disorders; 1996. pp. 37-46.

31. Rasmussen SA, Tsuang MT. Clinical characteristics and family history in DSM-III obsessive-compulsive disorder. Am J Psychiatry. 1986;143(3):317-22.

32. Eilam D, Zor R, Szechtman H, Hermesh H. Rituals, stereotypy and compulsive behavior in animals and humans. Neurosci Biobehav Rev. 2006;30(4):456-71.

33. Joel D. Current animal models of obsessive compulsive disorder: a critical review. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(3):374-88.

34. Korff S, Harvey BH. Animal models of obsessive-compulsive disorder: rationale to understanding psychobiology and pharmacology. Psychiatr Clin North Am. 2006;29(2):371-90.

35. Stein DJ, Dodman NH, Borchelt P, Hollander E. Behavioral disorders in veterinary practice: relevance to psychiatry. Compr Psychiatry. 1994;35(4):275-85.

36. Veith L. Acral lick dermatitis in the dog. Canine Practice. 1986(13):15-22.

37. Garner JP, Weisker SM, Dufour B, Mench JA. Barbering (fur and whisker trimming) by laboratory mice as a model of human trichotillomania and obsessive-compulsive spectrum disorders. Comp Med. 2004;54(2):216-24.

38. Sarna JR, Dyck RH, Whishaw IQ. The Dalila effect: C57BL6 mice barber whiskers by plucking. Behav Brain Res. 2000;108(1):39-45.

39. Einat H, Szechtman H. Perseveration without hyperlocomotion in a spontaneous alternation task in rats sensitized to the dopamine agonist quinpirole. Physiol Behav. 1995;57(1):55-9.

40. Yadin E, Friedman E, Bridger WH. Spontaneous alternation behavior: an animal model for obsessive-compulsive disorder? Pharmacol Biochem Behav. 1991;40(2):311-5.

41. Szechtman H, Sulis W, Eilam D. Quinpirole induces compulsive checking behavior in rats: a potential animal model of obsessive-compulsive disorder (OCD). Behav Neurosci. 1998;112(6):1475-85.

42. Henderson JG, Pollard CA. Three types of obsessive compulsive disorder in a community sample. J Clin Psychol. 1988;44(5):747-52.

43. Rasmussen SA, Eisen JL. The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry. 1994;55(Suppl):5-10;discussion 1-4.

44. Szechtman H, Eckert MJ, Tse WS, Boersma JT, Bonura CA, McClelland JZ, Culver KE, Eilam D. Compulsive checking behavior of quinpirole-sensitized rats as an animal model of Obsessive-Compulsive Disorder(OCD): form and control. BMC Neurosci. 2001;2:4.

45. Leckman JF, Goodman WK, North WG, Chappell PB, Price LH, Pauls DL, Anderson GM, Riddle MA, McDougle CJ, Barr LC, Cohen DJ. The role of central oxytocin in obsessive compulsive disorder and related normal behavior. Psychoneuroendocrinology. 1994;19(8):723-49.

46. Leckman J, Goodman W, North W, Chappell P, Price L, Pauls D, derson GM, Riddle MA, McSwiggan-Hardin M, McDougle CJ, et al. Elevated cerebrospinal fluid levels of oxytocin in obsessive-compulsive disorder. Comparison with Tourette's syndrome and healthy controls. Arch Gen Psychiatry. 1994;51(10):782-92.

47. Marroni SS, Nakano FN, Gati CD, Oliveira JA, Antunes-Rodrigues J, Garcia-Cairasco N. Neuroanatomical and cellular substrates of hypergrooming induced by microinjection of oxytocin in central nucleus of amygdala, an experimental model of compulsive behavior. Mol Psychiatry. 2007;12(12):1103-17.

48. Sachs BD. The development of grooming and its expression in adult animals. Ann N Y Acad Sci. 1988;525:1-17.

49. Spruijt BM, van Hooff JA, Gispen WH. Ethology and neurobiology of grooming behavior. Physiol Rev. 1992;72(3):825-52.

50. Altemus M, Glowa JR, Galliven E, Leong YM, Murphy DL. Effects of serotonergic agents on food-restriction-induced hyperactivity. Pharmacol Biochem Behav. 1996;53(1):123-31.

51. Altemus M, Glowa JR, Murphy DL. Attenuation of foodrestriction- induced running by chronic fluoxetine treatment. Psychopharmacol Bull. 1993;29(3):397-400.

52. Falk JR, Halmi KA, Tryon WW. Activity measures in anorexia nervosa. Arch Gen Psychiatry. 1985;42(8):811-4. 53. Kron L, Katz JL, Gorzynski G, Weiner H. Hyperactivity in anorexia nervosa: a fundamental clinical feature. Compr Psychiatry. 1978;19(5):433-40.

54. Joel D, Avisar A. Excessive lever pressing following post-training signal attenuation in rats: a possible animal model of obsessive compulsive disorder? Behav Brain Res. 2001;123(1):77-87.

55. Joel D, Ben-Amir E, Doljansky J, Flaisher S. 'Compulsive' lever-pressing in rats is attenuated by the serotonin re-uptake inhibitors paroxetine and fluvoxamine but not by the tricyclic antidepressant desipramine or the anxiolytic diazepam. Behav Pharmacol. 2004;15(3):241-52.

56. Joel D, Doljansky J. Selective alleviation of compulsive leverpressing in rats by D1, but not D2, blockade: possible implications for the involvement of D1 receptors in obsessive-compulsive disorder. Neuropsychopharmacology. 2003;28(1):77-85.

57. Broekkamp CL, Rijk HW, Joly-Gelouin D, Lloyd KL. Major tranquillizers can be distinguished from minor tranquillizers on the basis of effects on marble burying and swim-induced grooming in mice. Eur J Pharmacol. 1986;126(3):223-9.

58. Londei T, Valentini AM, Leone VG. Investigative burying by laboratory mice may involve non-functional, compulsive, behaviour. Behav Brain Res. 1998;94(2):249-54.

59. Njung'e K, Handley SL. Effects of 5-HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents. Br J Pharmacol. 1991;104(1):105-12.

60. Treit D, Pinel JP, Fibiger HC. Conditioned defensive burying: a new paradigm for the study of anxiolytic agents. Pharmacol Biochem Behav. 1981;15(4):619-26.

61. Hoexter MQ, de Souza Duran FL, D'Alcante CC, Dougherty DD, Shavitt RG, Lopes AC, Diniz JB, Deckersbach T, Batistuzzo MC, Bressan RA, Miguel EC, Busatto RGF. Gray matter volumes in obsessive-compulsive disorder before and after fluoxetine or cognitive-behavior therapy: a randomized clinical trial. Neuropsychopharmacology. 2012;37(3):734-45.

62. Saxena S, Rauch SL. Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. Psychiatr Clin North Am. 2000;23(3):563-86.

63. Milad MR, Rauch SL. Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci. 2012;16(1):43-51.

64. Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35(1):169-91.

65. Lehman JF, Greenberg BD, McIntyre CC, Rasmussen SA, Haber SN. Rules ventral prefrontal cortical axons use to reach their targets: implications for diffusion tensor imaging tractography and deep brain stimulation for psychiatric illness. J Neurosci. 2011;31(28):10392-402.

66. Menzies L, Chamberlain SR, Laird AR, Thelen SM, Sahakian BJ, Bullmore ET. Integrating evidence from neuroimaging and neuropsychological studies of obsessivecompulsive disorder: the orbitofronto-striatal model revisited. Neurosci Biobehav Rev. 2008;32(3):525-49.

67. Ongür D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000;10(3):206-19.

68. Milad MR, Rauch SL, Pitman RK, Quirk GJ. Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol. 2006;73(1):61-71.

69. Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry. 2007;62(5):446-54.

70. Rauch SL, Dougherty DD, Malone D, Rezai A, Friehs G, Fischman AJ, Alpert NM, Haber SN, Stypulkowski PH, Rise MT, Rasmussen SA, Greenberg BD. A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder. J Neurosurg. 2006;104(4):558-65.

71. Hughes KC, Shin LM. Functional neuroimaging studies of post-traumatic stress disorder. Expert Rev Neurother. 2011;11(2):275-85.

72. de Carvalho MR, Dias GP, Cosci F, de-Melo-Neto VL, Bevilaqua MC, Gardino PF, Nardi AE. Current findings of fMRI in panic disorder: contributions for the fear neurocircuitry and CBT effects. Expert Rev Neurother. 2010;10(2):291-303.

73. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164(10):1476-88.

74. Etkin A, Prater KE, Hoeft F, Menon V, Schatzberg AF. Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder. Am J Psychiatry. 2010;167(5):545-54.

75. Simon D, Kaufmann C, Müsch K, Kischkel E, Kathmann N. Fronto-striato-limbic hyperactivation in obsessive-compulsive disorder during individually tailored symptom provocation. Psychophysiology. 2010;47(4):728-38.

76. Cardoner N, Harrison BJ, Pujol J, Soriano-Mas C, Hernández- Ribas R, López-Solá M, Real E, Deus J, Ortiz H, Alonso P, Menchón rJM. Enhanced brain responsiveness during active emotional face processing in obsessive compulsive disorder. World J Biol Psychiatry. 2011;12(5):349-63.

77. Cannistraro PA, Wright CI, Wedig MM, Martis B, Shin LM, Wilhelm S, Rauch SL. Amygdala responses to human faces in obsessivecompulsive disorder. Biol Psychiatry. 2004;56(12):916-20.

78. Hofmann SG. Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders. Clin Psychol Rev. 2008;28(2):199-210.

79. Foa EB, Zinbarg R, Rothbaum BO. Uncontrollability and unpredictability in post-traumatic stress disorder: an animal model. Psychol Bull. 1992;112(2):218-38.

80. McTeague LM, Lang PJ, Laplante MC, Bradley MM. Aversive imagery in panic disorder: agoraphobia severity, comorbidity, and defensive physiology. Biol Psychiatry. 2011;70(5):415-24.

81. Holstein DH, Vollenweider FX, Jäncke L, Schopper C, Csomor PA. P50 suppression, prepulse inhibition, and startle reactivity in the same patient cohort suffering from posttraumatic stress disorder. J Affect Disord. 2010;126(1-2):188-97.

82. Cornwell BR, Heller R, Biggs A, Pine DS, Grillon C. Becoming the center of attention in social anxiety disorder: startle reactivity to a virtual audience during speech anticipation. J Clin Psychiatry. 2011;72(7):942-8.

83. Ray WJ, Molnar C, Aikins D, Yamasaki A, Newman MG, Castonguay L, Borkovec TD. Startle response in generalized anxiety disorder. Depress Anxiety. 2009;26(2):147-54.

84. Buhlmann U, Wilhelm S, Deckersbach T, Rauch SL, Pitman RK, Orr SP. Physiologic responses to loud tones in individuals with obsessive-compulsive disorder. Psychosom Med. 2007;69(2):166-72.

85. Kumari V, Kaviani H, Raven PW, Gray JA, Checkley SA. Enhanced startle reactions to acoustic stimuli in patients with obsessivecompulsive disorder. Am J Psychiatry. 2001;158(1):134-6.

86. Maren S. Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci. 2001;24:897-931.

87. Fredrikson M, Annas P, Georgiades A, Hursti T, Tersman Z. Internal consistency and temporal stability of classically conditioned skin conductance responses. Biol Psychol. 1993;35(2):153-63.

88. Bankart CP, Elliott R. Heart rate and skin conductance in anticipation of shocks with varying probability of occurrence. Psychophysiology. 1974;11(2):160-74.

89. Merckelbach H, de Ruiter C, van den Hout MA, Hoekstra R. Conditioning experiences and phobias. Behav Res Ther. 1989;27(6):657-62.

90. Haddad AD, Lissek S, Pine DS, Lau JY. How do social fears in adolescence develop? Fear conditioning shapes attention orienting to social threat cues. Cogn Emot. 2011;25(6):1139-47.

91. Lissek S, Levenson J, Biggs AL, Johnson LL, Ameli R, Pine DS, Grillon C. Elevated fear conditioning to socially relevant unconditioned stimuli in social anxiety disorder. Am J Psychiatry. 2008;165(1):124-32.

92. Michael T, Blechert J, Vriends N, Margraf J, Wilhelm FH. Fear conditioning in panic disorder: Enhanced resistance to extinction. J Abnorm Psychol. 2007;116(3):612-7.

93. Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK. Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J Psychiatr Res. 2008;42(7):515-20.

94. Orr SP, Metzger LJ, Pitman RK. Psychophysiology of post-traumatic stress disorder. Psychiatr Clin North Am. 2002;25(2):271-93.

95. Nanbu M, Kurayama T, Nakazawa K, Matsuzawa D, Komiya Z, Haraguchi T, Ogura H, Hashimoto T, Yoshida S, Iyo M, Shimizu E. Impaired P50 suppression in fear extinction in obsessivecompulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(2):317-22.

96. Braff DL, Geyer MA, Swerdlow NR. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl). 2001;156(2-3):234-58.

97. Ludewig S, Ludewig K, Geyer MA, Hell D, Vollenweider FX. Prepulse inhibition deficits in patients with panic disorder. Depress Anxiety. 2002;15(2):55-60.

98. Ludewig S, Geyer MA, Ramseier M, Vollenweider FX, Rechsteiner E, Cattapan-Ludewig K. Information-processing deficits and cognitive dysfunction in panic disorder. J Psychiatry Neurosci. 2005;30(1):37-43.

99. Grillon C, Morgan CA, Southwick SM, Davis M, Charney DS. Baseline startle amplitude and prepulse inhibition in Vietnam veterans with posttraumatic stress disorder. Psychiatry Res. 1996;64(3):169-78.

100. Hoenig K, Hochrein A, Quednow BB, Maier W, Wagner M. Impaired prepulse inhibition of acoustic startle in obsessivecompulsive disorder. Biol Psychiatry. 2005;57(10):1153-8.

101. Ahmari SE, Risbrough VB, Geyer MA, Simpson HB. Impaired Sensorimotor gating in unmedicated adults with obsessivecompulsive disorder. Neuropsychopharmacology. 2012 [Epub ahead of print] .

102. Swerdlow NR, Karban B, Ploum Y, Sharp R, Geyer MA, Eastvold A. Tactile prepuff inhibition of startle in children with Tourette's syndrome: in search of an "fMRI-friendly" startle paradigm. Biol Psychiatry. 2001;50(8):578-85.

103. Castellanos FX, Fine EJ, Kaysen D, Marsh WL, Rapoport JL, Hallett M. Sensorimotor gating in boys with Tourette's syndrome and ADHD: preliminary results. Biol Psychiatry. 1996;39(1):33-41.

104. Lipschitz DS, Mayes LM, Rasmusson AM, Anyan W, Billingslea E, Gueorguieva R, Southwick SM. Baseline and modulated acoustic startle responses in adolescent girls with posttraumatic stress disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(8):807-14.

105. Schall U, Schön A, Zerbin D, Eggers C, Oades RD. Eventrelated potentials during an auditory discrimination with prepulse inhibition in patients with schizophrenia, obsessive-compulsive disorder and healthy subjects. Int J Neurosci. 1996;84(1-4):15-33.

106. Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl). 2001;156(2-3):117-54.

107. Swerdlow NR, Braff DL, Geyer MA. Animal models of deficient sensorimotor gating: what we know, what we think we know, and what we hope to know soon. Behav Pharmacol. 2000;11(3- 4):185-204.

108. Chamberlain S, Blackwell A, Fineberg N, Robbins T, Sahakian B. The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers. Neurosci Biobehav Rev. 2005;29(3):399-419.

109. Grisham JR, Anderson TM, Poulton R, Moffitt TE, Andrews G. Childhood neuropsychological deficits associated with adult obsessive-compulsive disorder. Br J Psychiatry. 2009;195(2):138-41.

110. Chamberlain SR, Menzies L. Endophenotypes of obsessivecompulsive disorder: rationale, evidence and future potential. Expert Rev Neurother. 2009;9(8):1133-46.

111. Purcell R, Maruff P, Kyrios M, Pantelis C. Neuropsychological deficits in obsessive-compulsive disorder: a comparison with unipolar depression, panic disorder, and normal controls. Arch Gen Psychiatry. 1998;55(5):415-23.

112. Clayton IC, Richards JC, Edwards CJ. Selective attention in obsessive-compulsive disorder. J Abnorm Psychol. 1999;108(1):171-5.

113. Boldrini M, Del Pace L, Placidi GP, Keilp J, Ellis SP, Signori S, Placidi GF, Cappa SF. Selective cognitive deficits in obsessivecompulsive disorder compared to panic disorder with agoraphobia. Acta Psychiatr Scand. 2005;111(2):150-8.

114. Bannon S, Gonsalvez CJ, Croft RJ, Boyce PM. Executive functions in obsessive-compulsive disorder: state or trait deficits? Aust N Z J Psychiatry. 2006;40(11-12):1031-8.

115. Cisler JM, Olatunji BO. Components of attentional biases in contamination fear: evidence for difficulty in disengagement. Behav Res Ther. 2010;48(1):74-8.

116. Bar-Haim Y, Lamy D, Pergamin L, Bakermans-Kranenburg MJ, van IJzendoorn MH. Threat-related attentional bias in anxious and nonanxious individuals: a meta-analytic study. Psychol Bull. 2007;133(1):1-24.

117. Kwak SM, Na DL, Kim G, Kim GS, Lee JH. Use of eye movement to measure smokers' attentional bias to smoking-related cues. Cyberpsychol Behav. 2007;10(2):299-304.

118. Rinck M, Becker ES. Spider fearful individuals attend to threat, then quickly avoid it: evidence from eye movements. J Abnorm Psychol. 2006;115(2):231-8.

119. Lavy E, van den Hout M, Arntz A. Attentional bias and spider phobia: conceptual and clinical issues. Behav Res Ther. 1993;31(1):17-24.

120. Amir N, Elias J, Klumpp H, Przeworski A. Attentional bias to threat in social phobia: facilitated processing of threat or difficulty disengaging attention from threat? Behav Res Ther. 2003;41(11):1325-35.

121. Spector IP, Pecknold JC, Libman E. Selective attentional bias related to the noticeability aspect of anxiety symptoms in generalized social phobia. J Anxiety Disord. 2003;17(5):517-31.

122. Bradley BP, Mogg K, White J, Groom C, de Bono J. Attentional bias for emotional faces in generalized anxiety disorder. Br J Clin Psychol. 1999;38 ( Pt 3):267-78.

123. Fleurkens P, Rinck M, van Minnen A. Specificity and generalization of attentional bias in sexual trauma victims suffering from posttraumatic stress disorder. J Anxiety Disord. 2011;25(6):783-7.

124. Reinecke A, Cooper M, Favaron E, Massey-Chase R, Harmer C. Attentional bias in untreated panic disorder. Psychiatry Res. 2011;185(3):387-93.

125. Tata PR, Leibowitz JA, Prunty MJ, Cameron M, Pickering AD. Attentional bias in obsessional compulsive disorder. Behav Res Ther. 1996;34(1):53-60.

126. Moritz S, von Mühlenen A. Investigation of an attentional bias for fear-related material in obsessive-compulsive checkers. Depress Anxiety. 2008;25(3):225-9.

127. Harkness EL, Harris LM, Jones MK, Vaccaro L. No evidence of attentional bias in obsessive compulsive checking on the dot probe paradigm. Behav Res Ther. 2009;47(5):437-43.

128. Sizino da Victoria M, Nascimento AL, Fontenelle LF. Symptom-specific attentional bias to threatening stimuli in obsessive-compulsive disorder. Compr Psychiatry. 2012; [Epub ahead of print] .

129. Ravindran LN, Stein MB. The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiatry. 2010;71(7):839-54.

130. Andersch S, Rosenberg NK, Kullingsjö H, Ottosson JO, Bech P, Bruun-Hansen J, Hanson L, Lorentzen K, Mellergård M, Rasmussen S, et al. Efficacy and safety of alprazolam, imipramine and placebo in treating panic disorder. A Scandinavian multicenter study. Acta Psychiatr Scand Suppl. 1991;365:18-27.

131. Taylor CB, Hayward C, King R, Ehlers A, Margraf J, Maddock R, Clark D, Roth WT, Agras WS. Cardiovascular and symptomatic reduction effects of alprazolam and imipramine in patients with panic disorder: results of a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 1990;10(2):112-8.

132. Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized anxiety disorder. A placebocontrolled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry. 1993;50(11):884-95.

133. Davidson J, Kudler H, Smith R, Mahorney SL, Lipper S, Hammett E, Saunders WB, Cavenar JO Jr. Treatment of posttraumatic stress disorder with amitriptyline and placebo. Arch Gen Psychiatry. 1990;47(3):259-66.

134. Fineberg N, Bullock T, Montgomery D, Montgomery S. Serotonin reuptake inhibitors are the treatment of choice in obsessive compulsive disorder. Int Clin Psychopharmacol. 1992;7(Suppl1):43-7.

135. Lowry CA, Hale MW, Evans AK, Heerkens J, Staub DR, Gasser PJ, Shekhar A. Serotonergic systems, anxiety, and affective disorder: focus on the dorsomedial part of the dorsal raphe nucleus. Ann N Y Acad Sci. 2008;1148:86-94.

136. Lowry CA, Johnson PL, Hay-Schmidt A, Mikkelsen J, Shekhar A. Modulation of anxiety circuits by serotonergic systems. Stress. 2005;8(4):233-46.

137. Bespalov AY, van Gaalen MM, Gross G. Antidepressant treatment in anxiety disorders. Curr Top Behav Neurosci. 2010;2:361-90.

138. Powers MB, Halpern JM, Ferenschak MP, Gillihan SJ, Foa EB. A meta-analytic review of prolonged exposure for posttraumatic stress disorder. Clin Psychol Rev. 2010;30(6):635-41.

139. Pachana NA, Woodward RM, Byrne GJ. Treatment of specific phobia in older adults. Clin Interv Aging. 2007;2(3):469-76.

140. Singh JS, Hope DA. Cognitive-behavioral approaches to the treatment of social anxiety disorder. Isr J Psychiatry Relat Sci. 2009;46(1):62-9.

141. Ham P, Waters DB, Oliver MN. Treatment of panic disorder. Am Fam Physician. 2005;71(4):733-9.

142. Belotto-Silva C, Diniz JB, Malavazzi DM, Valério C, Fossaluza V, Borcato S, Seixas AA, Morelli D, Miguel EC, Shavitt RG. Group cognitive-behavioral therapy versus selective serotonin reuptake inhibitors for obsessive-compulsive disorder: a practical clinical trial. J Anxiety Disord. 2012;26(1):25-31.

143. Kaplan GB, Heinrichs SC, Carey RJ. Treatment of addiction and anxiety using extinction approaches: neural mechanisms and their treatment implications. Pharmacol Biochem Behav. 2011;97(3):619-25.

144. Storch E, Mariaskin A, Murphy T. Psychotherapy for obsessive-compulsive disorder. Curr Psychiatry Rep. 2009;11(4):296-301.

Publication Dates

• Publication in this collection
  19 June 2012
• Date of issue
  June 2012