H. Blair Simpson

Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior

What Causes Obsessive Compulsive Disorder? Obsessive compulsive disorder is a severe, chronic mental illness that affects millions of individuals. However, the mechanisms underlying this disease are still largely unknown (see the Perspective by Rauch and Carlezon Jr.). Ahmari et al. (p. 1234) stimulated glutamatergic pathways between the orbitofrontal cortex and the ventromedial striatum and used grooming to assess obsessive compulsive behavior in mice. Repetitive stimulation over days triggered changes in the neuronal responses of the ventromedial striatum. Over time, the behavior of the animals became independent of stimulation and could be prevented by the antidepressant fluoxetine. Burguière et al. (p. 1243) investigated the neural basis of obsessive compulsive symptoms in a mutant mouse that showed excessive expression of a conditioned form of grooming. Hyperactivation of projections from the orbitofrontal cortex to the striatum increases repetitive grooming in mice. [Also see Perspective by Rauch and Carlezon] Although cortico-striato-thalamo-cortical (CSTC) circuit dysregulation is correlated with obsessive compulsive disorder (OCD), causation cannot be tested in humans. We used optogenetics in mice to simulate CSTC hyperactivation observed in OCD patients. Whereas acute orbitofrontal cortex (OFC)–ventromedial striatum (VMS) stimulation did not produce repetitive behaviors, repeated hyperactivation over multiple days generated a progressive increase in grooming, a mouse behavior related to OCD. Increased grooming persisted for 2 weeks after stimulation cessation. The grooming increase was temporally coupled with a progressive increase in light-evoked firing of postsynaptic VMS cells. Both increased grooming and evoked firing were reversed by chronic fluoxetine, a first-line OCD treatment. Brief but repeated episodes of abnormal circuit activity may thus set the stage for the development of persistent psychopathology.

OBSESSIVE-COMPULSIVE DISORDER: A REVIEW OF THE DIAGNOSTIC CRITERIA AND POSSIBLE SUBTYPES AND DIMENSIONAL SPECIFIERS FOR DSM-V

Background: Since the publication of the DSM‐IV in 1994, research on obsessive–compulsive disorder (OCD) has continued to expand. It is timely to reconsider the nosology of this disorder, assessing whether changes to diagnostic criteria as well as subtypes and specifiers may improve diagnostic validity and clinical utility. Methods: The existing criteria were evaluated. Key issues were identified. Electronic databases of PubMed, ScienceDirect, and PsycINFO were searched for relevant studies. Results: This review presents a number of options and preliminary recommendations to be considered for DSM‐V. These include: (1) clarifying and simplifying the definition of obsessions and compulsions (criterion A); (2) possibly deleting the requirement that people recognize that their obsessions or compulsions are excessive or unreasonable (criterion B); (3) rethinking the clinical significance criterion (criterion C) and, in the interim, possibly adjusting what is considered “time‐consuming” for OCD; (4) listing additional disorders to help with the differential diagnosis (criterion D); (5) rethinking the medical exclusion criterion (criterion E) and clarifying what is meant by a “general medical condition”; (6) revising the specifiers (i.e., clarifying that OCD can involve a range of insight, in addition to “poor insight,” and adding “tic‐related OCD”); and (7) highlighting in the DSM‐V text important clinical features of OCD that are not currently mentioned in the criteria (e.g., the major symptom dimensions). Conclusions: A number of changes to the existing diagnostic criteria for OCD are proposed. These proposed criteria may change as the DSM‐V process progresses. Depression and Anxiety, 2010.

Fluoxetine in children and adolescents with OCD: a placebo-controlled trial.

OBJECTIVE To examine the safety and efficacy of fluoxetine in child and adolescent obsessive-compulsive disorder (OCD). METHOD Between 1991 and 1998, 43 patients were randomly assigned to fluoxetine or placebo for 8 weeks. Dosing was fixed for the first 6 weeks (up to 60 mg/day) and then could be increased to 80 mg/day. Responders entered an 8-week maintenance phase. The primary outcome measures were the Childrens Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinical Global Impression-Improvement (CGI-I) scale. Analyses were done on the intent-to-treat sample. RESULTS Fluoxetine patients (n = 21) had significantly lower CY-BOCS scores than placebo patients (n = 22) after 16 (but not 8) weeks. Fluoxetine responders (n = 11) had significantly lower CY-BOCS scores than placebo responders (n = 7) after an additional 8 weeks of treatment. After 16 weeks, 57% of fluoxetine (versus 27% of placebo) patients were much or very much improved on the CGI-I scale (p <.05). No patient terminated the study because of adverse medication effects. CONCLUSION Fluoxetine was well tolerated and effective for the treatment of child and adolescent OCD, but fluoxetines full effect took more than 8 weeks to develop.

Quality of life and functional impairment in obsessive–compulsive disorder: a comparison of patients with and without comorbidity, patients in remission, and healthy controls†

Background: Several studies have demonstrated that obsessive–compulsive disorder (OCD) is associated with interference in quality of life (QOL) and functional impairment. However, these studies did not compare individuals in remission to individuals who continue to have the disorder, predominantly used comparisons with norms and not with a matched normal sample, and did not always consider the impact of comorbidity. Methods: We administered multiple measures that assess QOL and functional impairment to 66 OCD patients who had previously consented for a clinical trial and to 36 age and sex matched individuals who denied any psychiatric history. Results: Results confirm that OCD was associated with significantly lower QOL and functional impairment compared to healthy controls (HCs) in areas of work, social life, and family life. Individuals with OCD and other comorbid psychiatric diagnoses showed the poorest QOL and functioning, with comorbid depression accounting for much of the variance. The levels of QOL and functioning in individuals in remission tended to lie in between HCs and individuals with current OCD: their QOL or functioning did not differ significantly from HCs nor did they consistently differ significantly from those who had current OCD. Conclusion: These results suggest that individuals who are in remission have improved levels of QOL and functioning, whereas individuals with OCD are significantly impaired, and individuals with OCD and comorbid disorders are the most impaired. Treatment strategies should be focused on achieving remission of all symptoms to have the greatest impact on functioning and QOL. Depression and Anxiety, 2009. Published 2008 Wiley‐Liss, Inc.

Increased Capacity to Delay Reward in Anorexia Nervosa

Individuals with anorexia nervosa (AN) are often characterized as possessing excessive self-control and are unusual in their ability to reduce or avoid the consumption of palatable foods. This behavior promotes potentially life-threatening weight loss and suggests disturbances in reward processing. We studied whether individuals with AN showed evidence of increased self-control by examining the tendency to delay receipt of a monetary, non-food related, reward. Underweight AN (n = 36) and healthy controls (HC, n = 28) completed a monetary intertemporal choice task measuring delay discounting factor. Individuals with AN reduced the value of a monetary reward over time significantly less than HC (F[1,61] = 5.03; p = 0.029). Secondary analyses indicated that the restricting subtype of AN, in particular, showed significantly less discounting than HC (F[1,46] = 8.3; p = 0.006). These findings indicate that some individuals with AN show less temporal discounting than HC, suggestive of enhanced self-control that is not limited to food consumption. This is in contrast to other psychiatric disorders, for example, substance abuse, which are characterized by greater discounting. Though preliminary, these findings suggest that excessive self-control may contribute to pathological processes and individuals with AN may have neuropsychological characteristics that enhance their ability to delay reward and thereby may help to maintain persistent food restriction.

Impaired sensorimotor gating in unmedicated adults with obsessive-compulsive disorder.

Functional and structural imaging studies suggest that obsessive–compulsive disorder (OCD) symptoms arise from dysfunction in cortico-striato-thalamo-cortical circuits. It has therefore been hypothesized that neurophysiological tasks subserved by these circuits should be abnormal in OCD patients. One neurocognitive probe associated with this circuitry is prepulse inhibition (PPI) of the acoustic startle response. PPI deficits are thought to reflect abnormalities in processing and integration of sensory and motor information. Two prior studies found that OCD patients had PPI deficits at single prepulse (PP) intensities. However, most patients in these studies were taking psychotropic medications at the time of PPI testing, and preclinical studies have demonstrated effects of psychotropic medications on PPI. We examined PPI in 22 unmedicated OCD patients and 22 matched healthy controls at three different PP intensities (74, 78, and 86 dB). OCD patients had significantly less PPI across all three PP intensities compared with controls. Exploratory analyses indicated that OCD patients with a history of tics had lower levels of PPI. Our results demonstrate that unmedicated OCD patients have impaired sensorimotor gating as measured by PPI. This indicates that PPI deficits are present in OCD patients and are not the result of medication effects. Our findings also suggest that OCD patients with a history of tics may have greater impairment in sensorimotor gating than the general OCD population. Future studies should be designed to examine whether PPI deficits characterize tic-related OCD.

Reduced functional connectivity within the limbic cortico-striato-thalamo-cortical loop in unmedicated adults with obsessive-compulsive disorder

Cortico‐striato‐thalamo‐cortical (CSTC) loops project from the cortex to the striatum, then from the striatum to the thalamus via the globus pallidus, and finally from the thalamus back to the cortex again. These loops have been implicated in Obsessive‐Compulsive Disorder (OCD) with particular focus on the limbic CSTC loop, which encompasses the orbitofrontal and anterior cingulate cortices, as well as the ventral striatum. Resting state functional‐connectivity MRI (rs‐fcMRI) studies, which examine temporal correlations in neural activity across brain regions at rest, have examined CSTC loop connectivity in patients with OCD and suggest hyperconnectivity within these loops in medicated adults with OCD. We used rs‐fcMRI to examine functional connectivity within CSTC loops in unmedicated adults with OCD (n = 23) versus healthy controls (HCs) (n = 20). Contrary to prior rs‐fcMRI studies in OCD patients on medications that report hyperconnectivity in the limbic CSTC loop, we found that compared with HCs, unmedicated OCD participants had reduced connectivity within the limbic CSTC loop. Exploratory analyses revealed that reduced connectivity within the limbic CSTC loop correlated with OCD symptom severity in the OCD group. Our finding of limbic loop hypoconnectivity in unmedicted OCD patients highlights the potential confounding effects of antidepressants on connectivity measures and the value of future examinations of the effects of pharmacological and/or behavioral treatments on limbic CSTC loop connectivity. Hum Brain Mapp 35:2852–2860, 2014.

Pre-meal anxiety and food intake in anorexia nervosa ☆ ☆☆ ★

Anorexia nervosa (AN) is a serious mental illness characterized by reduced caloric intake that often persists after acute weight restoration. This preliminary study assesses the relationship between pre-meal anxiety and food intake in recently weight-restored individuals with AN. We hypothesized that pre-meal anxiety is inversely related to caloric intake in AN. Caloric intake and pre-meal anxiety were measured in three laboratory-based assessments (yogurt snack, multi-item lunch, macaroni and cheese lunch). Anxiety was measured by Spielberger State-Trait Anxiety Inventory (STAI-S) administered prior to the meal. Acutely weight-restored patients with AN were compared with healthy controls (HCs). Associations between anxiety and intake were analyzed first within each meal type separately and then using a model to combine the sample. In the multi-item lunch and the macaroni and cheese lunch, AN ate significantly less than HC (p=0.01, p<0.001). Pre-meal anxiety was significantly correlated with intake among AN, but not HC. In the yogurt snack, there was no significant association between anxiety and intake among patients or controls, and the groups did not differ in caloric intake. The association between pre-meal anxiety and intake among weight-restored individuals with AN suggests a potential target for relapse prevention treatment.

Rationale for the application of exposure and response prevention to the treatment of anorexia nervosa.

OBJECTIVE Anorexia nervosa (AN) is a life threatening and difficult to treat illness with a high relapse rate. Current treatments are inadequate and new approaches to treatment are needed. METHOD We review the data on anxiety in AN, the relationship between anxiety disorders and AN, and the use of Exposure and Response Prevention in treatment. RESULTS The overlap between AN and anxiety disorders suggest a model of AN in which baseline anxiety features yield eating related fears, avoidance behaviors, and ritualized safety behaviors that promote the underweight state and the perpetuation of the disorder. We propose an Exposure and Response Prevention treatment to prevent relapse in AN. DISCUSSION Overlap between AN and anxiety disorders suggests that Exposure and Response Prevention may be a new and beneficial approach to preventing relapse in individuals with AN.

Myth of the pure obsessional type in obsessive–compulsive disorder†‡

Background: Several studies have identified discrete symptom dimensions in obsessive–compulsive disorder (OCD), derived from factor analyses of the individual items or symptom categories of the Yale–Brown Obsessive–Compulsive Scale Symptom Checklist (YBOCS‐SC). This study aims to extend previous work on the relationship between obsessions and compulsions by specifically including mental compulsions and reassurance‐seeking. Because these compulsions have traditionally been omitted from prior factor analytic studies, their association to what have been called “pure obsessions” may have been overlooked. Method: Participants (N=201) were recruited from two multi‐site randomized clinical treatment trials for OCD. The YBOCS‐SC was used to assess OCD symptoms, as it includes a comprehensive list of obsessions and compulsions, arranged by content category. Each category was given a score based on whether symptoms were present and if the symptom was a primary target of clinical concern, and a factor analysis was conducted. Mental compulsions and reassurance‐seeking were considered separate categories for the analysis. Results: Using an orthogonal geomin rotation of 16 YBOCS‐SC categories/items, we found a five‐factor solution that explained 67% of the total variance. Inspection of items that composed each factor suggests five familiar constructs, with mental compulsions and reassurance‐seeking included with sexual, aggressive, and religious obsessions (unacceptable/taboo thoughts). Conclusions: This study suggests that the concept of the “pure obsessional” (e.g., patients with unacceptable/taboo thoughts yet no compulsions) may be a misnomer, as these obsessions were factorially associated with mental compulsions and reassurance‐seeking in these samples. These findings may have implications for DSM‐5 diagnostic criteria. Depression and Anxiety, 2011.