Nicole McLaughlin

Diffusion tensor imaging of the corpus callosum: a cross-sectional study across the lifespan

Previous studies have demonstrated strong developmental trends of white matter using in vivo neuroimaging. However, few studies have examined white matter using diffusion tensor imaging across the lifespan. In the present study we examined fractional anisotropy and volume in the corpus callosum in four groups (children, adolescents, young adults, and elderly). Results revealed a curvilinear relationship in the analysis of the fractional anisotropy values for these four groups, with fractional anisotropy values increasing in childhood and adolescence, reaching their peak in young adulthood, followed by a non‐significant decline in the elderly. Volumetric analysis of corpus callosum regions revealed a similar pattern, with an increase in volume from childhood and adolescence through young adulthood, and a non‐significant decrease in volume in the elderly group. These results define the microstructural development of the white matter across the lifespan. Future studies are required to examine the neurobehavioral correlates of these neuroimaging indices.

Extinction retention and fear renewal in a lifetime obsessive–compulsive disorder sample

Obsessive-compulsive disorder (OCD), like other illnesses with prominent anxiety, may involve abnormal fear regulation and consolidation of safety memories. Impaired fear extinction memory (extinction recall, ER) has been shown in individuals with current symptoms of OCD [1]. However, contrary to expectations, the only previous study investigating this phenomenon showed a positive correlation between extinction recall abilities and OCD symptomology (i.e., as OCD symptoms worsened, extinction memory improved). The purpose of the current study was to determine if patients with a lifetime diagnosis of OCD (not necessarily currently symptomatic) also demonstrate impairments in extinction memory, and the relationship between OCD symptomology and extinction memory in this type of sample. In addition, we also examined fear renewal, which has never been investigated in an OCD sample. We enrolled 37 patients with OCD, the majority of whom were on serotonin reuptake inhibitors, and 18 healthy control participants in a 2-day paradigm assessing fear conditioning and extinction (Day 1) and extinction retention and renewal (Day 2). Skin conductance responses (SCRs) were the dependent measure. Results, as in the prior study, indicated that the only between-group difference was impaired ER in OCD patients relative to controls. Contrary to our prediction, OCD symptom severity was not correlated with the magnitude of extinction recall. There were no differences in fear renewal between OCD patients and controls.

Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as ‘response’ (n=514) or ‘non-response’ (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10−8), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10−5) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10−6 and 8.41 × 10−6, respectively. The other 35 variations with signals of potential significance (P<10−4) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

Visuospatial Memory Improvement after Gamma Ventral Capsulotomy in Treatment Refractory Obsessive-Compulsive Disorder Patients.

Gamma ventral capsulotomy (GVC) radiosurgery is intended to minimize side effects while maintaining the efficacy of traditional thermocoagulation techniques for the treatment of refractory obsessive–compulsive disorder (OCD). Neuropsychological outcomes are not clear based on previous studies and, therefore, we investigated the effects of GVC on cognitive and motor performance. A double-blind, randomized controlled trial (RCT) was conducted with 16 refractory OCD patients allocated to active treatment (n=8) and sham (n=8) groups. A comprehensive neuropsychological evaluation including intellectual functioning, attention, verbal and visuospatial learning and memory, visuospatial perception, inhibitory control, cognitive flexibility, and motor functioning was applied at baseline and one year after the procedure. Secondary analysis included all operated patients: eight from the active group, four from the sham group who were submitted to surgery after blind was broken, and five patients from a previous open pilot study (n=5), totaling 17 patients. In the RCT, visuospatial memory (VSM) performance significantly improved in the active group after GVC (p=0.008), and remained stable in the sham group. Considering all patients operated, there was no decline in cognitive or motor functioning after one year of follow-up. Our initial results after 1 year of follow-up suggests that GVC not only is a safe procedure in terms of neuropsychological functioning but in fact may actually improve certain neuropsychological domains, particularly VSM performance, in treatment refractory OCD patients.

ADHD and executive functioning deficits in OCD youths who hoard

Hoarding is common among youth with obsessive compulsive disorder (OCD), with up to 26% of OCD youth exhibiting hoarding symptoms. Recent evidence from adult hoarding and OCD cohorts suggests that hoarding symptoms are associated with executive functioning deficits similar to those observed in subjects with attention deficit hyperactivity disorder (ADHD). However, while hoarding behavior often onsets during childhood, there is little information about executive function deficits and ADHD in affected children and adolescents. The study sample included 431 youths (ages 6-17 years) diagnosed with OCD who participated in the OCD Collaborative Genetics Study and the OCD Collaborative Genetics Association Study and completed a series of clinician-administered and parent report assessments, including diagnostic interviews and measures of executive functioning (Behavior Rating Inventory of Executive Functioning; BRIEF) and hoarding severity (Hoarding Rating Scale-Interview; HRS-I). 113 youths (26%) had clinically significant levels of hoarding compulsions. Youths with and without hoarding differed significantly on most executive functioning subdomains and composite indices as measured by the parent-rated BRIEF. Groups did not differ in the frequency of full DSM-IV ADHD diagnoses; however, the hoarding group had significantly greater number of inattention and hyperactivity symptoms compared to the non-hoarding group. In multivariate models, we found that overall BRIEF scores were related to hoarding severity, adjusting for age, gender and ADHD symptoms. These findings suggest an association between hoarding and executive functioning deficits in youths with OCD, and assessing executive functioning may be important for investigating the etiology and treatment of children and adolescents with hoarding and OCD.

OCD behavior therapy before and after gamma ventral capsulotomy: Case report

We report the case of a patient requiring gamma ventral capsulotomy (GVC), a neurosurgical intervention to address severe refractory obsessive–compulsive disorder (OCD). GVC involves stereotactic lesions in the ventral anterior limb of the internal capsule and adjacent ventral striatum. This study details the course of an extinction-based behavioral therapy, namely exposure and response prevention (ERP). The patient experienced significant changes in motivation and ability to tolerate ERP post-surgery. Furthermore, he was better able to absorb and remember exposure sessions. GVC surgery may affect the neural mechanisms involved in the extinction learning process, the same process implicated in ERP treatment.

Polygenic risk score and heritability estimates reveals a genetic relationship between ASD and OCD.

Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9×10-7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data.

An investigation of doubt in obsessive–compulsive disorder

BACKGROUND Clinicians have long considered doubt to be a fundamental characteristic of obsessive-compulsive disorder (OCD). However, the clinical relevance of doubt in OCD has not been addressed. METHODS Participants included 1182 adults with OCD who had participated in family and genetic studies of OCD. We used a clinical measure of the severity of doubt, categorized as none, mild, moderate, severe, or extreme. We evaluated the relationship between doubt and OCD clinical features, Axis I disorders, personality and personality disorder dimensions, impairment, and treatment response. RESULTS The severity of doubt was inversely related to the age at onset of OCD symptoms. Doubt was strongly related to the number of checking symptoms and, to a lesser extent, to the numbers of contamination/cleaning and hoarding symptoms. Doubt also was related to the lifetime prevalence of recurrent major depression and generalized anxiety disorder; to the numbers of avoidant, dependent, and obsessive-compulsive personality disorder traits; and to neuroticism and introversion. Moreover, doubt was strongly associated with global impairment and poor response to cognitive behavioral treatment (CBT), even adjusting for OCD severity and other correlates of doubt. CONCLUSIONS Doubt is associated with important clinical features of OCD, including impairment and cognitive-behavioral treatment response.

Stop Signal Reaction Time Deficits in a Lifetime Obsessive-Compulsive Disorder Sample

OBJECTIVES Several studies have found impaired response inhibition, measured by a stop-signal task (SST), in individuals who are currently symptomatic for obsessive-compulsive disorder (OCD). The aim of this study was to assess stop-signal reaction time (SSRT) performance in individuals with a lifetime diagnosis of OCD, in comparison to a healthy control group. This is the first study that has examined OCD in participants along a continuum of OCD severity, including approximately half of whom had sub-syndromal symptoms at the time of assessment. METHODS OCD participants were recruited primarily from within the OCD clinic at a psychiatric hospital, as well as from the community. Healthy controls were recruited from the community. We used the stop signal task to examine the difference between 21 OCD participants (mean age, 42.95 years) and 40 healthy controls (mean age, 35.13 years). We also investigated the relationship between SST and measures of OCD, depression, and anxiety severity. RESULTS OCD participants were significantly slower than healthy controls with regard to mean SSRT. Contrary to our prediction, there was no correlation between SSRT and current levels of OCD, anxiety, and depression severity. CONCLUSIONS Results support prior studies showing impaired response inhibition in OCD, and extend the findings to a sample of patients with lifetime OCD who were not all currently above threshold for diagnosis. These findings indicate that response inhibition deficits may be a biomarker of OCD, regardless of current severity levels. (JINS, 2016, 22, 785-789).

Differential Contributions of Lateral Prefrontal Cortex Regions to Visual Memory Processes

The prefrontal cortex (PFC) is the seat of higher level control operations, with recognition and working memory processes critical to those operations. While not strictly organized by the principle of localization, certain functions are clearly more associated with one region than another within PFC dynamic systems. We set out to test the hypothesis that active visual memory comparison (making judgments of novelty) was most associated with the ventrolateral prefrontal cortex (VLPFC), while the monitoring and manipulation of visual information was most associated with the mid-dorsolateral prefrontal cortex (mid-DLPFC). The current study used magnetic resonance volumetry to define the VLPFC and mid-DLPFC as regions of interest (ROIs), and analyzed those in relation to types of visual memory processes. We observed a functional dissociation of working memory within the PFC corresponding to comparison versus monitoring processes. One of the blocks of the monitoring and manipulation task showed a significant positive relationship with left, right, and total mid-DLPFC volume, with no significant relationship to the VLPFC. Performance on a memory comparison task bore a significant positive relationship with right and total VLPFC volume, and no relationship with the mid-DLPFC.