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Biomedical subjects

Benjamin D Greenberg

Publications and source records attributed to Benjamin D Greenberg.

At least 19 recordsLinked to original sources
PubMed2006

Familiality of factor analysis-derived YBOCS dimensions in OCD-affected sibling pairs from the OCD Collaborative Genetics Study.

BACKGROUND: Identification of familial, more homogenous characteristics of obsessive-compulsive disorder (OCD) may help to define relevant subtypes and increase the power of genetic and neurobiological studies of OCD. While factor-analytic studies have found consistent, clinically meaningful OCD symptom dimensions, there have been only limited attempts to evaluate the familiality and potential genetic basis of such dimensions. METHODS: Four hundred eighteen sibling pairs with OCD were evaluated using the Structured Clinical Interview for DSM-IV and the Yale-Brown Obsessive Compulsive Scale (YBOCS) Symptom Checklist and Severity scales. RESULTS: After controlling for sex, age, and age of onset, robust sib-sib intraclass correlations were found for two of the four YBOCS factors: Factor IV (hoarding obsessions and compulsions (p = .001) and Factor I (aggressive, sexual, and religious obsessions, and checking compulsions; p = .002). Smaller, but still significant, familiality was found for Factor III (contamination/cleaning; p = .02) and Factor II (symmetry/ordering/arranging; p = .04). Limiting the sample to female subjects more than doubled the familiality estimates for Factor II (p = .003). Among potentially relevant comorbid conditions for genetic studies, bipolar I/II and major depressive disorder were strongly associated with Factor I (p < .001), whereas ADHD, alcohol dependence, and bulimia were associated with Factor II (p < .01). CONCLUSIONS: Factor-analyzed OCD symptom dimensions in sibling pairs with OCD are familial with some gender-dependence, exhibit relatively specific relationships to comorbid psychiatric disorders and thus may be useful as refined phenotypes for molecular genetic studies of OCD.

Comorbidity↗
PubMed2006

Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder.

Deep brain stimulation (DBS) of the anterior limb of the internal capsule has been shown to be beneficial in the short term for obsessive-compulsive disorder (OCD) patients who exhaust conventional therapies. Nuttin et al, who published the first DBS for OCD series, found promising results using a capsule target immediately rostral to the anterior commissure extending into adjacent ventral capsule/ventral striatum (VC/VS). Published long-term outcome data are limited to four patients. In this collaborative study, 10 adult OCD patients meeting stringent criteria for severity and treatment resistance had quadripolar stimulating leads implanted bilaterally in the VC/VS. DBS was activated openly 3 weeks later. Eight patients have been followed for at least 36 months. Group Yale-Brown Obsessive Compulsive Scale (YBOCS) scores decreased from 34.6+/-0.6 (mean+/-SEM) at baseline (severe) to 22.3+/-2.1 (moderate) at 36 months (p < 0.001). Four of eight patients had a > or =35% decrease in YBOCS severity at 36 months; in two patients, scores declined between 25 and 35%. Global Assessment of Functioning scores improved from 36.6+/-1.5 at baseline to 53.8+/-2.5 at 36 months (p < 0.001). Depression and anxiety also improved, as did self-care, independent living, and work, school, and social functioning. Surgical adverse effects included an asymptomatic hemorrhage, a single seizure, and a superficial infection. Psychiatric adverse effects included transient hypomanic symptoms, and worsened depression and OCD when DBS was interrupted by stimulator battery depletion. This open study found promising long-term effects of DBS in highly treatment-resistant OCD.

Adult↗
PubMed2006

Hoarding in obsessive-compulsive disorder: results from the OCD Collaborative Genetics Study.

Hoarding behavior occurs frequently in obsessive-compulsive disorder (OCD). Results from previous studies suggest that individuals with OCD who have hoarding symptoms are clinically different than non-hoarders and may represent a distinct clinical group. In the present study, we compared 235 hoarding to 389 non-hoarding participants, all of whom had OCD, collected in the course of the OCD Collaborative Genetics Study. We found that, compared to non-hoarding individuals, hoarders were more likely to have symmetry obsessions and repeating, counting, and ordering compulsions; poorer insight; more severe illness; difficulty initiating or completing tasks; and indecision. Hoarders had a greater prevalence of social phobia and generalized anxiety disorder. Hoarders also had a greater prevalence of obsessive-compulsive and dependent personality disorders. Five personality traits were independently associated with hoarding: miserliness, preoccupation with details, difficulty making decisions, odd behavior or appearance, and magical thinking. Hoarding and indecision were more prevalent in the relatives of hoarding than of non-hoarding probands. Hoarding in relatives was associated with indecision in probands, independently of proband hoarding status. The findings suggest that hoarding behavior may help differentiate a distinct clinical subgroup of people with OCD and may aggregate in some OCD families. Indecision may be a risk factor for hoarding in these families.

Adolescent↗
PubMed2006

The OCD collaborative genetics study: methods and sample description.

Results from twin and family studies suggest that obsessive-compulsive disorder (OCD) may be transmitted in families but, to date, genes for the disorder have not been identified. The OCD Collaborative Genetics Study (OCGS) is a six-site collaborative genetic linkage study of OCD. Specimens and blinded clinical data will be made available through the National Institute of Mental Health (NIMH) cell repository. In this initial report, we describe the methods of the study and present clinical characteristics of affected individuals for researchers interested in this valuable resource for genetic studies of OCD. The project clinically evaluated and collected blood specimens from 238 families containing 299 OCD-affected sibling pairs and their parents, and additional affected relative pairs, for a genome-wide linkage study. Of the 999 individuals interviewed to date, 624 were diagnosed with "definite" OCD. The mean age of subjects was 36 years (range 7-95). The majority of affected individuals (66%) were female. The mean age at onset of obsessive-compulsive symptoms was 9.5 years. Specific mood disorders, anxiety disorders, eating disorders, and skin picking were more prevalent in female cases, whereas tics, Tourette disorder, and alcohol dependence were more prevalent in male cases. Compared to "definite" cases of OCD, "probable" cases (n = 82) had, on average, later age at onset of obsessive-compulsive symptoms, lower severity score, and fewer numbers of different categories of obsessions and compulsions, and they were less likely to have received treatment for their symptoms.

Adolescent↗
PubMed2006

Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder.

A functional serotonin transporter promoter polymorphism, HTTLPR, alters the risk of disease as well as brain morphometry and function. Here, we show that HTTLPR is functionally triallelic. The L(G) allele, which is the L allele with a common G substitution, creates a functional AP2 transcription-factor binding site. Expression assays in 62 lymphoblastoid cell lines representing the six genotypes and in transfected raphe-derived cells showed codominant allele action and low, nearly equivalent expression for the S and L(G) alleles, accounting for more variation in HTT expression than previously recognized. The gain-of-function L(A)L(A) genotype was approximately twice as common in 169 whites with obsessive-compulsive disorder (OCD) than in 253 ethnically matched controls. We performed a replication study in 175 trios consisting of probands with OCD and their parents. The L(A) allele was twofold overtransmitted to the patients with OCD. The HTTLPR L(A)L(A) genotype exerts a moderate (1.8-fold) effect on risk of OCD, which crystallizes the evidence that the HTT gene has a role in OCD.

Adult↗
PubMed2006

A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder.

OBJECT: Deep brain stimulation (DBS) of the ventral [anterior internal] capsule/ventral striatum (VC/VS) is under investigation as an alternative to anterior capsulotomy for severe obsessive-compulsive disorder (OCD). In neuroimaging studies of patients with OCD, dysfunction in the orbitofrontal and anterior cingulate cortex, striatum, and thalamus has been identified; and modulation of activity in this circuit has been observed following successful nonsurgical treatment. The purpose of the current study was to test hypotheses regarding changes in regional cerebral blood flow (rCBF) during acute DBS at the VC/VS target in patients with OCD who were participating in a clinical DBS trial. METHODS: Six patients enrolled in a DBS trial for OCD underwent positron emission tomography to measure rCBF; the rCBF measured during acute DBS at high frequency was then compared with those measured during DBS at low frequency and off (control) conditions. On the basis of neuroanatomical knowledge about the VC/VS and neuroimaging data on OCD, the authors predicted that acute DBS at this target would result in modulation of activity within the implicated frontal-basal ganglia-thalamic circuit. Data were analyzed using statistical parametric mapping. In a comparison of acute high-frequency DBS with control conditions, the authors found significant activation of the orbitofrontal cortex, anterior cingulate cortex, striatum, globus pallidus, and thalamus. CONCLUSIONS: Acute DBS at the VC/VS target is associated with activation of the circuitry implicated in OCD. Further studies will be necessary to replicate these findings and to determine the neural effects associated with chronic VC/VS DBS. Moreover, additional data are needed to investigate whether pretreatment imaging profiles can be used to predict a patient's subsequent clinical response to chronic DBS.

Adult↗
PubMed2006

The brown longitudinal obsessive compulsive study: treatments received and patient impressions of improvement.

OBJECTIVE: The primary aim of this study was to assess the extent to which individuals with obsessive-compulsive disorder (OCD) received recommended doses of treatment and perceived a response to these treatments. METHOD: Participants were 293 adults with primary OCD (DSM-IV) who were enrolled in the Brown Longitudinal Obsessive Compulsive Study, a naturalistic, prospective study of course in OCD. Data were collected at intake interviews between June 2001 and October 2004. Patient impressions of response to treatments received were assessed using the Clinical Global Impressions-Improvement Scale-patient version. RESULTS: Of the 182 participants taking recommended doses of serotonin reuptake inhibitors (SRIs) at intake, 112 (62%) rated themselves as being very much or much improved. The remaining participants rated themselves as minimally improved, unchanged, or worse while taking recommended doses of SRIs. These participants (N = 70) reported receiving their current SRI for a mean (SD) of 2.7 (3.2) years. Twelve (29%) of the 42 participants receiving neuroleptic augmentation of SRIs reported a response. Thirty-eight percent of the sample received the recommended number of 13 sessions of cognitive-behavioral therapy (CBT) lifetime. Only 24% reported completing a continuous course of 13 weekly sessions. Eighteen (67%) of the 27 participants who received a course of CBT in the past year rated themselves as very much or much improved. CONCLUSIONS: In this large, naturalistic study of OCD, over one third of participants receiving recommended doses of SRIs did not perceive substantial long-term benefit from pharmaco-therapy. Relatively few participants received recommended doses of CBT. Clinical implications and future directions are discussed.

Adult↗
PubMed2006

Metabolic imaging of anterior capsular stimulation in refractory obsessive-compulsive disorder: a key role for the subgenual anterior cingulate and ventral striatum.

UNLABELLED: High-frequency anterior capsular stimulation is a new, promising, and reversible neuromodulatory treatment in the research stage for patients with refractory obsessive-compulsive disorder (OCD). The mechanism of action is unknown but hypothesized to be secondary to interruption of the corticothalamostriatocortical circuit. METHODS: (18)F-FDG PET was performed on 6 consecutive OCD patients preoperatively and after stimulation. The results were compared with those of 20 age- and sex-matched healthy volunteers by using both a standardized volume-of-interest-based approach for subcortical areas and statistical parametric mapping. Correlations were investigated with Yale-Brown Obsessive Compulsive Scale scores (Y-BOCS) and Hamilton Depression Rating Scale scores (HAM-D). RESULTS: Chronic anterior capsular electrostimulation resulted in a further decrease of prefrontal metabolic activity, especially in the subgenual anterior cingulate (P < 0.001). Correlation analysis demonstrated that decreases in Y-BOCS and HAM-D with anterior capsular electrostimulation were inversely related to the metabolic activity changes in the left ventral striatum, left amygdala, and left hippocampus (P < 0.01). Preoperative resting metabolic activity in the subgenual anterior cingulate was predictive of therapeutic response (P = 0.001). CONCLUSION: These observations provide evidence that the subgenual anterior cingulate and ventral striatum have a key role in the neuronal circuitry involved in the pathophysiology of OCD with associated major depression and in the neuromodulatory mechanism of anterior capsular stimulation.

Adult↗
PubMed2006

Vagus nerve stimulation and deep brain stimulation for treatment resistant depression.

Neurostimulation techniques are potentially useful options for severely depressed patients who have failed trial after trial of medication and psychotherapy. Cervical VNS therapy for chronic or recurrent depression which does not resolve with pharmacotherapy was recently approved by the FDA. DBS for severe intractable depression has been studied in two pilot studies with very few patients to date. Further investigations are currently underway in order to more fully evaluate both of these neurostimulation therapies, with the hope of substantially improving the treatment of refractory depression.

Deep Brain Stimulation↗
PubMed2005

Obsessive-compulsive disorder symptom dimensions show specific relationships to psychiatric comorbidity.

The goals of this study were to examine relationships among symptom categories in obsessive-compulsive disorder (OCD), to establish OCD symptom dimensions by factor- and cluster-analytic analyses, and to explore associations between OCD symptom dimensions and comorbid neuropsychiatric conditions. A total of 317 OCD participants underwent a systematic diagnostic interview using the Structured Clinical Interview for DSM-IV. OCD symptoms assessed by the Yale-Brown Obsessive-Compulsive Scale Symptom Checklist (N=169) and by the Thoughts and Behaviors Inventory (N=275) were subjected to factor and cluster analyses. An identical four-factor solution emerged in two different data sets from overlapping samples, in agreement with most smaller factor-analytic studies employing the YBOCS checklist alone. The cluster analysis confirmed the four-factor solution and provided additional information on the similarity among OCD symptom categories at five different levels. OCD symptom dimensions showed specific relationships to comorbid psychiatric disorders: Factor I (aggressive, sexual, religious and somatic obsessions, and checking compulsions) was broadly associated with comorbid anxiety disorders and depression; Factor II (obsessions of symmetry, and repeating, counting and ordering/arranging compulsions) with bipolar disorders and panic disorder/agoraphobia; and Factor III (contamination obsessions and cleaning compulsions) with eating disorders. Factors I and II were associated with early onset OCD. This study encourages the use of cluster analyses as a supplementary method to factor analyses to establish psychiatric symptom dimensions. The frequent co-occurrence of OCD with other psychiatric disorders and the relatively specific association patterns between OCD symptom dimensions and comorbid disorders support the importance of OCD subtyping for treatment, genetic, and other research studies of this heterogeneous disorder.

Anxiety Disorders↗
PubMed2004

Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients.

Repetitive transcranial magnetic stimulation (rTMS) is a recent putative treatment for affective disorders. Several studies have demonstrated antidepressant effects of rTMS in younger patients; we aimed to assess its effect in older outpatients with treatment-resistant major depression. Twenty-four outpatients (mean age=62 years, S.D.=12) with major depression were randomized for sham or real stimulation and received 10 daily rTMS sessions (20 Hz, 2-s trains, 28-s intertrain intervals, 100% of motor threshold) in addition to the antidepressant medication. For sham stimulation, the coil was tilted 90 degrees. Depression severity was assessed using the Hamilton Depression Rating Scale, the Beck Depression Inventory, items from the NIMH self-rated symptom scale, and a visual analog depression scale. Mini-Mental Status Examination performance, memory, and executive and attentional functions were measured to control for cognitive side effects. Depression ratings revealed significant antidepressant effects within 2 weeks in both sham and real stimulation groups; however, there were no between-group differences. Treatment with rTMS was safe; adverse events were rare and not more prevalent in either group, and cognitive assessment did not show any deterioration. We were unable to demonstrate any additional antidepressant effects of real stimulation in elderly patients with treatment-resistant major depression. Therapeutic effects of rTMS in this clinically challenging patient group remain to be demonstrated.

Aged↗
PubMed2004

What's in a "smile?" Intra-operative observations of contralateral smiles induced by deep brain stimulation.

OBJECTIVE: To describe smiling and euphoria induced by deep brain stimulation (DBS). BACKGROUND AND SIGNIFICANCE: The brain systems inducing emotional experiences and displays are not entirely known, but the ventral striatum including the nucleus accumbens has been posited to play a critical role in mediating emotions with positive valence. DBS has been successfully employed for the treatment of movement disorders, and most recently obsessive compulsive disorder (OCD). The purpose of this report is to describe the emotional changes associated with stimulation of the ventral striatum. METHODS: A single patient with intractable OCD had electrode arrays placed in the right and left anterior limbs of the internal capsule and region of the nucleus accumbens. Changes in facial movement during stimulation were quantified by video recording. Ten video segments, time locked to the onset of stimulation, were digitized and changes in pixel intensity that occurred over both sides of the lower face, on a frame by frame basis, following stimulation onset were computed. These summed changes in pixel intensity represented the dependent variable of "entropy" and directly corresponded to changes in light reflectance that occur during facial movement. RESULTS: During stimulation on both the right and left side, the patient consistently developed a half smile on the side of the face contralateral to the stimulating electrode, and also became euphoric. The effect ceased when DBS was discontinued. CONCLUSIONS: DBS in the region of the nucleus accumbens produced smile and euphoria suggesting that alterations in the ventral striatum may result in emotional experience and displays. We hypothesize the existence of a limbic-motor network responsible for such changes. This observation suggests that DBS may be useful as a therapy for mood disorders.

Adult↗
PubMed2003

Transcranial magnetic stimulation.

TMS is a powerful new tool with extremely interesting research and therapeutic potentials. Further understanding of the ways by which TMS changes neuronal function, especially as a function of its use parameters, will improve its ability to answer neuroscience questions as well as to treat diseases. Because of its noninvasiveness, it does not readily fit under the umbrella of neurosurgery. Nevertheless, it is important for neurosurgeons to be aware of TMS, because findings from TMS studies will have implications for neurosurgical approaches like DBS and VNS. Indeed, it is possible to think of using TMS as a potential noninvasive initial screening tool to identify whether perturbation of a circuit has short-term clinical effects. In the example of chronic refractory depression or OCD, which is generally a chronic illness, it might then follow that rather than having daily or weekly TMS for the rest of their lives, patients would have DBS electrodes implanted in the same circuit. Whatever road the future takes, TMS is an important new tool that will likely be of interest to neurosurgeons over the next 20 years and perhaps even longer.

Brain↗
PubMed2003

Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues.

Intractable OCD and depression cause tremendous suffering in those affected and in their families. The impaired ability to function of those affected imposes a heavy burden on society as a whole. Existing data suggest that lesion procedures offer benefit to a large proportion (ranging from about 35%-70%) of patients with intractable OCD and depression. The literature also suggests that although serious long-term adverse events have occurred, these are relatively infrequent overall. Methodologic limitations of the earlier reports on any of these procedures were described previously in this article. The major academic centers conducting this work have since been obtaining systematic prospective data using modern assessment tools. Nevertheless, even with improved methodologies, more recent studies confront some remaining issues that have been difficult to overcome fully. First, the number of patients who have received any one procedure has been relatively small, constraining statistical power. This limits the ability of researchers to enhance patient selection based on clinical characteristics. This is important, because patients with intractable OCD and depression referred for neurosurgery have high rates of comorbid Axis I diagnoses, personality disorders, and functional impairments, which may have value in predicting response. Other features, such as age of onset, chronicity, and symptom subtypes, may be likewise useful. Another key factor in response may be postoperative management, which has varied most over time but also across patients enrolled in trials. As noted previously, randomized controlled trials of neurosurgical treatment for intractable psychiatric illness have not been reported, although one has been proposed for gamma knife capsulotomy in intractable OCD [23]. The development of deep brain stimulation has also made sham-controlled studies possible and also allows within-patient designs to be considered. Bearing these problems in mind, the literature does provide important guidance on a number of key points, including approaches to referral, patient selection, and the need for long-term prospective follow-up and postoperative management. Nevertheless, important gaps in knowledge remain in all these areas. Research is expected to narrow these gaps in a number of ways, including patient selection, optimizing the procedures themselves, and understanding the mechanisms of therapeutic action. Neuroimaging studies will play a key role in achieving these aims (see the article by Rauch in this issue). So will cross-species translational research on the anatomy and physiology of the pathways implicated in the pathophysiology and response to treatment in these disorders. Future research in psychiatric neurosurgery must proceed cautiously. A recent editorial statement of the OCD-DBS Collaborative Group [26] recommends a minimum set of standards for any multidisciplinary teams contemplating work in this domain. The rationale for those standards is found throughout this issue and is especially developed in the article by Fins. The need for safe and effective therapeutic options for people suffering with these severe illnesses is just as clear. The experience over the last several decades provides grounds for careful optimism that refined lesion procedures or reversible deep brain stimulation may relieve suffering and improve the lives of people with these devastating disorders.

Brain↗