Alterations of default mode and cingulo-opercular salience network and frontostriatal circuit: A candidate endophenotype of obsessive-compulsive disorder.

Background It is gradually becoming clear that obsessive-compulsive disorder (OCD) patients have aberrant resting-state large-scale intrinsic networks of cingulo-opercular salience (SN), default mode (DMN), and front-parietal network (FPN). However, it remains unknown whether unaffected first-degree relatives of OCD patients have these alterations as a vulnerability marker to the disorder. Methods We performed resting-state functional magnetic resonance imaging (rsfMRI) scans of 47 medication-free OCD patients, 21 unaffected healthy first-degree relatives of OCD patients, and 62 healthy control (HC) participants. We explored differences between the three groups in the functional connectivity from SN (seeds: anterior-insula (AI) and dorsal anterior cingulate cortex (dACC)), DMN (seeds: medial prefrontal cortex (MPFC) and posterior parietal cortex (PCC)), and FPN (seeds: dorsolateral prefrontal cortex (DLPFC)). Results Compared to HC, both OCD patients and first-degree relatives showed significantly greater functional connectivity between AI and PCC and between DLPFC and the thalamus. Compared to first-degree relatives and HC, OCD patients showed reduced functional connectivity between PCC and DLPFC, and this altered functional connectivity was negatively correlated with anxiety and depressive symptom within OCD group. Conclusions OCD patients and unaffected first-degree relatives of OCD patients showed overlapping alterations in resting state functional connectivity between the regions of SN and DMN and between DLPFC and the thalamus. Our results suggested that alterations between large-scale intrinsic networks and within the dorsal cognitive cortico-striato-thalamo-cortical (CSTC) circuit could represent endophenotype markers of OCD.

Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.

Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.

Serotonin transporter gene polymorphism implicates reduced orbito-frontal cortex in obsessive-compulsive disorder.

Although a number of magnetic resonance imaging (MRI) and genetic studies have been performed on obsessive-compulsive disorder (OCD), only limited studies in which genetic and neuroanatomical variables are evaluated concurrently have been performed. Therefore, the aim of our present study is (to understand) better understanding how genetic variation in the promoter region of the 5-HTT gene (5-HTTLPR) is associated with key brain structures in OCD, orbito-frontal cortex (OFC), thalamus and anterior cingulate. 5-HTT genotypes (SS, SL, LL) were determined for 40 patients with OCD and the same number of healthy controls. MRI-derived volumes of the OFC, thalamus, and anterior cingulate were determined by reliable tracing techniques. Volumetric measurements were made with T1-weighted coronal MRI images, with 1.5-mm-thick slices, at 1.5T, and were done blindly. In comparison with controls, OCD patients demonstrated volumes reduction in OFC, increased volumes of thalamus and total white matter volumes, but no difference in total brain volume, total gray matter volumes and anterior cingulate volumes. No significant difference was observed in allelic frequencies between the patients and controls. The stronger effects of 5-HTT polymorphism on brain morphology in OCD than those in controls were determined in the both OFC and thalamus. On the other hand, for the OCD patients, ANCOVA revealed a significant main effect of genotype for both the OFC and thalamus and a significant genotype-by-side interaction for the OFC, demonstrating that the short variants had a smaller right OFC than the long variants. In conclusion, we found a significant genotype-diagnosis interaction effects on key brain structures, with a stronger effects of 5-HTT polymorphism in OFC and thalamus of OCD patients, whereas no morphological changes related to the polymorphism were found in normal individuals.

The serotonin transporter availability in untreated early-onset and late-onset patients with obsessive-compulsive disorder.

The pathogenetic role of central serotonin transporters (SERT) in obsessive-compulsive disorder (OCD) has been investigated in vivo by positron emission tomography (PET) or single-photon emission computed tomography (SPECT) studies with inconsistent results. This might reflect methodological differences but possibly also the pathophysiological heterogeneity of the disorder, i.e. the age at onset of OCD. The aim of our study was to compare SERT availability in patients with OCD to healthy controls (HC) taking into account the onset type, other factors and covariates (e.g. SERT genotype, age, depression level, gender). We studied 19 drug-naive OCD patients (36±13 yr, eight females) with early onset (EO-OCD, n=6) or with late onset (LO-OCD, n=13), and 21 HC (38±8 yr, nine females) with PET and the SERT-selective radiotracer [11C]DASB. Statistical models indicated that a variety of covariates and their interaction influenced SERT availability measured by distribution volume ratios (DVR). These models revealed significant effects of onset type on DVR with lower values in LO-OCD (starting at age 18 yr) compared to EO-OCD and HC in limbic (e.g. the amygdala), paralimbic brain areas (the anterior cingulate cortex), the nucleus accumbens and striatal regions, as well as borderline significance in the thalamus and the hypothalamus. The putamen, nucleus accumbens and hypothalamus were found with significant interaction between two SERT gene polymorphisms (SERT-LPR and VNTR). These findings suggest that late but not early onset of OCD is associated with abnormally low SERT availability. In part, functional polymorphisms of the SERT gene might determine the differences.

Dopamine transporter genotype influences N-acetyl-aspartate in the left putamen.

INTRODUCTION: Dopaminergic activity in the brain is modulated by the dopamine transporter (DAT). Several lines of evidence suggest that a variable number of tandem repeats (VNTR) polymorphism of the DAT1 gene (SLC6A3) influences its gene expression. The aim of this study was to determine whether the DAT1VNTR polymorphism alters the metabolic ratios NAA/Cho, NAA/Cr, Cho/Cr and Ins/Cr in the left dorsolateral prefrontal cortex, anterior cingulate cortex, and putamen in healthy subjects and psychiatric patients irrespective of clinical diagnosis. MATERIAL AND METHODS: Sixty-four individuals (30 patients with bipolar disorder, 18 patients with obsessive-compulsive disorder, and 16 healthy subjects) participated in the study. The 3'-UTR VNTR polymorphism of DAT1 (SLC6A3) gene was genotyped in all individuals. (1)H-MRS was performed in the above-mentioned brain regions. RESULTS: The individuals with the homozygous DAT1 10-repeat genotype presented significantly higher ratios of NAA/Cho and NAA/Cr in the left putamen compared to the group of individuals with the 9/9-repeat or 9/10-repeat genotype. CONCLUSION: The VNTR polymorphism of the DAT1-gene modulates NAA/Cho and NAA/Cr in the left putamen independent of psychiatric diagnosis status. These results suggest an association of DAT1 VNTR polymorphism, dopaminergic activity, and neuronal function in putamen.

Obsessive compulsive disorder among idiopathic focal dystonia patients: an epidemiological and family study.

BACKGROUND: A disturbed function of striato-thalamo-cortical circuitry is hypothesized to underlie idiopathic focal dystonia (IFD) and obsessive compulsive disorder (OCD), two severe and disabling neurologic and psychiatric disorders. Previous studies on small samples showed either higher obsessionality scores or higher frequency of OCD in dystonic patients than in normal control subjects. The aim of this study was to evaluate the frequency and familial loading of OCD in a population of patients with IFD. METHODS: We evaluated OCD diagnosis and family history in 76 patients affected by IFD. RESULTS: Of our subjects 19.7% satisfied DSM-IV criteria for OCD diagnosis and had a family morbidity risk for OCD of 13.8%, significantly higher than that found in the general population. CONCLUSIONS: Our results support the hypothesis of a common pathologic background for OCD and IFD, at least in a subgroup of IFD, indicating basal ganglia dysfunction.

[Invisible fathers: child development and family dynamics after heterologous insemination]. / Unsichtbare Väter: Kindliche Entwicklung und Familiendynamik nach heterologer Insemination (DI).

This study presents the long term outcome of the psychotherapy of a girl over seven years, which was born after donor insemination (DI) and aged eight became ill with a compulsive disorder. Aspects of child development, communication within the family and family dynamics related to this specific constellation are pointed out. This case-study presents one of the very few supplements to statistic data elaborated about assitsed-reproduction-families. Implications for individual therapy and therapeutic management of the family are discussed according to development of bonding and identity of the DI-child, father's role, dynamics of the couple and the incognito of the "invisible father".

Vasopressin-dependent flank marking in golden hamsters is suppressed by drugs used in the treatment of obsessive-compulsive disorder.

BACKGROUND: Alterations in arginine vasopressin regulation and secretion have been proposed as one possible biochemical abnormality in patients with obsessive-compulsive disorder. In golden hamsters, arginine vasopressin microinjections into the anterior hypothalamus trigger robust grooming and flank marking, a stereotyped scent marking behaviors. The intensity and repetition of the behaviors induced by arginine vasopressin is somewhat reminiscent of Obsessive Compulsive Disorder in humans. The present experiments were carried out to test whether pharmacological agents used to alleviate obsessive compulsive disorder could inhibit arginine vasopressin-induced flank marking and grooming. RESULTS: Male golden hamsters were treated daily for two weeks with either vehicle, fluoxetine, clomipramine, or desipramine (an ineffective drug), before being tested for arginine vasopressin-induced flank marking and grooming. Flank marking was significantly inhibited in animals treated with fluoxetine or clomipramine but unaffected by treatment with desipramine. Grooming behavior was not affected by any treatment. CONCLUSION: These data suggest that arginine vasopressin-induced flank marking may serve as an animal model for screening drugs used in the control of Obsessive Compulsive Disorder.

Obsessive compulsive symptoms in Gilles de la Tourette syndrome and obsessive compulsive disorder: differences by diagnosis and family history.

The distribution of obsessive compulsive symptoms was compared in 16 individuals with primary obsessive compulsive disorder (OCD) and 16 individuals with Gilles de la Tourette syndrome (GTS) and associated obsessive compulsive behaviors (OCB). The two groups showed significant differences in the distribution of OC symptomatology. Furthermore, those OCD probands who shared a similar symptom profile with GTS individuals all had a positive family history of OCD. All of the other OCD probands were isolated cases. Implications of this finding on the etiology and pathogenesis of the two disorders are discussed.

Obsessive-compulsive disorder in Huntington's disease.

Two patients with Huntington's disease (HD) and obsessive-compulsive disorder (OCD) are reported. The OCD was manifested by repetitive, stereotyped, complex, egodystonic behaviors that were disabling. These cases and other neurological syndromes with OCD (Gilles de la Tourette syndrome, neuroacanthocytosis, postencephalitic parkinsonism, caudate infarction, carbon monoxide poisoning, manganese intoxication, anoxia, progressive supranuclear palsy, Sydenham's chorea, and frontal lobe lesions) indicate that the frontal lobe, caudate nucleus, and globus pallidus are members of a complex circuit that plays a key role in mediating the symptoms of OCD. Evidence of excitatory subcortical output to cortex is shared by many neurological disorders manifesting OCD.