Deficiency of long-chain acyl-CoA synthetase 4 leads to lipopolysaccharide-induced mortality in a mouse model of septic shock.

Long-chain acyl-CoA synthetase 4 (ACSL4) converts free highly unsaturated fatty acids (HUFAs) into their acyl-CoA esters and is important for HUFA utilization. HUFA-containing phospholipids produced via ACSL4-dependent reactions are involved in pathophysiological events such as inflammatory responses and ferroptosis as a source for lipid mediators and/or a target of oxidative stress, respectively. However, the in vivo role of ACSL4 in inflammatory responses is not fully understood. This study sought to define the effects of ACSL4 deficiency on lipopolysaccharide (LPS)-induced systemic inflammatory responses using global Acsl4 knockout (Acsl4 KO) mice. Intraperitoneal injection of LPS-induced more severe symptoms, including diarrhea, hypothermia, and higher mortality, in Acsl4 KO mice within 24 h compared with symptoms in wild-type (WT) mice. Intestinal permeability induced 3 h after LPS challenge was also enhanced in Acsl4 KO mice compared with that in WT mice. In addition, plasma levels of some eicosanoids in Acsl4 KO mice 6 h post-LPS injection were 2- to 9-fold higher than those in WT mice. The increased mortality observed in LPS-treated Acsl4 KO mice was significantly improved by treatment with the general cyclooxygenase inhibitor indomethacin with a partial reduction in the severity of illness index for hypothermia, diarrhea score, and intestinal permeability. These results suggest that ACSL4 deficiency enhances susceptibility to endotoxin at least partly through the overproduction of cyclooxygenase-derived eicosanoids.

Extracellular Vesicles Derived from 3T3-L1 Adipocytes Enhance Procoagulant Activity.

Obesity is associated with the risk of venous thromboembolism. Thrombi are constantly formed via the coagulation cascade and degraded by the fibrinolytic system, so they tend to form in obese individuals. Adipocytes are involved in thrombus formation in obesity, but it is not clear whether bioactive factors from adipocytes directly initiate or enhance coagulation and thrombosis. In this study, we confirmed that adipocyte-derived extracellular vesicles (ADEVs) enhance procoagulant activity in vitro. ADEVs prepared from the culture supernatant of mature 3T3-L1 adipocytes shortened plasma clotting times. Moreover, the effect of ADEVs on clotting time was weakened when using plasma lacking factors of the extrinsic pathway, but not the intrinsic pathway. ADEVs contain tissue factors and phosphatidylserine, which are involved in the extrinsic pathway, and blockade of these molecules diminished the effects of ADEVs on plasma clotting time. Additionally, the effect of ADEVs on plasma clotting time was further enhanced when cells were stimulated with the proinflammatory cytokine tumor necrosis factor-α. Thus, ADEVs may be a factor in thrombus formation in obesity.

Activation of PPARγ at an Early Stage of Differentiation Enhances Adipocyte Differentiation of MEFs Derived from Type II Diabetic TSOD Mice and Alters Lipid Droplet Morphology.

Type 2 diabetic Tsumura, Suzuki, obese, diabetes (TSOD) mice gradually gain weight as compared to corresponding Tsumura, Suzuki, non-obesity (TSNO) control mice, and develop insulin resistance. Although development of type 2 diabetes mellitus is associated with dysfunction of adipocytes, little is known about the properties of adipocytes from TSOD mice. Therefore, we attempted to remove intracorporeal factors and elucidate inherent properties of adipocytes of TSOD mice using adipocytes differentiated from mouse embryonic fibroblasts (MEFs) in vitro. Here, we show that MEFs of TSOD have low potency for differentiation into adipocytes. The percentage of Oil red O-stained cells and levels of adipogenic markers in cells differentiated from MEFs of TSOD are lower than those in cells differentiated from MEFs of TSNO. We further show that treatment with an agonist of peroxisome proliferator-activated receptor-γ (PPARγ) (rosiglitazone) at an early stage of differentiation increases the percentage of Oil red O-stained cells in TSOD-MEFs differentiated into adipocytes. Moreover, the lipid droplet size in those adipocytes is larger than that in the adipocytes differentiated from MEFs of TSNO. Although persistent treatment of MEFs of TSOD with rosiglitazone during differentiation increases the percentage of Oil red O-stained cells, the lipid droplet size in adipocytes treated as such does not reach the size of those treated in early stage only. Thus, activation of PPARγ by its agonist at an early stage of differentiation compensates for the low potency toward adipogenic differentiation of, and accelerates formation of enlarged lipid droplets in adipocytes derived from, MEFs of TSOD mice.

Development of simultaneous determination of dopamine 2, histamine 1, and muscarinic acetylcholine receptor occupancies by antipsychotics using liquid chromatography with tandem mass spectrometry.

Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an indicator of the efficacy and central side effects of antipsychotics because many of these drugs have binding affinities for various receptors, such as dopamine 2 (D2), histamine 1 (H1), and muscarinic acetylcholine (mACh) receptors. The purpose of this study was to develop a method for the simultaneous measurement of multiple receptor occupancies in the brain by the simultaneous quantification of unlabeled tracer levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rats were pre-administered with a vehicle, displacer, or olanzapine, and mixed solutions of raclopride, doxepin, and 3-quinuclidinyl benzilate (3-QNB) were administered (3, 10, and 30 µg/kg). The brain tissue and plasma tracer concentrations were quantified 45 min later using LC-MS/MS, and the binding potential was calculated. The highest binding potential was observed at 3 µg/kg raclopride, 10 µg/kg doxepin, and 30 µg/kg 3-QNB. Tracer-specific binding at these optimal tracer doses in the cerebral cortex was markedly reduced by pre-administration of displacers. D2, H1, and mACh receptor occupancy by olanzapine increased in a dose-dependent manner, reaching 70-95%, 19-43%, and 12-45%, respectively, at an olanzapine dose range of 3-10 mg/kg. These results suggest that simultaneous determination of in vivo D2, H1, and mACh receptor occupancy is possible using LC-MS/MS.

Investigating the Transepithelial Transport and Enzymatic Stability of Lactononadecapeptide (NIPPLTQTPVVVPPFLQPE), a 19-Amino Acid Casein-Derived Peptide in Caco-2 Cells.

Lactononadecapeptide (LNDP; NIPPLTQTPVVVPPFLQPE), a casein-derived peptide comprising 19 residues, is known for its capacity to enhance cognitive function. This study aimed to explore the transepithelial transport and stability of LNDP. Results showed that LNDP retained over 90% stability after 2 h of treatment with gastrointestinal enzymes. The stability of LNDP on Caco-2 cell monolayers ranged from 93.4% ± 0.9% to 101.1% ± 1.2% over a period of 15-60 min, with no significant differences at each time point. The permeability of LNDP across an artificial lipid membrane was very low with the effective permeability of 3.6 × 10-11 cm/s. The Caco-2 assay demonstrated that LNDP could traverse the intestinal epithelium, with an apparent permeability of 1.22 × 10-6 cm/s. Its transport was significantly inhibited to 67.9% ± 5.0% of the control by Gly-Pro, a competitor of peptide transporter 1 (PEPT1). Furthermore, PEPT1 knockdown using siRNA significantly inhibited LNDP transport by 77.6% ± 1.9% in Caco-2 cell monolayers. The LNDP uptake in PEPT1-expressing HEK293 cells was significantly higher (54.5% ± 14.6%) than that in mock cells. These findings suggest that PEPT1 plays a crucial role in LNDP transport, and LNDP exhibits good resistance to gastrointestinal enzymes.

Predicting muscarinic receptor occupancy in human bladder mucosa from urinary concentrations of antimuscarinic agents for overactive bladder.

To assess the pharmacologically relevant and selective muscarinic receptor occupancy in the bladder mucosa, we considered not only plasma drug concentrations but also urinary drug concentrations. The purpose of this study was to predict muscarinic receptor occupancy in the human bladder mucosa based on urinary concentrations in response to clinical dosages of antimuscarinic agents used to treat overactive bladder. The calculated mean plasma or serum unbound steady state concentrations were 0.06-11 nM in clinical dosages of five antimuscarinic agents. Urinary concentrations calculated from the mean plasma or serum and renal clearance ranged between 19 nM and 2 µM, which were >10-fold higher than the Ki values for bladder muscarinic receptors excluding propiverine. Bladder mucosal muscarinic receptor occupancy estimated from the urinary concentrations and the Ki values was >90 % at a steady state in clinical dosages of five antimuscarinic agents. The bladder muscarinic receptor occupancy was higher than that in the parotid gland calculated based on the mean plasma or serum unbound concentrations and Ki values for muscarinic receptors in the parotid gland. These results suggest that sufficient and selective muscarinic receptor occupancy by antimuscarinic agents, to exert pharmacological effects, in the bladder mucosa can be predicted using urinary concentrations.

Sexual obsessions in pediatric obsessive-compulsive disorder: clinical characteristics and treatment outcomes.

BACKGROUND: Sexual obsessions are common in adults with obsessive-compulsive disorder (OCD), cause great distress, and are sometimes misinterpreted as indicating risk to others. Little is known about the prevalence, clinical correlates, and prognosis of such symptoms in young people. METHODS: Three hundred and eighty-three patients referred to a specialist pediatric OCD clinic were administered a series of measures at intake and, for those treated at the clinic, again after treatment. Patients with and without sexual obsessions were compared on socio-demographic and clinical characteristics. Mixed model analyses of variance compared treatment outcomes in both groups. RESULTS: A quarter of patients had sexual obsessions at baseline (age range 8-17); they had slightly more severe OCD symptoms and were more depressed than those without sexual obsessions. Aggressive and religious obsessions, magical thinking, fear of saying certain things, repeating rituals, superstitious games, mental rituals, and the need to tell, ask, or confess were more frequent in participants with sexual obsessions. Crucially, no differences in treatment outcome were found between the groups. CONCLUSIONS: Sexual obsessions are common in pediatric OCD, even in very young children. Although they may be associated with particular clinical features, they do not interfere with treatment response. The occurrence of sexual obsessions in children should be recognized and these symptoms understood as ordinary, nonthreatening OCD symptoms, which pose no risk to others. They respond to the standard treatment strategies, so children and families should receive the usual message of optimism regarding the chances of recovery.

Children with very early onset obsessive-compulsive disorder: clinical features and treatment outcome.

BACKGROUND: There is emerging evidence that early onset obsessive-compulsive disorder (OCD) may be a phenomenologically distinct subtype of the disorder. Previous research has shown that individuals who report an early onset display greater severity and persistence of symptoms, and they may be less responsive to treatment. To date, this question has been investigated solely in adult samples. The present study represents the first investigation into the effect of age at onset of OCD on clinical characteristics and response to treatment in a paediatric sample. METHOD: A total of 365 young people referred to a specialist OCD clinic were included in the study. Clinical records were used to examine potential differences in key clinical characteristics between those who had a very early onset of the disorder (before 10 years) and those who had a late onset (10 years or later). Group differences in treatment responsiveness were also examined within a subgroup that received cognitive behaviour therapy (CBT) alone or CBT plus medication (n = 109). RESULTS: The very early onset group were characterised by a longer duration of illness, higher rates of comorbid tics, more frequent ordering and repeating compulsions and greater parent-reported psychosocial difficulties. There were no differences in treatment response between the groups, and when age at onset was examined as a continuous variable, it did not correlate with treatment response. CONCLUSIONS: Very early onset OCD may be associated with different symptoms and comorbidities compared with late onset OCD. However, these differences do not appear to impact on responsiveness to developmentally tailored CBT alone or in combination with medication. These findings further indicate the value in early detection and treatment of OCD in childhood.

Obsessions and compulsions in children with Asperger's syndrome or high-functioning autism: a case-control study.

OBJECTIVE: To compare the clinical characteristics and symptom severity of children with obsessive disorder (OCD) plus autism spectrum disorders (ASD) with those of children with OCD plus Tourette's syndrome (TS) or OCD alone. METHOD: Children with OCD and ASD (OCD/ASD) (n = 12, mean age = 14.33, range: 12-18) were compared to children with OCD and TS (OCD/TS) (n = 12, mean age = 13.92, range: 9-17) and children with OCD-alone (OCD) (n = 12, mean age = 12.92, range: 9-17) on measures of obsessive-compulsive (OC) symptom frequency, severity, interference and other clinical variables. RESULTS: Patients from the OCD/ASD group rated their OC symptoms as equally distressing, time consuming and contributing to a similar level of interference in functioning as patients in the OCD/TS and OCD groups. The types of symptoms were similar across groups but patients with OCD/TS reported greater frequency of ordering and arranging compulsions, and a trend towards more sexual obsessions. Patients with OCD/ASD reported more peer relationship problems compared with the other two groups. CONCLUSIONS: Children with ASD may experience a similar level of impairment from OC symptoms as children with TS plus OCD and children with OCD only. It is suggested that it is useful to establish both diagnoses given that obsessions and compulsions may respond to treatment, and their alleviation may improve functioning in children on the autism spectrum.

[Efficacy of intravitreal bevacizumab for age-related macular degeneration].

PURPOSE: To investigate the efficacy of intravitreal bevacizumab (IVB) for neovascular age-related macular degeneration (AMD). METHODS: We conducted a retrospective study of 29 eyes of 29 patients with AMD (19 eyes) and polypoidal choroidal vasculopathy (PCV; 10 eyes), who were followed up at least 1 year after the initial IVB (1.0 mg/0.04 ml). The eyes were classified according to the lesion type and size. Best-corrected visual acuity (BCVA) and central retinal thickness were examined before and 3 months, 6 months and 12 months after the IVB. RESULTS: The mean application times of IVB were 2.1 in 1 year. When classifying the eyes according to the lesion type, BCVA improved in 5 (26.3%) eyes with AMD and 1 (10.0%) eye with PCV by over 0.2 logarithmic minimum angle of resolution (logMAR) units. The BCVA decreased significantly 1 year after the IVB in eyes with PCV (p = 0.032). When classifying the eyes according to the lesion size, BCVA improved by over 0.2 logMAR units in the 4 (50.0%) eyes with a size of less than 1 disc diameter, 1 (10.0%) eye with the size of 1 to 3 disc diameters, and 1 (9.1%) eye with the size of over 4 disc diameters. The BCVA decreased significantly 1 year after the IVB in the eyes with the size of 1 to 3 disc diameters and with the size of over 4 disc diameters (p = 0.028, 0.013, respectively). The central retinal thickness did not change significantly at any time point compared to that before the IVB. CONCLUSIONS: These results suggest that IVB may be efficacious in preserving visual acuity in AMD eyes and in eyes with the size of less than 1 disc diameter.

Duration effect of obsessive-compulsive disorder on cognitive function: a functional MRI study.

BACKGROUND: The inconsistency of previous reports examining cognitive function in obsessive-compulsive disorder (OCD) suggests its heterogeneity. In this study, we examined the effect of illness duration on cognitive function in OCD. METHODS: We examined the cognitive function of 32 OCD patients and 16 healthy volunteers by neuropsychological tests and functional magnetic resonance imaging while they performed the Stroop and N-back tasks to assess attention and nonverbal memory. The patients were divided into two groups by illness duration: a short-term group (n=17, 5.5+/-3.1 years) and a long-term group (n=15, 20.3+/-6.1 years). Statistical analysis was performed to determine the differences between these two groups and the normal control group (n=16). RESULTS: The long-term group showed attention deficit and nonverbal memory dysfunction on the neuropsychological tests. In contrast, on functional magnetic resonance imaging, the short-term group showed weaker activation of the right caudate during the Stroop task and stronger activation of the right dorso-lateral prefrontal cortex during the N-back task than the long-term and normal control groups. CONCLUSIONS: The results suggested that abnormal brain activation occurs in the early phase of OCD and that the long-term persistence of OCD might involve a decline in cognitive function.

Long-chain acyl-CoA synthetase 4 participates in the formation of highly unsaturated fatty acid-containing phospholipids in murine macrophages.

Long-chain acyl-coenzyme A synthetases (ACSLs) are a family of enzymes that convert free long-chain fatty acids into their acyl-coenzyme A (CoA) forms. ACSL4, belonging to the ACSL family, shows a preferential use of arachidonic acid (AA) as its substrate and plays a role in the remodeling of AA-containing phospholipids by incorporating free AA. However, little is known about the roles of ACSL4 in inflammatory responses. Here, we assessed the roles of ACSL4 on the effector functions of bone marrow-derived macrophages (BMDMs) obtained from mice lacking ACSL4. Liquid chromatography-tandem mass spectrometry analysis revealed that various highly unsaturated fatty acid (HUFA)-derived fatty acyl-CoA species were markedly decreased in the BMDMs obtained from ACSL4-deficient mice compared with those in the BMDMs obtained from wild-type mice. BMDMs from ACSL4-deficient mice also showed a reduced incorporation of HUFA into phosphatidylcholines. The stimulation of BMDMs with lipopolysaccharide (LPS) elicited the release of prostaglandins (PGs), such as PGE2, PGD2 and PGF2α, and the production of these mediators was significantly enhanced by ACSL4 deficiency. In contrast, neither the LPS-induced release of cytokines, such as IL-6 and IL-10, nor the endocytosis of zymosan or dextran was affected by ACSL4 deficiency. These results suggest that ACSL4 has a crucial role in the maintenance of HUFA composition of certain phospholipid species and in the incorporation of free AA into the phospholipids in LPS-stimulated macrophages. ACSL4 dysfunction may facilitate inflammatory responses by an enhanced eicosanoid storm.

Functional MRI study of brain activation alterations in patients with obsessive-compulsive disorder after symptom improvement.

Dysfunction of the frontal-subcortical circuits has been the most common finding in the pathophysiology of obsessive-compulsive disorder (OCD), and recent neuropsychological studies have shown cognitive impairments in OCD. To clarify the pathophysiology of OCD without the confounding effects of medication, we investigated the alterations of brain function in OCD patients and changes after clinical improvement due solely to behavior therapy. The participants were 11 outpatients with OCD and 19 normal controls. The patients received 12 weeks of behavior therapy. We investigated the differences in the behavioral performance and functional magnetic resonance imaging results during the Stroop test in the patients and normal controls, and their changes after treatment in the patients. The patients showed less activation in the anterior cingulate gyrus and cerebellum than control subjects. Following significant improvement in OC symptoms, the cerebellum and parietal lobe showed increased activation, and the orbitofrontal cortex, middle frontal gyrus, and temporal regions showed decreased activation during the Stroop task, and performance of the task itself improved. Our findings suggest that dysfunction of the posterior brain regions, especially the cerebellum, is involved in the pathogenesis of OCD, and that normalization in function can occur with improvement of OC symptoms.

Brain activation of patients with obsessive-compulsive disorder during neuropsychological and symptom provocation tasks before and after symptom improvement: a functional magnetic resonance imaging study.

BACKGROUND: Functional neuroimaging studies have implicated hyperactivity of the frontal cortex in obsessive-compulsive disorder (OCD); however, relationships between abnormal brain activity, clinical improvement, and neuropsychological function have not been clarified in OCD. To clarify the pathophysiology of this disorder, regional changes in brain function were examined during administration of cognitive and symptom provocation tasks in patients with OCD before and after treatment. METHODS: Ten outpatients with OCD participated in the study. Functional magnetic resonance imaging (fMRI) was performed before and after treatment. Stroop and symptom provocation tasks were administered during fMRI. Each patient was randomly allocated to receive either pharmacotherapy with fluvoxamine 200 mg/day (n = 4) or behavior therapy (n = 6) for 12 weeks. RESULTS: After 12-week treatment, mean (+/- SD) total score on the Yale-Brown Obsessive-Compulsive Scale decreased from 29.00 +/- 3.59 to 14.60 +/- 9.22, representing symptomatic improvement from moderate to mild. After symptom improvement, symptom provocation-related activation in the orbitofrontal, dorsolateral-prefrontal, and anterior cingulate cortices decreased. Conversely, Stroop task-related activation in the parietal cortex and cerebellum increased. CONCLUSIONS: After improvement of OCD with either fluvoxamine or behavioral therapy, hyperactivation of the frontal lobe related to a symptom-provocative state decreases, and posterior brain activity related to action-monitoring function increases.

A functional MRI comparison of patients with obsessive-compulsive disorder and normal controls during a Chinese character Stroop task.

Recent functional neuroimaging and neuropsychological studies have suggested that abnormal activity in the anterior cingulate cortex (ACC) might cause an action-monitoring dysfunction in obsessive-compulsive disorder (OCD). To identify the relationship between brain dysfunction and cognitive dysfunction, we examined regional brain changes in OCD with functional magnetic resonance imaging (fMRI) during the performance of a cognitive task. Participants comprised 24 patients with OCD and 14 normal controls. First, we compared the cognitive function in the two groups as assessed by several neuropsychological tests. Then we used fMRI to explore brain correlates of their performance during the Chinese character version of the Stroop test, a task that is strongly related to action-monitoring function. The two groups did not differ on the neuropsychological tests. Both groups also showed similar activation pattern on fMRI. The patients, however, showed weaker activation than the normal controls in the ACC and the right caudate nucleus.

[Duration effect on neuropsychological function and treatment response of OCD].

Because of inconsistency among previous reports that examined neuropsychological function and treatment response of OCD patients, we here consider the heterogeneity of OCD; for example: symptom-based clusters, degree of insight, age of onset, and comorbid diagnoses. In this study, we examined neuropsychological function and the treatment response of OCD patients. Thirty-two OCD patients participated in this study. We examined their clinical symptoms by Y-BOCS, MOCI and other scales, and examined their cognitive function with several neuropsychological tests including: WAIS-R, Stroop test, WCST, WMS-R and R-OCFT. We then randomly assigned them to three treatment packages including: behavior therapy, pharmacotherapy by fluvoxamine, and controlled therapy. The patients were divided into two groups by duration of illness: short to middle range group (Group S, n=17, 5.5+/-3.1 years), and long range group (Group L, n=15, 20.3+/-6.1 years). The mean age of Group L was higher than that of Group S (Group S: 30.6+/-9.7 years old, Group L: 36.1+/-6.2 years old). There was no significant group difference in sex ratio or number of years of education. The mean age of onset of Group L was significantly lower than that of Group S (Group S; 25.5+/-10.2 years old, Group L; 15.3+/-7.1 years old). The total Y-BOCS mean score and MOCI score showed no group differences. These two groups showed similar clinical characteristics such as the severity of OC symptom, OC subtypes, and comorbid depression. Group S, however, demonstrated significantly more obsession with the need for correction. Group L had significantly higher levels of anxiety and compulsion. There were also no group differences in the mean HDRS or STAI scores. As a result, compared to Group S, Group L showed significant attention deficit in the Stroop test and the WMS-R though other neuropsychological dysfunctions such as intellectual level, executive function, verbal memory, and nonverbal memory were found in this group. Concerning treatment response, Group L showed little improvement by pharmacotherapy. Behavior therapy brought significant improvement to all patients of both groups. Long duration of the illness might cause attention deficit and a lowered pharmaceutical response in OCD patients.

Effects of behavior therapy on regional cerebral blood flow in obsessive-compulsive disorder.

Very few functional neuroimaging studies have been performed on patients with obsessive-compulsive disorder (OCD) undergoing behavior therapy, even though it is recognized to be an effective treatment for this disorder. We measured the regional cerebral blood flow (rCBF) using the Xenon inhalation method in 31 treatment-refractory patients with OCD and the same number of age-matched normal controls. We also studied changes in rCBF in 22 OCD patients who had demonstrated a significant improvement after the behavior therapy. The OCD patients showed a significant bilateral elevation in the rCBF in the basal ganglia compared with the normal controls. After successful treatment, a significant decrease was found in the rCBF in the right head of the caudate nucleus that tended to correlate with clinical improvement.

Are the symptoms of obsessive-compulsive disorder temporally stable in children/adolescents? A prospective naturalistic study.

Obsessive-compulsive disorder (OCD) symptoms tend to be temporally stable in adults, but much less is known about their stability in young people. We examined the temporal stability of OCD symptoms in a clinical pediatric sample. As part of a naturalistic longitudinal study, 74 children and adolescents with OCD were assessed with the Children's Yale-Brown Obsessive Compulsive Scale on two separate occasions ranging from 1 to 11 years apart (average 5 years). Analysis of variance and multiple regression models examined changes within and between symptoms and symptom dimensions. Changes within individual symptom categories were observed in approximately 15-45% of the cases, depending on the specific symptom. In most of those cases, symptoms went from present to absent at follow-up rather than from absent to present. Changes were no longer significant when individuals who were in remission at follow-up were excluded. Multiple regression analyses indicated that the strongest predictor of a particular symptom dimension at follow-up was the presence of the same dimension at baseline. Shifts from one dimension to another were rare. The content of OCD symptoms is relatively stable across time in young people. Most changes observed were attributable to clinical improvement/remission and occurred within rather than between symptom dimensions.

Predictors of treatment response to fluvoxamine in obsessive-compulsive disorder: an fMRI study.

Recent neuroimaging studies suggest that the pathophysiology of obsessive-compulsive disorder (OCD) may involve more widely distributed large-scale brain systems, including the parietal, occipital, and cerebellar areas, rather than the conventional orbitofronto-striatal model. We hypothesized that not only orbitofrontal cortex and caudate nucleus activities but also posterior brain regions might be associated with subsequent treatment response to serotonin reuptake inhibitors in OCD. The participants were 17 patients with OCD. Each patient was required to undergo fluvoxamine pharmacotherapy for 12 weeks. Before treatment, fMRI images of the subjects were obtained in the context of a symptom-provocation paradigm. The percentage changes in total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, from pre- to post-treatment, served as the index of treatment response. Statistical Parametric Mapping was used to identify brain loci where pre-treatment brain activation significantly correlated with the subsequent treatment response. Fifteen of 17 patients completed the 12-week treatment. During the symptom provocation task, patients showed brain activation in the left superior temporal gyrus (STG), left precuneus, left frontal cortices, right cerebellum, and right frontal cortices. We found that pre-treatment activation in the right cerebellum (Z-score=5.10, x,y,z=22,-84,-18) and the left STG (Z-score=4.95, x,y,z=-62,-22,0) was positively correlated with the improvement in the Y-BOCS score. Our results suggest that pre-treatment activation in the right cerebellum and in the left STG predict subsequent reduction in OCD symptom severity. There is every possibility that fMRI can be used as a tool to predict treatment response.