Neural dysfunction in ADHD with Reading Disability during a word rhyming Continuous Performance Task.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous, neurodevelopmental disorder which co-occurs often with Reading Disability (RD). ADHD with and without RD consistently have higher inattentive ratings compared with typically developing controls, with co-occurring ADHD and RD also demonstrating impaired phonological processing. Accordingly, inattention has been associated with greater phonological impairment, though the neural correlates of the association are poorly understood from a functional neuroimaging perspective. It was postulated that only the co-occurring subgroup would demonstrate hypoactivation of posterior, left hemispheric, reading-related areas and, to a lesser extent, alterations in right hemispheric, attention areas compared with controls. METHODS: A novel word rhyming Continuous Performance Task assesses functional activation differences in phonology- and attention-related areas between three groups: ten boys with ADHD and RD, fourteen boys with ADHD without RD, and fourteen typically developing controls. Subjects respond to words that rhyme with a target word as mono- and disyllabic, English words are visually presented over 90s blocks. RESULTS: Behavioral performance was not different between groups. Some hypoactivation of left hemispheric, reading-related areas was apparent in ADHD and RD, but not ADHD without RD, compared with controls. Right hemispheric, attention areas showed alterations in both ADHD subgroups relative to controls; however, the differences for each subgroup were dissimilar. CONCLUSIONS: The dorsal decoding subnetwork may not be grossly compromised in ADHD with Reading Disability. The role of cognitive impairments, including the level of inattention, on phonology requires clarification from a neuroimaging perspective.

Cognitive behavior therapy in treatment-naive children and adolescents with obsessive-compulsive disorder: an open trial.

This work aims is to evaluate the therapeutic efficacy of cognitive behavior therapy (CBT) in pediatric patients with obsessive-compulsive disorder (OCD) who had not previously been treated with either pharmacotherapy or psychotherapy and who remained medication-free during CBT. Sixteen OCD outpatients, 8-17 years of age, were treated in a 12-week open trial with manualized CBT. Target symptoms were rated at two-week intervals with the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the National Institute of Mental Health Global Obsessive-Compulsive Scale (NIMH Global), the Clinical Global Impression Scale (CGI), and the Hamilton Anxiety Rating Scale (Ham-A). Statistical analyses showed a significant benefit for treatment. Ten patients experienced at least a 50% reduction in symptoms on the CY-BOCS; seven were asymptomatic on the NIMH Global. These results build on previous reports that CBT may be effective in the acute treatment of pediatric OCD. Further, the results of this study suggest that CBT can be efficacious in alleviating OCD symptoms in the absence of pharmacotherapy. These results must be considered preliminary, given the small sample size and open administration of treatment.

Abnormalities of the corpus callosum in first episode, treatment naive schizophrenia.

BACKGROUND: Structural alterations in the association cortices as well as in the corpus callosum (CC) have been described in schizophrenia, and have been considered to reflect developmental abnormalities. Areas of primary and association cortices have been topographically mapped in the CC. OBJECTIVE: To investigate whether, in schizophrenia, there are alterations in CC subdivisions that connect association, but not primary, cortices, and also to see if the normative, developmentally mediated increase in CC size with age is absent in this disorder. METHODS: The midsagittal magnetic resonance imaging scans of 31 first episode, neuroleptic naive, schizophrenic patients, 12 non-schizophrenic, psychotic patients, and 31 healthy controls were compared. The total area of CC as well as that of anterior, middle and posterior genu, body, isthmus, and anterior, middle, and posterior splenii were measured. RESULTS: Patients with schizophrenia as a group had a smaller CC, anterior genu, anterior body, isthmus, and anterior splenium than normal controls. Furthermore, the age related increase in CC size seen in normal subjects was absent in the patients. CONCLUSIONS: The observed reductions in size in selected regions of CC suggest a reduction in axonal connections between the heteromodal association cortices, which typically involve small diameter fibres. Furthermore, the absence of an age related increase in CC size in patients with schizophrenia suggests a neurodevelopmental abnormality that may extend into adolescence and early adulthood.

Increased medial thalamic choline in pediatric obsessive-compulsive disorder as detected by quantitative in vivo spectroscopic imaging.

The thalamus has been implicated in the pathophysiology of obsessive-compulsive disorder. Using a multislice spectroscopic imaging sequence, we reported reductions in right and left medial thalamic N-acetylaspartate/cytosolic choline + creatine/phosphocreatine and N-acetylaspartate/cytosolic choline levels in 11 pediatric patients with obsessive-compulsive disorder, 8 to 15 years, versus 11 case-matched healthy controls. These changes may reflect a change in N-acetylaspartate, cytosolic choline, or creatine concentrations. Therefore, using a validated phantom replacement methodology, we obtained absolute measures (mmol/L) of N-acetylaspartate, a putative marker of neuronal viability, cytosolic choline, and creatine in these subjects. A significant increase in cytosolic choline was observed in right and left medial but not lateral thalami in patients with obsessive-compulsive disorder versus controls. N-acetylaspartate and creatine did not differ significantly between case-control pairs in the medial or lateral thalamus. These findings provide new evidence of cytosolic choline abnormalities in the thalamus in pediatric obsessive-compulsive disorder.

Case study: caudate glutamatergic changes with paroxetine persist after medication discontinuation in pediatric OCD.

Proton magnetic resonance spectroscopy (1H-MRS) was used to examine glutamatergic (Glx) abnormalities in the caudate nucleus in pediatric obsessive-compulsive disorder (OCD), associated with severity of illness and response to acute (12 weeks) treatment with paroxetine. In this report, OCD symptoms improved markedly in an 8-year-old girl treated for 14 months with the selective serotonin reuptake inhibitor paroxetine (titrated from 10 to 40 mg/day). Paroxetine dose was then decreased in 10-mg decrements and discontinued without symptom recurrence. Serial 1H-MRS examinations were acquired before and after 12 weeks of paroxetine treatment (40 mg/day) and 3 months after medication discontinuation. A striking decrease in caudate Glx was observed after 12 weeks of treatment which persisted after medication discontinuation. These data provide further support for a reversible glutamatergically mediated dysfunction of the caudate nucleus in OCD that may serve as a pathophysiological and treatment response marker.

Brain anatomy and chemistry may predict treatment response in paediatric obsessive--compulsive disorder.

Obsessive--compulsive disorder (OCD) is a severe, highly prevalent and often chronically disabling illness with frequent onset in childhood and adolescence. This underscores the importance of studying the illness during childhood near the onset of illness to minimize potential confounds of long-term illness duration and treatment intervention as well as to examine the developmental underpinnings of the illness. In this review, the authors focus on an integrated series of brain-imaging studies in paediatric OCD suggesting a reversible glutamatergically mediated thalamo-cortical--striatal dysfunction in OCD and their relevance for improved diagnosis and treatment of the condition. Developmental neurobiological models for OCD are presented and particular attention is devoted to evaluating neuroimaging studies designed to test these models and how they may help predict treatment response in paediatric OCD.

Thalamic volumes in patients with first-episode schizophrenia.

OBJECTIVE: The thalamus, a highly evolved sensory and motor gateway to the cortex, has been implicated in the pathophysiology of several illnesses, including schizophrenia. Several studies have suggested thalamic volume differences in patients with schizophrenia, although only a few studies have examined thalamic structure in new-onset patients. METHOD: The authors used magnetic resonance imaging to measure thalamic volumes in previously untreated patients with first-episode schizophrenia (N=16) relative to those of healthy comparison subjects (N=25). The age range of the patients and comparison subjects was 15 to 45 years of age. Thalamic volumes in the right and left hemispheres were segmented and analyzed, both separately and as total thalamic volume, by a rater blind to clinical data. The thalamus was further segmented into regions that roughly reflected individual thalamic nuclei. Analysis of covariance was used to control for intracranial volume. RESULTS: Right, left, and total thalamic volumes of the patients with schizophrenia were significantly smaller than those of the comparison subjects. Significantly smaller volumes were found in the left central medial subdivision of the patients as well as a smaller volume in the right central medial subdivision that approached significance. These regions primarily comprised the dorsomedial nucleus, a thalamic nucleus thought to be an important component of aberrant circuitry in schizophrenia. Significant volume differences were also seen in the left anterior, right anterior, and right posterior medial subdivisions. CONCLUSIONS: These findings suggest significant thalamic volumetric differences between patients with newly diagnosed schizophrenia and healthy comparison subjects. Future analysis of individual thalamic nuclei may reveal important, specific relationships between thalamic abnormalities and schizophrenia.

Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine.

OBJECTIVE: To measure in vivo neurochemical changes in the caudate nucleus in pediatric obsessive-compulsive disorder (OCD) before and after treatment. METHOD: Single-voxel proton magnetic resonance spectroscopic (1H-MRS) examinations of the left caudate were conducted in 11 psychotropic drug-naive children, aged 8 to 17 years, with OCD before and after 12 weeks of monotherapy with the selective serotonin reuptake inhibitor paroxetine (10-60 mg/day) and 11 healthy children aged 8 to 17 years. A different sample of 8 pediatric OCD patients and 8 healthy children had a 1H-MRS examination of occipital cortex. RESULTS: Caudate glutamatergic concentrations (Glx) were significantly greater in treatment-naive OCD patients than in controls but declined significantly after paroxetine treatment to levels comparable with those of controls. Decrease in caudate Glx was associated with decrease in OCD symptom severity. Occipital Glx did not differ between OCD patients and controls. CONCLUSIONS: These preliminary findings provide new evidence of Glx abnormalities in the caudate nucleus in pediatric OCD and suggest that paroxetine treatment may be mediated by a serotonergically modulated reduction in caudate Glx.

Thalamic volume in pediatric obsessive-compulsive disorder patients before and after cognitive behavioral therapy.

BACKGROUND: Neurobiologic abnormalities in the thalamus have been implicated in the pathophysiology of obsessive-compulsive disorder. We recently reported increased thalamic volume in treatment-naive pediatric obsessive-compulsive disorder patients versus case-matched healthy comparison subjects that decreased to levels comparable to control subjects after effective paroxetine therapy. To our knowledge, no prior study has measured neuroanatomic changes in the thalamus of obsessive-compulsive disorder patients near illness onset before and after cognitive behavioral therapy. METHODS: Volumetric magnetic resonance imaging studies were conducted in 11 psychotropic drug-naive 8-17-year-old children with obsessive-compulsive disorder before and after 12 weeks of effective cognitive behavioral therapy monotherapy (> or =30% reduction in obsessive-compulsive disorder symptom severity). RESULTS: No significant change in thalamic volume was observed in obsessive-compulsive disorder patients before and after cognitive behavioral therapy. CONCLUSIONS: Our findings suggest that reduction in thalamic volume after paroxetine therapy may be specific to paroxetine treatment and not the result of a general treatment response or spontaneous improvement. These results are preliminary in view of the small sample studied.

Decrease in thalamic volumes of pediatric patients with obsessive-compulsive disorder who are taking paroxetine.

BACKGROUND: Thalamic dysfunction has been implicated in obsessive-compulsive disorder (OCD). While OCD frequently has its onset during childhood, to our knowledge, no prior study has measured neuroanatomical changes in the thalamus of patients with OCD near the onset of illness, and before and after treatment. METHODS: Volumetric magnetic resonance imaging studies were conducted in 21 psychotropic drug-naive children, aged 8 to 17 years, with OCD and 21 case-matched healthy comparison subjects. Magnetic resonance imaging studies were also conducted in 10 of the 21 patients with OCD after 12 weeks of monotherapy with the selective serotonin reuptake inhibitor, paroxetine hydrochloride. RESULTS: Thalamic volumes were significantly greater in treatment-naive patients with OCD than in controls but declined significantly after paroxetine monotherapy to levels comparable with those of controls. Decrease in thalamic volume in patients with OCD was associated with reduction in OCD symptom severity. CONCLUSIONS: Our findings provide new evidence of thalamic abnormalities in pediatric OCD and further suggest that paroxetine treatment may be paralleled by a reduction in thalamic volume. These reductions may, however, not be specific to paroxetine treatment and could be due to a more general treatment response, and/or spontaneous improvement in symptoms. Our findings are preliminary given the small sample size and our inability to measure discrete thalamic nuclei.

Proton spectroscopic imaging of the thalamus in treatment-naive pediatric obsessive-compulsive disorder.

BACKGROUND: Neurobiological abnormalities in the thalamus, particularly the dorsomedial nucleus of the thalamus, are believed to be involved in the pathophysiology of obsessive-compulsive disorder. Although obsessive-compulsive disorder commonly arises in childhood and adolescence, no prior study has examined the thalamus in pediatric obsessive-compulsive disorder patients. METHODS: In this study, N-acetyl-aspartate, a putative marker of neuronal viability, creatine/phosphocreatine, and choline levels were measured in the lateral and medical subregions of the left and right thalami using a multislice proton magnetic resonance spectroscopic imaging sequence in 11 treatment-naive, nondepressed obsessive-compulsive disorder outpatients, 8-15 years old, and 11 case-matched control subjects. RESULTS: A significant reduction in N-acetyl-aspartate/choline and N-acetyl-aspartate/(creatine/phosphocreatine + choline) was observed in both the right and left medial thalami in obsessive-compulsive disorder patients compared with control subjects. The N-acetyl-aspartate/choline and N-acetyl-aspartate/(creatine/phosphocreatine + choline) levels did not differ significantly between case-control pairs in either the left or the right lateral thalamus. Reduction in N-acetyl-aspartate levels in the left medial thalamus was inversely correlated with increased obsessive-compulsive disorder symptom severity. CONCLUSIONS: These findings provide new evidence of localized functional neurochemical marker abnormalities in the thalamus in pediatric obsessive-compulsive disorder. Our results must be considered preliminary, however, given the small sample size.

Genetic and imaging strategies in obsessive-compulsive disorder: potential implications for treatment development.

In recent years, advances in brain research have resulted in a striking strategic shift in studies designed to develop new, effective treatments for neuropsychiatric disorders. This involves a multidisciplinary approach with recursive interactions among respective disciplines with the ultimate goal of contributing to treatment development. In this review we focus on treatment implications of brain imaging and molecular and pharmacogenetic studies in obsessive-compulsive disorder. Translational components of this research are addressed, including the potential for integrating advances in brain imaging and molecular and pharmacogenetic assessments as they may potentially relate to neurodiagnostic assessment and treatment development. Studies of putative susceptibility alleles in obsessive-compulsive disorder involving the serotonergic, glutamatergic, and dopaminergic systems may provide a focus for these divergent approaches. Taken together, neuroimaging and genetic methods may ultimately lead to a mechanistic understanding of the pathogenesis and maintenance of neuropsychiatric disorders such as obsessive-compulsive disorder that may, in turn, result in the development of new neurodiagnostic and treatment approaches.

Paroxetine open-label treatment of pediatric outpatients with obsessive-compulsive disorder.

OBJECTIVE: Paroxetine is a selective serotonin reuptake inhibitor with demonstrated efficacy in treating obsessive-compulsive disorder (OCD) in adults. This study evaluates the safety and effectiveness of paroxetine in pediatric OCD patients. METHOD: In a 12-week, open-label trial of paroxetine, 20 OCD outpatients, aged 8 to 17 years, were treated for OCD with daily doses ranging from 10 to 60 mg. Target symptoms were rated at regular intervals with the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the Children's Global Assessment Scale, the Clinical Global Impression Scale, the Hamilton Anxiety Rating Scale, and the Yale Global Tic Severity Scale. RESULTS: Paroxetine proved relatively safe in this brief trial with a small sample and appeared to be effective in patients with OCD; mean CY-BOCS scores decreased significantly (z = 3.49, p = .0005) from 30.6 +/- 3.5 to 21.6 +/- 6.8 on medication. The most common side effects (n > or = 2) were hyperactivity/behavioral activation, headache, insomnia, nausea, and anxiety. Paroxetine did not have to be discontinued in any of the patients because of side effects; the most serious side effects included hyperactivity/behavioral activation in 3 younger patients (< 10 years) necessitating dosage reduction but not discontinuation. CONCLUSIONS: Preliminary evidence suggests that short-term treatment of pediatric OCD outpatients with paroxetine may be relatively safe and effective.

Risperidone augmentation of serotonin reuptake inhibitor treatment of pediatric obsessive compulsive disorder.

In this case series, risperidone augmentation of treatment with a serotonin reuptake inhibitor (SRI) is described in four pediatric patients diagnosed with obsessive compulsive disorder (OCD). An improved treatment response was observed in all cases, albeit in different ways. All four of the patients had failed prior SRI monotherapy. Comorbid tics were observed in two cases and aggressive behavior or violent images were seen in three. Possible predictors of response to risperidone in patients with OCD and future research avenues are explored.

Neurobiology of childhood obsessive-compulsive disorder.

Despite the observation that obsessive-compulsive disorder (OCD) frequently has its onset during childhood or adolescence, most studies have examined OCD in adults. Because pediatric OCD patients are near illness onset with limited or no medication exposure, this population represents a unique window through which to view the neurobiology of OCD. In this article, the authors summarize data from existing studies of pediatric OCD and attempt to interpret the data within the context of a neurobiologic discourse based largely on research in adults. The authors review current neuroanatomic models of OCD and examine neuroimaging and neuropsychologic studies designed to test those models. In addition, the authors examine irregularities of neurotransmitter systems though to be involved in OCD.

Corpus callosal signal intensity in treatment-naive pediatric obsessive compulsive disorders.

1. Obsessive compulsive disorder (OCD) is increasingly recognized as a severe, highly prevalent and chronically disabling disorder, emerging during childhood in as many as 80% of cases. The authors previously found significant abnormalities in the region of the corpus callosum (CC) connecting ventral prefrontal cortex and striatum in pediatric OCD patients compared to controls that correlated significantly with OCD symptom severity. We speculated that this abnormality might reflect aberrant myelinization in OCD patients. 2. In order to better characterize the abnormality, the authors examined CC signal intensity (SI), believed to be a reliable index of myelinization of the CC. Lower numbers would indicate a greater concentration of white matter, while higher numbers indicate higher concentrations of gray matter. We compared the SI from midsagittal magnetic resonance images of 21 treatment-naive OCD patients, 7.2-17.7 years, and 21 case-matched healthy controls to examine regional CC signal intensity of the anterior, middle and posterior genu, body, isthmus, and the anterior, middle and the posterior splenii. 3. Mean total genu SI for the patient group (.993 + .006) was significantly less than the total genu SI of controls (.994 + .006) at F(1,37) = 4.73; p = .036. This abnormality in SI was localized to the CC region connecting ventral PFC and striatum, the anterior genu for the OCD group (.991 + .007) which was also less than control (.995 + .007) at F(1,37) = 5.47; p = .025., with no abnormality observed in middle or posterior genu regions. Genu SI was also inversely correlated with OCD symptom severity (r = -.55, p = .013) but not illness duration. Genu SI also correlated positively with genu area (r = .52, p = .020) in OCD patients but not controls. 4. Developmental abnormalities in genu size may arise from abnormalities in myelination in early onset OCD patients. The increased genu myelination observed in OCD patients may alter signal transduction and function of VPFC-striatal association circuits.

Neuropsychological study of frontal lobe function in psychotropic-naive children with obsessive-compulsive disorder.

OBJECTIVE: The authors' goal was to evaluate cognition in children with obsessive-compulsive disorder (OCD) early in their illness. METHOD: They administered neuropsychological tests to 21 pediatric patients with OCD and 21 healthy children matched for age, sex, socioeconomic status, and intelligence. The children with OCD were not depressed, and none had ever received psychotropic medication. The neuropsychological tests were used to assess the relationship between psychiatric symptoms and cognitive function. RESULTS: The children with OCD performed as well as the healthy children on the neuropsychological tests. Psychiatric symptoms and cognitive performance were not related. CONCLUSIONS: Nondepressed children with recently diagnosed OCD who had never received psychotropic medication demonstrated no cognitive impairment according to their performance on neuropsychological tests. The authors conclude that OCD symptoms may not interfere with cognitive abilities early in the illness.

Combination treatment with clomipramine and selective serotonin reuptake inhibitors for obsessive-compulsive disorder in children and adolescents.

Medication management of obsessive-compulsive disorder (OCD) has consisted of monotherapy with either clomipramine (CMI) or selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine, paroxetine, or sertraline. Frequently, OCD patients receiving monotherapy experience low treatment response rates and problematic side effects that may result in discontinuation or noncompliance. This open-label case series presents 7 patients (6 male, 1 female) ages 9 to 23 years with OCD who were effectively treated with combination of CMI plus an SSRI. Treatment effects persisted through 5 to 22 months of follow-up from onset of combination therapy. The drug combination was effective in the 2 patients with OCD and no mood/anxiety comorbidity. Side effects appeared in 5 of 7 patients; cardiovascular side effects were the most common adverse effects. Two patients had prolongation of QTc intervals and 2 developed tachycardia while taking CMI and SSRI combinations. Other risks might include serotonin syndrome, manic switch, insomnia, and possibly headaches, EPS, and sexual dysfunction. Recommendations are made to monitor electrocardiograms, CMI blood concentrations, and vital signs in all cases because SSRIs can increase the blood levels of CMI and/or its active metabolite, desmethylclomipramine (DCMI). CMI could also potentially increase SSRI absorption and/or protein binding. The use of CMI and SSRI combination therapy was found to be more effective compared with their monotherapy in all 7 cases.

Manic behaviors associated with fluoxetine in three 12- to 18-year-olds with obsessive-compulsive disorder.

In a sample of 40 youths (ages 11-17) with obsessive-compulsive disorder (OCD) and mood disorders who were treated with behavior therapy, 20 patients received serotonin reuptake inhibitors (SRIs) and 20 did not. In open-label clinical treatment, 30% of the patients (6/20) treated with SRIs developed manic or hypomanic symptoms (5/15 on fluoxetine, 1/1 on sertraline). Symptoms included impulsivity, grandiosity, pressured speech, and disinhibition and did not resemble akathisia or "behavioral activation." These behaviors emerged despite gradual dose elevation (2-5 mg/wk), conservative dosing (maximum 40 mg daily), and careful weekly outpatient monitoring of each patient. Fluoxetine-induced mania occurred at doses as low as 10 mg daily. It is unclear whether mania/hypomania would appear in OCD children without comorbid mood disorders or, alternatively, whether OCD is a stronger risk factor than mood disorder for manic switch in SRI-treated youths. Clinicians are advised to be aware of the risk and to be vigilant in monitoring manic and hypomanic behaviors when using SRIs to treat OCD in youth, even with low doses and gradual dose elevation.