Evidence for neuroplastic compensation in the cerebral cortex of persons with depressive illness.

We yoked anatomical brain magnetic resonance imaging to a randomized, double-blind, placebo-controlled trial (RCT) of antidepressant medication for 10-week's duration in patients with dysthymia. The RCT study design mitigated ascertainment bias by randomizing patients to receive either duloxetine or placebo, and it supported true causal inferences about treatment effects on the brain by controlling treatment assignment experimentally. We acquired 121 anatomical scans: at baseline and end point in 41 patients and once in 39 healthy controls. At baseline, patients had diffusely thicker cortices than did healthy participants, and patients who had thicker cortices had proportionately less severe symptoms. During the trial, symptoms improved significantly more in medication-compared with placebo-treated patients; concurrently, thicknesses in medication-treated patients declined toward values in healthy controls, but they increased slightly, away from control values, in placebo-treated patients. Changes in symptom severity during the trial mediated the association of treatment assignment with the change in thickness, suggesting that the beneficial effects of medication on symptom severity were at least partially responsible for normalizing cortical thickness. Together our findings suggest that baseline cortical hypertrophy in medication-free patients likely represented a compensatory, neuroplastic response that attenuated symptom severity. Medication then reduced symptoms and lessened the need for compensation, thereby normalizing thickness. This is to the best of our knowledge the first study to report within an RCT a differential change in cortical morphology during medication treatment for depressive illness and the first to provide within an RCT in vivo evidence for the presence of neuroanatomical plasticity in humans.

Alterations in amygdala-prefrontal circuits in infants exposed to prenatal maternal depression.

Prenatal exposure to maternal depression is common and puts offspring at risk for developing a range of neuropsychiatric disorders. Despite its prevalence and adverse associations, neurobiological processes by which prenatal maternal depression (PMD) confers risk remain poorly understood. Maternal mood and fetal behavior were assessed between 34 and 37 gestational weeks. Using resting-state functional magnetic resonance imaging (fMRI) and diffusion MRI, we examined functional and structural connectivity within amygdala-prefrontal circuits in 64 infants (mean age=5.8±1.7 weeks) with (n=20) and without (n=44) in utero exposure to PMD. Resting fMRI and diffusion MRI both indicated atypical amygdala-prefrontal connectivity in PMD-exposed infants: Resting fMRI indicated increased inverse, or negative, functional connectivity between the amygdala and the dorsal prefrontal cortex (PFC), bilaterally, and diffusion MRI indicated decreased structural connectivity between the right amygdala and the right ventral PFC. Spectral dynamic causal modeling supported these findings suggesting altered amygdala-PFC effective (or directed) connectivity in PMD-exposed infants. Last, path analyses supported a mechanistic account relating PMD to a third-trimester fetal behavior: PMD alters amygdala-PFC connectivity, which in turn, is associated with an increase in fetal heart rate reactivity to in utero perturbation. These data suggest that the maturation and coordination of central and peripheral physiology are altered by prenatal exposure to maternal depression. To the best of our knowledge, this is the first study to directly associate infant MRI measures with a behavior-fetal heart rate response, and supports hypotheses that PMD-associated variations in the development of amygdala-PFC circuits are relevant for future neurobehavioral maturation.

Longitudinal magnetic resonance imaging reveals striatal hypertrophy in a rat model of long-term stimulant treatment.

Stimulant treatment is highly effective in mitigating symptoms associated with attention-deficit/hyperactivity disorder (ADHD), though the neurobiological underpinnings of this effect have not been established. Studies using anatomical magnetic resonance imaging (MRI) in children with ADHD have suggested that long-term stimulant treatment may improve symptoms of ADHD in part by stimulating striatal hypertrophy. This conclusion is limited, however, as these studies have either used cross-sectional sampling or did not assess the impact of treatment length on their dependent measures. We therefore used longitudinal anatomical MRI in a vehicle-controlled study design to confirm causality regarding stimulant effects on striatal morphology in a rodent model of clinically relevant long-term stimulant treatment. Sprague Dawley rats were orally administered either lisdexamfetamine (LDX, 'Vyvanse') or vehicle (N=12 per group) from postnatal day 25 (PD25, young juvenile) until PD95 (young adult), and imaged one day before and one day after the 70-day course of treatment. Our LDX dosing regimen yielded blood levels of dextroamphetamine comparable to those documented in patients. Longitudinal analysis of striatal volume revealed significant hypertrophy in LDX-treated animals when compared to vehicle-treated controls, with a significant treatment by time point interaction. These findings confirm a causal link between long-term stimulant treatment and striatal hypertrophy, and support utility of longitudinal MRI in rodents as a translational approach for bridging preclinical and clinical research. Having demonstrated comparable morphological effects in both humans and rodents using the same imaging technology, future studies may now use this rodent model to identify the underlying cellular mechanisms and behavioral consequences of stimulant-induced striatal hypertrophy.

Compressed sensing MRI combined with SENSE in partial k-space.

Compressed sensing (CS), parallel imaging and partial Fourier (PF) acquisition are all effective methods to reduce k-space sampling and therefore accelerate MR acquisition. The combined use of these methods gives us more options to balance the needs for scan speed and image quality. We conducted simulations on full k-space data to demonstrate the potential use of combining CS-SENSE with PF acquisition in anatomical MRIs of the human brain. To test the accelerated acquisition of high-resolution T1-weighted images of brain, we modified a 3D FSPGR sequence on a GE 3T scanner to implement different undersampling schemes based on CS, including partial Fourier CS-SENSE. Partially sampled k-space data were acquired and then reconstructed to brain images. CS-SENSE combined with PF sampling is able to provide better reconstructed images than CS only, or than CS-SENSE without PF for the same total acceleration. Combining PF sampling with CS-SENSE enables us to further accelerate image acquisition or improve image quality while holding the acceleration rate constant.

Selectively reduced posterior corpus callosum size in a population-based sample of young adults born with low birth weight.

BACKGROUND AND PURPOSE: Several studies suggest that VLBW is associated with a reduced CC size later in life. We aimed to clarify this in a prospective, controlled study of 19-year-olds, hypothesizing that those with LBWs had smaller subregions of CC than the age-matched controls, even after correcting for brain volume. MATERIALS AND METHODS: One hundred thirteen survivors of LBW (BW <2000 grams) without major handicaps and 100 controls underwent a 3T MR examination of the brain. The cross-sectional area of the CC (total callosal area, and the callosal subregions of the genu, truncus, and posterior third) was measured. Callosal areas were adjusted for head size. RESULTS: The posterior third subregion of the CC was significantly smaller in individuals born with a LBW compared with controls, even after adjusting for size of the forebrain. Individuals who were born with a LBW had a smaller CC (mean area, 553.4 mm(2)) than the controls (mean area, 584.1 mm(2)). Differences in total area, however, did not remain statistically significant after adjusting for FBV. CONCLUSIONS: The uncorrected callosal size in 19-years-olds born with LBW was smaller than that of normal controls. However, after adjusting for FBV, the group difference was restricted to the posterior third. The clinical impact of a smaller posterior part needs further investigation.

Challenges of using MR spectroscopy to detect neural progenitor cells in vivo.

A recent report of detection of neural progenitor cells (NPCs) in living human brain by using in vivo proton MR spectroscopy ((1)H-MR spectroscopy) has sparked great excitement in the field of biomedicine because of its potential influence and utility in clinical neuroscience research. On the other hand, the method used and the findings described in the report also caused heated debate and controversy. In this article, we will briefly detail the reasons for the debate and controversy from the point of view of the in vivo (1)H-MR spectroscopy methodology and will propose some technical strategies in both data acquisition and data processing to improve the feasibility of detecting NPCs in future studies by using in vivo (1)H-MR spectroscopy.

Using perturbation theory to compute the morphological similarity of diffusion tensors.

Computing the morphological similarity of diffusion tensors (DTs) at neighboring voxels within a DT image, or at corresponding locations across different DT images, is a fundamental and ubiquitous operation in the postprocessing of DT images. The morphological similarity of DTs typically has been computed using either the principal directions (PDs) of DTs (i.e., the direction along which water molecules diffuse preferentially) or their tensor elements. Although comparing PDs allows the similarity of one morphological feature of DTs to be visualized directly in eigenspace, this method takes into account only a single eigenvector, and it is therefore sensitive to the presence of noise in the images that can introduce error intothe estimation of that vector. Although comparing tensor elements, rather than PDs, is comparatively more robust to the effects of noise, the individual elements of a given tensor do not directly reflect the diffusion properties of water molecules. We propose a measure for computing the morphological similarity of DTs that uses both their eigenvalues and eigenvectors, and that also accounts for the noise levels present in DT images. Our measure presupposes that DTs in a homogeneous region within or across DT images are random perturbations of one another in the presence of noise. The similarity values that are computed using our method are smooth (in the sense that small changes in eigenvalues and eigenvectors cause only small changes in similarity), and they are symmetric when differences in eigenvalues and eigenvectors are also symmetric. In addition, our method does not presuppose that the corresponding eigenvectors across two DTs have been identified accurately, an assumption that is problematic in the presence of noise. Because we compute the similarity between DTs using their eigenspace components, our similarity measure relates directly to both the magnitude and the direction of the diffusion of water molecules. The favorable performance characteristics of our measure offer the prospect of substantially improving additional postprocessing operations that are commonly performed on DTI datasets, such as image segmentation, fiber tracking, noise filtering, and spatial normalization.

Constrained least absolute deviation neural networks.

It is well known that least absolute deviation (LAD) criterion or L(1)-norm used for estimation of parameters is characterized by robustness, i.e., the estimated parameters are totally resistant (insensitive) to large changes in the sampled data. This is an extremely useful feature, especially, when the sampled data are known to be contaminated by occasionally occurring outliers or by spiky noise. In our previous works, we have proposed the least absolute deviation neural network (LADNN) to solve unconstrained LAD problems. The theoretical proofs and numerical simulations have shown that the LADNN is Lyapunov-stable and it can globally converge to the exact solution to a given unconstrained LAD problem. We have also demonstrated its excellent application value in time-delay estimation. More generally, a practical LAD application problem may contain some linear constraints, such as a set of equalities and/or inequalities, which is called constrained LAD problem, whereas the unconstrained LAD can be considered as a special form of the constrained LAD. In this paper, we present a new neural network called constrained least absolute deviation neural network (CLADNN) to solve general constrained LAD problems. Theoretical proofs and numerical simulations demonstrate that the proposed CLADNN is Lyapunov stable and globally converges to the exact solution to a given constrained LAD problem, independent of initial values. The numerical simulations have also illustrated that the proposed CLADNN can be used to robustly estimate parameters for nonlinear curve fitting, which is extensively used in signal and image processing.

A placebo-controlled trial of risperidone in Tourette syndrome.

OBJECTIVE: To evaluate the efficacy and safety of risperidone in children and adults with Tourette syndrome. METHODS: This was an 8-week, randomized, double-blind, placebo-controlled trial. The primary outcome measure was the Total Tic score of the Yale Global Tic Severity Scale (YGTSS). RESULTS: Thirty-four medication-free subjects (26 children and 8 adults) ranging in age from 6 to 62 years (mean = 19.7 +/- 17.0 years) participated. YGTSS Total Tic scores were similar at baseline (26.0 +/- 5.1 for risperidone vs 27.4 +/- 8.5 for placebo). After 8 weeks of treatment (mean daily dose of 2.5 +/- 0.85), the 16 subjects on risperidone showed a 32% reduction in tic severity from baseline, compared to a 7% reduction for placebo patients (n = 18) (F[2,64] = 6.07; p = 0.004). The 12 children randomized to risperidone showed a 36% reduction in tic symptoms compared to an 11% decrease in the 14 children on placebo (F[2,48] = 6.38; p = 0.004). Two children on risperidone showed acute social phobia, which resolved with dose reduction in one subject but resulted in medication discontinuation in the other. A mean increase in body weight of 2.8 kg was observed in the risperidone group compared to no change in placebo (F[2,64] = 10.68; p = 0.0001). No extrapyramidal symptoms and no clinically significant alterations in cardiac conduction times or laboratory measures were observed. CONCLUSION: Risperidone appears to be safe and effective for short-term treatment of tics in children or adults with Tourette syndrome. Longer-term studies are needed to evaluate the durability of efficacy and safety over time.

Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette's syndrome, Sydenham's chorea, and autoimmune disorders.

BACKGROUND: Some cases of Tourette's syndrome (TS) are hypothesized to be caused by autoantibodies that develop in response to a preceding group A beta hemolytic streptococcal infection. METHODS: To test this hypothesis, we looked for the presence ot total and IgG antibodies against neural, nuclear, cytoskeletal and streptococcal epitopes using indirect immunofluorescent assays and Western blot techniques in three patient groups: TS (n = 81), SC (n = 27), and a group of autoimmune disorders (n = 52) and in normal controls (n = 67). Subjects were ranked after titrations of autoantibodies from 0 to 227 according to their level of immunoreactivity. RESULTS: TS patients had a significantly higher mean rank for total antineural and antinuclear antibodies, as well as antistreptolysin O titers. However, among children and adolescents, only the total antinuclear antibodies were increased in TS patients compared to age matched controls. Compared to SC patients, TS patients had a significantly lower mean rank for total and IgG class antineural antibodies, significantly lower IgG class anticytoskeletal antibodies, and a significantly higher rank for total antinuclear antibodies. Compared to a mixed group of autoimmune disorders, the TS patients had a significantly lower mean rank for total and IgG class antineural antibodies, total and IgG class antinuclear antibodies, IgG class anticytoskeletal antibodies, and a significantly higher rank for antistreptococcal antibodies. CONCLUSIONS: TS patients had significantly higher levels of total antineural and antinuclear antibodies than did controls. Their relation to IgG class antineural and antinuclear antibodies, markers for prior streptococcal infection, and other clinical characteristics, especially chronological age, was equivocal.

Prospective, longitudinal study of tic, obsessive-compulsive, and attention-deficit/hyperactivity disorders in an epidemiological sample.

OBJECTIVE: Understanding the interrelatedness of tics, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD) has been complicated by studying only cross-sectional samples of clinically referred subjects. The authors report the cross-sectional and longitudinal associations of these disorders in an epidemiological sample of children followed prospectively into early adulthood. METHOD: Structured diagnostic interview information was acquired on 976 children, aged 1 to 10 years, who were randomly selected from families living in upstate New York in 1975. Reassessments were acquired in 776 of these subjects 8, 10, and 15 years later. Diagnostic prevalences were estimated at each time point. The associations among tics, OCD, and ADHD were assessed within and across time points, as were their associations with comorbid illnesses and demographic risk factors. RESULTS: In temporal cross-section, tics and ADHD symptoms were associated with OCD symptoms in late adolescence and early adulthood after demographic features and comorbid psychiatric symptoms were controlled. In prospective analyses, tics in childhood and early adolescence predicted an increase in OCD symptoms in late adolescence and early adulthood. ADHD symptoms in adolescence predicted more OCD symptoms in early adulthood, and OCD in adolescence predicted more ADHD symptoms in adulthood. The associations of tics with ADHD were unimpressive in temporal cross-section and were not significant in prospective analyses. Tics, OCD, and ADHD shared numerous complex associations with demographic and psychopathological risk factors. ADHD was associated with lower IQ and lower social status, whereas OCD was associated with higher IQ. CONCLUSIONS: Tics and OCD were significantly associated in this sample, as were OCD and ADHD. These findings are in general consistent with those from family studies, and they help to define the natural history, comorbid illnesses, and interrelatedness of these conditions.

Regional brain and ventricular volumes in Tourette syndrome.

BACKGROUND: The pathophysiology of Tourette syndrome (TS) is thought to involve disturbances in cortico-striato-thalamo-cortical circuitry. The morphological characteristics of the cortical and associated white matter portions of these circuits have not been previously examined in TS subjects. METHODS: High-resolution anatomical magnetic resonance images were acquired in 155 TS and 131 healthy children and adults. The cerebrums and ventricles were isolated and then parcellated into subregions using standard anatomical landmarks. RESULTS: For analyses that included both children and adults, TS subjects were found to have larger volumes in dorsal prefrontal regions, larger volumes in parieto-occipital regions, and smaller inferior occipital volumes. Significant inverse associations of cerebral volumes with age were seen in TS subjects that were not seen in healthy controls. Sex differences in the parieto-occipital regions of healthy subjects were diminished in the TS group. The age-related findings were most prominent in TS children, whereas the diminished sex differences were most prominent in TS adults. Group differences in regional ventricular volumes were less prominent than in the cerebrum. Regional cerebral volumes were significantly associated with the severity of tic symptoms in orbitofrontal, midtemporal, and parieto-occipital regions. CONCLUSIONS: Broadly distributed cortical systems are involved in the pathophysiology of TS. Developmental processes, sexual dimorphisms, and compensatory responses in these cortical regions may help to modulate the course and severity of tic symptoms.

Effects of image orientation on the comparability of pediatric brain volumes using three-dimensional MR data.

PURPOSE: The purpose of this study was to examine the comparability of morphometric measurements made on pediatric data sets collected at five scanner locations, each using variations on a 3D spoiled gradient-recalled echo (SPGR) pulse sequence. METHOD: Archived MR data from 60 typically developing children were collected and separated into seven groups based on the pulse sequence used. A highly automated image-processing procedure was used to segment the brain data into white tissue, gray tissue, and CSF compartments and into various neuroanatomic regions of interest. RESULTS: Volumetric comparisons between groups revealed differences in areas of the temporal and occipital lobes. These differences were observed when comparing data sets with different image orientations and appeared to be due to partial volume averaging (PVA) and susceptibility-induced geometric distortions. CONCLUSION: Our results indicate that slice selection and image resolution should be controlled in volumetric studies using aggregated data from multiple centers to minimize the effects of PVA and susceptibility-induced geometric distortions.

Mutual information analysis of the EEG in patients with Alzheimer's disease.

OBJECTIVE: Mutual information provides a measure of both the linear and nonlinear statistical dependencies between two time series. Cross-mutual information (CMI) is used to quantify the information transmitted from one time series to another, while auto mutual information (AMI) in a time series estimates how much on average the value of the time series can be predicted from values of the time series at preceding points. The aim of this study is to assess information transmission between different cortical areas in Alzheimer's disease (AD) patients by estimating the average CMI between EEG electrodes. METHODS: We recorded the EEG from 16 scale electrodes in 15 AD patients and 15 age-matched normal controls, and estimated the local, distant, and interhemispheric CMIs of the EEG in both groups. The rate of decrease (with increasing delay) of the AMI of the EEG was also measured to evaluate the complexity of the EEG in AD patients. RESULTS: The local CMI in AD subjects was lower than that in normal controls, especially over frontal and antero-temporal regions. A prominent decrease in information transmission between distant electrodes in the right hemisphere and between corresponding interhemispheric electrodes was detected in the AD patients. In addition, the AMIs throughout the cerebrums of the AD patients decreased significantly more slowly with delay than did the AMIs of normal controls. CONCLUSIONS: These results are consistent with previous findings that suggest the association of EEG abnormalities in AD patients with functional impairment of information transmission in long cortico-cortical connections.

The question of PANDAS in adults.

BACKGROUND: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are a well-defined cause of obsessive-compulsive disorder in children. However, they have not been described or fully investigated in adults newly diagnosed with obsessive-compulsive disorder. METHODS: We describe an adult with onset of obsessive-compulsive disorder at 25 years of age after a severe antibiotic-responsive pharyngitis. He was evaluated with multiple psychiatric rating scales for obsessive-compulsive disorder and Tourette's syndrome, as well as with serologic assays and radiologic studies. RESULTS: In all respects except age our patient fulfilled established criteria for PANDAS. Assays for antibodies to group A beta-hematolytic streptococci, serum D8,17 lymphocytes, antistriatal (neuronal) antibodies, and anticytoskeletal antibodies all supported the hypothesis that a poststreptococcal process was active. Magnetic resonance imaging was abnormal and is described. CONCLUSIONS: The findings suggest that this patient's illness is similar to PANDAS in presentation and that poststreptococcal disease may result in adult-onset obsessive-compulsive disorder.

Neonatal auditory activation detected by functional magnetic resonance imaging.

The objective of this study was to detect auditory cortical activation in non-sedated neonates employing functional magnetic resonance imaging (fMRI). Using echo-planar functional brain imaging, subjects were presented with a frequency-modulated pure tone; the BOLD signal response was mapped in 5 mm-thick slices running parallel to the superior temporal gyrus. Twenty healthy neonates (13 term, 7 preterm) at term and 4 adult control subjects. Blood oxygen level-dependent (BOLD) signal in response to auditory stimulus was detected in all 4 adults and in 14 of the 20 neonates. FMRI studies of adult subjects demonstrated increased signal in the superior temporal regions during auditory stimulation. In contrast, signal decreases were detected during auditory stimulation in 9 of 14 newborns with BOLD response. fMRI can be used to detect brain activation with auditory stimulation in human infants.

Automated measurement of latent morphological features in the human corpus callosum.

Our objective was to develop a novel factor-based analysis of the morphology of the corpus callosum and assess its applicability to the study of normal development, intelligence, and other subject characteristics. The contour of the corpus callosum was defined in the midsagittal planes of the MRI scans of 325 subjects, 6 to 88 years of age. The contours were coregistered, rescaled, and resampled to 50 points that were then entered into a principal components analysis with varimax rotation. The analysis yielded 8 factors for the contours of 138 healthy subjects. A second analysis of contours from 187 subjects in a patient group extracted 8 similar factors. Correlations of factor scores with conventional measures of callosum shape supported the construct validity of the assignment of morphological features to each of the factors. Correlations of factor scores with age, sex, handedness, ventricular volume, and IQ demonstrated the predictive validity of the factor structure and helped to define the neural correlates of these subject characteristics. We conclude that factor-based measures capture latent morphological features of the corpus callosum that are reliable and valid. Future studies will determine whether these novel measures are more closely related to neurobiologically important features of the corpus than are conventional measures of callosum size and shape.