Patricia Gruner

White Matter Development in Adolescence: Diffusion Tensor Imaging and Meta-Analytic Results

BACKGROUND In light of the evidence for brain white matter (WM) abnormalities in schizophrenia, study of normal WM maturation in adolescence may provide critical insights relevant to the neurodevelopment of the disorder. Voxel-wise diffusion tensor imaging (DTI) studies have consistently demonstrated increases in fractional anisotropy (FA), a putative measure of WM integrity, from childhood into adolescence. However, the WM tracts that show FA increases have been variable across studies. Here, we aimed to assess which WM tracts show the most pronounced changes across adolescence. METHODS DTI was performed in 78 healthy subjects aged 8-21 years, and voxel-wise analysis conducted using tract-based spatial statistics (TBSS). In addition, we performed the first meta-analysis of TBSS studies on WM development in adolescence. RESULTS In our sample, we observed bilateral increases in FA with age, which were most significant in the left superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and anterior thalamic radiation. These findings were confirmed by the meta-analysis, and FA increase in the bilateral SLF was the most consistent finding across studies. Moreover, in our sample, FA of the bilateral SLF showed a positive association with verbal working memory performance and partially mediated increases in verbal fluency as a function of increasing age. CONCLUSIONS These data highlight increasing connectivity in the SLF during adolescence. In light of evidence for compromised SLF integrity in high-risk and first-episode patients, these data suggest that abnormal maturation of the SLF during adolescence may be a key target in the neurodevelopment of schizophrenia.

White Matter Abnormalities in Pediatric Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a prevalent and often severely disabling illness with onset generally in childhood or adolescence. Although white matter deficits have been implicated in the neurobiology of OCD, few studies have been conducted in pediatric patients when the brain is still developing and have examined their functional correlates. In this study, 23 pediatric OCD patients and 23 healthy volunteers, between the ages of 9 and 17 years, matched for sex, age, handedness, and IQ, received a diffusion tensor imaging exam on a 3T GE system and a brief neuropsychological battery tapping executive functions. Patient symptom severity was assessed using the Childrens Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Patients with OCD exhibited significantly greater fractional anisotropy compared to matched controls in the left dorsal cingulum bundle, splenium of the corpus callosum, right corticospinal tract, and left inferior fronto-occipital fasciculus. There were no regions of significantly lower fractional anisotropy in patients compared to controls. Higher fractional anisotropy in the splenium was significantly correlated with greater obsession severity on the CY-BOCS in the subgroup of psychotropic drug-naïve patients. Among patients, there was a significant association between greater fractional anisotropy in the dorsal cingulum bundle and better performance on measures of response inhibition and cognitive control. The overall findings suggest a pattern of greater directional coherence of white matter tracts in OCD very early in the course of illness, which may serve a compensatory mechanism, at least for response inhibition functions typically subserved by the cingulum bundle.

Distinct Subcortical Volume Alterations in Pediatric and Adult OCD: A Worldwide Meta- and Mega-Analysis.

OBJECTIVE Structural brain imaging studies in obsessive-compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta- and mega-analyses of data from OCD sites worldwide. METHOD T1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta-analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. RESULTS The meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohens d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. CONCLUSIONS The results indicate different patterns of subcortical abnormalities in pediatric and adult OCD patients. The pallidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful.

Abnormal temporal lobe white matter as a biomarker for genetic risk of bipolar disorder.

BACKGROUND Brain white matter (WM) abnormalities have been hypothesized to play an important role in the neurobiology of bipolar disorder (BD). The nature of these abnormalities is not well-characterized, however, and it is unknown whether they occur after disease onset or represent potential markers of genetic risk. METHODS We examined WM integrity (assessed via fractional anisotropy [FA]) with diffusion tensor imaging in patients with BD (n=26), unaffected siblings of patients with BD (n=15), and healthy volunteers (n=27) to identify WM biomarkers of genetic risk. RESULTS The FA differed significantly (p<.05; corrected) among the three groups within the right temporal WM. Unaffected siblings had FA values that were intermediate to and significantly different from those of healthy volunteers and patients with BD (healthy control subjects>unaffected siblings>BD). Moreover, FA values in this region correlated negatively and significantly with trait impulsivity in unaffected siblings. Probabilistic tractography indicated that the regional abnormality lies along the inferior fronto-occipital fasciculus, a large intrahemispheric association pathway. CONCLUSIONS Our results suggest that lower WM integrity in the right temporal lobe might be a biomarker for genetic risk of BD. It is conceivable that the attenuated nature of these WM abnormalities present in unaffected siblings allows for some preservation of adaptive emotional regulation, whereas more pronounced alterations observed in patients is related to the marked emotional dysregulation characteristic of BD.

Abnormal cingulum bundle development in autism: A probabilistic tractography study

There is now considerable evidence that white matter abnormalities play a role in the neurobiology of autism. Little research has been directed, however, at understanding (a) typical white matter development in autism and how this relates to neurocognitive impairments observed in the disorder. In this study we used probabilistic tractography to identify the cingulum bundle in 21 adolescents and young adults with Autism Spectrum Disorder (ASD), and 21 age- and sex-matched healthy volunteers. We investigated group differences in the relationships between age and fractional anisotropy, a putative measure of white matter integrity, within the cingulum bundle. Moreover, in a preliminary investigation, we examined the relationship between cingulum fractional anisotropy and executive functioning using the Behavior Rating Inventory of Executive Function (BRIEF). The ASD participants demonstrated significantly lower fractional anisotropy within the cingulum bundle compared to the typically developing volunteers. There was a significant group-by-age interaction such that the ASD group did not show the typical age-associated increases in fractional anisotropy observed among healthy individuals. Moreover, lower fractional anisotropy within the cingulum bundle was associated with worse BRIEF behavioral regulation index scores in the ASD group. The current findings implicate a dysregulation in cingulum bundle white matter development occurring in late adolescence and early adulthood in ASD, and suggest that greater disturbances in this trajectory are associated with executive dysfunction in ASD.

Independent component analysis of resting state activity in pediatric obsessive-compulsive disorder.

Obsessive‐compulsive disorder (OCD) is an often severely disabling illness with onset generally in childhood or adolescence. Little is known, however, regarding the pattern of brain resting state activity in OCD early in the course of illness. We therefore examined differences in brain resting state activity in patients with pediatric OCD compared with healthy volunteers and their clinical correlates. Twenty‐three pediatric OCD patients and 23 healthy volunteers (age range 9–17), matched for sex, age, handedness, and IQ completed a resting state functional magnetic resonance imaging exam at 3T. Patients completed the Childrens Yale Brown Obsessive Scale. Data were decomposed into 36 functional networks using spatial group independent component analysis (ICA) and logistic regression was used to identify the components that yielded maximum group separation. Using ICA we identified three components that maximally separated the groups: a middle frontal/dorsal anterior cingulate network, an anterior/posterior cingulate network, and a visual network yielding an overall group classification of 76.1% (sensitivity = 78.3% and specificity = 73.9%). Independent component expression scores were significantly higher in patients compared with healthy volunteers in the middle frontal/dorsal anterior cingulate and the anterior/posterior cingulate networks, but lower in patients within the visual network. Higher expression scores in the anterior/posterior cingulate network correlated with greater severity of compulsions among patients. These findings implicate resting state fMRI abnormalities within the cingulate cortex and related control regions in the pathogenesis and phenomenology of OCD early in the course of the disorder and prior to extensive pharmacologic intervention. Hum Brain Mapp 35:5306–5315, 2014.

Resting state functional connectivity predicts neurofeedback response

Tailoring treatments to the specific needs and biology of individual patients—personalized medicine—requires delineation of reliable predictors of response. Unfortunately, these have been slow to emerge, especially in neuropsychiatric disorders. We have recently described a real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback protocol that can reduce contamination-related anxiety, a prominent symptom of many cases of obsessive-compulsive disorder (OCD). Individual response to this intervention is variable. Here we used patterns of brain functional connectivity, as measured by baseline resting-state fMRI (rs-fMRI), to predict improvements in contamination anxiety after neurofeedback training. Activity of a region of the orbitofrontal cortex (OFC) and anterior prefrontal cortex, Brodmann area (BA) 10, associated with contamination anxiety in each subject was measured in real time and presented as a neurofeedback signal, permitting subjects to learn to modulate this target brain region. We have previously reported both enhanced OFC/BA 10 control and improved anxiety in a group of subclinically anxious subjects after neurofeedback. Five individuals with contamination-related OCD who underwent the same protocol also showed improved clinical symptomatology. In both groups, these behavioral improvements were strongly correlated with baseline whole-brain connectivity in the OFC/BA 10, computed from rs-fMRI collected several days prior to neurofeedback training. These pilot data suggest that rs-fMRI can be used to identify individuals likely to benefit from rt-fMRI neurofeedback training to control contamination anxiety.

Arbitration between Action Strategies in Obsessive-Compulsive Disorder

Decision making in a complex world, characterized both by predictable regularities and by frequent departures from the norm, requires dynamic switching between rapid habit-like, automatic processes and slower, more flexible evaluative processes. These strategies, formalized as “model-free” and “model-based” reinforcement learning algorithms, respectively, can lead to divergent behavioral outcomes, requiring a mechanism to arbitrate between them in a context-appropriate manner. Recent data suggest that individuals with obsessive-compulsive disorder (OCD) rely excessively on inflexible habit-like decision making during reinforcement-driven learning. We propose that inflexible reliance on habit in OCD may reflect a functional weakness in the mechanism for context-appropriate dynamic arbitration between model-free and model-based decision making. Support for this hypothesis derives from emerging functional imaging findings. A deficit in arbitration in OCD may help reconcile evidence for excessive reliance on habit in rewarded learning tasks with an older literature suggesting inappropriate recruitment of circuitry associated with model-based decision making in unreinforced procedural learning. The hypothesized deficit and corresponding circuitry may be a particularly fruitful target for interventions, including cognitive remediation.

Cognitive inflexibility in Obsessive-Compulsive Disorder

Obsessive-Compulsive Disorder (OCD) is characterized by maladaptive patterns of repetitive, inflexible cognition and behavior that suggest a lack of cognitive flexibility. Consistent with this clinical observation, many neurocognitive studies suggest behavioral and neurobiological abnormalities in cognitive flexibility in individuals with OCD. Meta-analytic reviews support a pattern of cognitive inflexibility, with effect sizes generally in the medium range. Heterogeneity in assessments and the way underlying constructs have been operationalized point to the need for better standardization across studies, as well as more refined overarching models of cognitive flexibility and executive function (EF). Neuropsychological assessments of cognitive flexibility include measures of attentional set shifting, reversal and alternation, cued task-switching paradigms, cognitive control measures such as the Trail-Making and Stroop tasks, and several measures of motor inhibition. Differences in the cognitive constructs and neural substrates associated with these measures suggest that performance within these different domains should be examined separately. Additional factors, such as the number of consistent trials prior to a shift and whether a shift is explicitly signaled or must be inferred from a change in reward contingencies, may influence performance, and thus mask or accentuate deficits. Several studies have described abnormalities in neural activation in the absence of differences in behavioral performance, suggesting that our behavioral probes may not be adequately sensitive, but also offering important insights into potential compensatory processes. The fact that deficits of moderate effect size are seen across a broad range of classic neuropsychological tests in OCD presents a conceptual challenge, as clinical symptomatology suggests greater specificity. Traditional cognitive probes may not be sufficient to delineate specific domains of deficit in this and other neuropsychiatric disorders; a new generation of behavioral tasks that test more specific underlying constructs, supplemented by neuroimaging to provide insight into the underlying processes, may be needed.

Pituitary volume in first-episode schizophrenia

Pituitary volumes were measured in 55 first-episode schizophrenia patients at a baseline timepoint with 38 receiving a followup scan after antipsychotic treatment. Fifty-nine healthy volunteers had baseline scans with 34 receiving a followup scan. There were no baseline group differences in pituitary volumes or changes in volume following antipsychotic treatment.