Caitlin Ravichandran

Functional connectivity magnetic resonance imaging classification of autism

Group differences in resting state functional magnetic resonance imaging connectivity between individuals with autism and typically developing controls have been widely replicated for a small number of discrete brain regions, yet the whole-brain distribution of connectivity abnormalities in autism is not well characterized. It is also unclear whether functional connectivity is sufficiently robust to be used as a diagnostic or prognostic metric in individual patients with autism. We obtained pairwise functional connectivity measurements from a lattice of 7266 regions of interest covering the entire grey matter (26.4 million connections) in a well-characterized set of 40 male adolescents and young adults with autism and 40 age-, sex- and IQ-matched typically developing subjects. A single resting state blood oxygen level-dependent scan of 8 min was used for the classification in each subject. A leave-one-out classifier successfully distinguished autism from control subjects with 83% sensitivity and 75% specificity for a total accuracy of 79% (P = 1.1 × 10(-7)). In subjects <20 years of age, the classifier performed at 89% accuracy (P = 5.4 × 10(-7)). In a replication dataset consisting of 21 individuals from six families with both affected and unaffected siblings, the classifier performed at 71% accuracy (91% accuracy for subjects <20 years of age). Classification scores in subjects with autism were significantly correlated with the Social Responsiveness Scale (P = 0.05), verbal IQ (P = 0.02) and the Autism Diagnostic Observation Schedule-Generics combined social and communication subscores (P = 0.05). An analysis of informative connections demonstrated that region of interest pairs with strongest correlation values were most abnormal in autism. Negatively correlated region of interest pairs showed higher correlation in autism (less anticorrelation), possibly representing weaker inhibitory connections, particularly for long connections (Euclidean distance >10 cm). Brain regions showing greatest differences included regions of the default mode network, superior parietal lobule, fusiform gyrus and anterior insula. Overall, classification accuracy was better for younger subjects, with differences between autism and control subjects diminishing after 19 years of age. Classification scores of unaffected siblings of individuals with autism were more similar to those of the control subjects than to those of the subjects with autism. These findings indicate feasibility of a functional connectivity magnetic resonance imaging diagnostic assay for autism.

Microstructural connectivity of the arcuate fasciculus in adolescents with high-functioning autism.

The arcuate fasciculus is a white matter fiber bundle of great importance in language. In this study, diffusion tensor imaging (DTI) was used to infer white matter integrity in the arcuate fasciculi of a group of subjects with high-functioning autism and a control group matched for age, handedness, IQ, and head size. The arcuate fasciculus for each subject was automatically extracted from the imaging data using a new volumetric DTI segmentation algorithm. The results showed a significant increase in mean diffusivity (MD) in the autism group, due mostly to an increase in the radial diffusivity (RD). A test of the lateralization of DTI measurements showed that both MD and fractional anisotropy (FA) were less lateralized in the autism group. These results suggest that white matter microstructure in the arcuate fasciculus is affected in autism and that the language specialization apparent in the left arcuate of healthy subjects is not as evident in autism, which may be related to poorer language functioning.

Atypical Diffusion Tensor Hemispheric Asymmetry in Autism

Background: Biological measurements that distinguish individuals with autism from typically developing individuals and those with other developmental and neuropsychiatric disorders must demonstrate very high performance to have clinical value as potential imaging biomarkers. We hypothesized that further study of white matter microstructure (WMM) in the superior temporal gyrus (STG) and temporal stem (TS), two brain regions in the temporal lobe containing circuitry central to language, emotion, and social cognition, would identify a useful combination of classification features and further understand autism neuropathology. Methods: WMM measurements from the STG and TS were examined from 30 high‐functioning males satisfying full criteria for idiopathic autism aged 7–28 years and 30 matched controls and a replication sample of 12 males with idiopathic autism and 7 matched controls who participated in a previous case–control diffusion tensor imaging (DTI) study. Language functioning, adaptive functioning, and psychotropic medication usage were also examined. Results: In the STG, we find reversed hemispheric asymmetry of two separable measures of directional diffusion coherence, tensor skewness, and fractional anisotropy. In autism, tensor skewness is greater on the right and fractional anisotropy is decreased on the left. We also find increased diffusion parallel to white matter fibers bilaterally. In the right not left TS, we find increased omnidirectional, parallel, and perpendicular diffusion. These six multivariate measurements possess very high ability to discriminate individuals with autism from individuals without autism with 94% sensitivity, 90% specificity, and 92% accuracy in our original and replication samples. We also report a near‐significant association between the classifier and a quantitative trait index of autism and significant correlations between two classifier components and measures of language, IQ, and adaptive functioning in autism.

A Primer in Longitudinal Data Analysis

Longitudinal data, comprising repeated measurements of the same individuals over time, arise frequently in cardiology and the biomedical sciences in general. For example, Frison and Pocock1 used repeated measurements of the liver enzyme creatine kinase in serum of cardiac patients to study changes in liver function over a 12-month study period. The main goal, indeed the raison d’etre , of a longitudinal study is characterization of changes in the response of interest over time. Ordinarily, changes in the response are also related to selected covariates. For example, Frison and Pocock1 compared changes in creatine kinase between patients randomized to active drug and placebo. The past 25 years have witnessed remarkable developments in statistical methods for the analysis of longitudinal data. Despite these important advances, researchers in the biomedical sciences have been somewhat slow to adopt these methods and often rely on statistical techniques that fail to adequately account for longitudinal study designs. The goal of the present report is to provide an overview of some recently developed methods for longitudinal analyses that are more appropriate, with a focus on 2 methods for continuous responses: the analysis of response profiles and linear mixed-effects models. The analysis of response profiles is better suited to settings with a relatively small number of repeated measurements, obtained on a common set of occasions, whereas linear mixed-effects models are suitable in more general settings. Before describing these methods, we review some of the defining features of longitudinal studies and highlight the main aspects of longitudinal data that complicate their analysis. ### Covariance Structure A common feature of repeated measurements on an individual is correlation; that is, knowledge of the value of the response on one occasion provides information about the likely value of the response on a future occasion. Another common feature of longitudinal data is heterogeneous …

Age‐related changes in brain energetics and phospholipid metabolism

Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus (31P) MRS. 31P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21–84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (−0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p = 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using 31P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non‐demented and psychiatrically stable older adults and specifically analyzed gray‐white matter differences in brain metabolism. Copyright

Two-year outcomes in first-episode psychotic depression: The McLean–Harvard first-episode project

OBJECTIVE Early assessment can guide accurate diagnosis, prognosis, and treatment-planning for patients with major mental illnesses. Longitudinal studies in psychotic depression from onset are rare, encouraging the present study. METHOD We followed 56 DSM-IV MDD patients with psychotic features prospectively and systematically to assess course and predictors of operationally-defined syndromal remission, syndromal recovery, symptomatic remission, functional recovery, and new episodes, and to evaluate diagnostic stability. RESULTS Among 49/56 cases followed for ≥2 years, 59% retained the initial diagnosis and most achieved syndromal remission (86%) and recovery (84%); 58% remitted symptomatically, and only 35% (17/49) recovered functionally. Syndromal recovery was earlier following subacute onset, lower initial depression scores, and lack of moodincongruent psychotic features. Within 2 years, 45% (22/49) experienced new episodes - earlier with younger onset and higher CGI scores. DSM diagnosis changed in 41%, to bipolar (33%), or schizoaffective disorders (12%), which followed early mania-like or schizophrenia-like features, respectively. CONCLUSIONS Within 2 years of first-hospitalizations, 41% of patients initially diagnosed with psychotic-depression met criteria for DSM-IV bipolar or schizoaffective disorders. Of the 59% retaining the initial diagnosis for 2 years, nearly half experienced new episodes, 42% remained symptomatic, and two-thirds failed to regain their own prior functional status.

31Phosphorus magnetic resonance spectroscopy study of tissue specific changes in high energy phosphates before and after sertraline treatment of geriatric depression

We investigated tissue specific differences in markers of energy metabolism, including high energy phosphate compounds (beta and total NTP, PCr) and pH, in older adults with depression compared with healthy controls, before and after a 12‐week treatment trial of sertraline.

Rapid mood-elevating effects of low field magnetic stimulation in depression.

BACKGROUND We previously reported rapid mood elevation following an experimental magnetic resonance imaging procedure in depressed patients with bipolar disorder (BPD). This prompted the design, construction, and testing of a portable electromagnetic device that reproduces only the rapidly oscillating (1 kHz, <1 V/m) electromagnetic field of the experimental procedure, called low field magnetic stimulation (LFMS). METHODS We used a randomized, double blind, sham controlled treatment protocol to study the effects of LFMS in a large group of stably medicated, depressed patients with either BPD (n = 41) or major depressive disorder (n = 22). Subjects received a single, 20-minute treatment. Change in mood was assessed immediately afterward using a visual analog scale (VAS), the 17-item Hamilton Depression Rating Scale (HDRS-17), and the Positive and Negative Affect Schedule scales. RESULTS Substantial improvement (>10% of baseline) in mood was observed following LFMS treatment relative to sham treatment for both diagnostic subgroups for our primary outcomes, the VAS and the HDRS-17. These differences were not statistically significant in primary analyses stratifying by diagnosis but were significant in secondary analyses combining data across the two diagnostic groups (p = .01 VAS, p = .02 HDRS-17). Rapid improvement in mood was also observed using the Positive and Negative Affect Schedule scales as secondary measures (positive affect scale p = .02 BPD, p = .002 combined group). A finite element method calculation indicates a broad penetration of the LFMS electric field throughout the cerebral cortex. CONCLUSIONS Low field magnetic stimulation may produce rapid changes in mood using a previously unexplored range of electromagnetic fields.

Cue reactivity in cannabis-dependent adolescents.

The authors measured event-related potentials with a craving manipulation to investigate the neural correlates of drug cue reactivity in 13 adolescents who are cannabis dependent (CD; ages 14-17). The P300 responses to marijuana (MJ) pictures (MJ-P300) and control pictures (C-P300) were assessed after handling neutral objects and again after handling MJ paraphernalia (MJP). Self-reported drug craving and heart rates also were measured. MJ-P300 were larger than C-P300 (p < .001), and both the MJ-P300 and craving increased significantly after handling MJP (p = .002 and p = .003, respectively), with no association between the magnitude of craving and MJ-P300. Heart rates were not affected by handling MJP. The results showed that adolescents who are CD have an attentional bias to MJ stimuli that increases after handling marijuana paraphernalia. Generally, the results are consistent with what has been reported for adult heavy chronic cannabis smokers, although there were some differences that require further investigation.

Coenzyme Q10 Effects on Creatine Kinase Activity and Mood in Geriatric Bipolar Depression

Introduction: Despite the prevalence, associated comorbidities, and functional consequences of bipolar depression (BPD), underlying disease mechanisms remain unclear. Published studies of individuals with bipolar disorder implicate abnormalities in cellular energy metabolism. This study tests the hypotheses that the forward rate constant (kfor) of creatine kinase (CK) is altered in older adults with BPD and that CoEnzyme Q10 (CoQ10), known to have properties that enhance mitochondrial function, increases kfor in elderly individuals with BPD treated with CoQ10 compared with untreated age- and sex-matched controls. Methods: Ten older adults (ages 55 and above) with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition [DSM IV]) bipolar disorder, current episode depressed and 8 older controls underwent two 4 Tesla 31Phosphorus magnetic resonance spectroscopy (31PMRS) scans 8 weeks apart using a magnetization transfer (MT) acquisition scheme to calculate kfor. The BPD group was treated with open-label CoEnzyme Q10 400 mg/d titrated up by 400 mg/d every 2 weeks to a maximum of 1200 mg/d. The Montgomery Asberg Depression Rating Scale (MADRS) was used to measure depression symptom severity. Baseline kfor and changes in kfor were compared between individuals with BPD and controls, not receiving CoQ. Clinical ratings were compared across time and associated with kfor changes using repeated measures linear regression. Results: The kfor of CK was nonsignificantly lower for BPD than healthy controls at baseline (BPD mean (standard deviation [SD]) = 0.19 (0.02), control mean (SD) = 0.20 (0.02), Wilcoxon rank sum exact P = .40). The kfor for both CoQ10-treated BPD and controls increased after 8 weeks (mean increase (SD) = 0.03 (0.04), Wilcoxon signed rank exact P = .01), with no significant difference in 8-week changes between groups (BPD mean change (SD) = 0.03 (0.03), control mean change (SD) = 0.03 (0.05), Wilcoxon rank sum exact P = .91). In an exploratory analysis, depression severity decreased with CoQ10 treatment in the group with BPD (F 3,7 = 4.87, P = .04) with significant reductions in the MADRS at weeks 2 (t 9 = −2.40, P = .04) and 4 (t 9 = −3.80, P = .004). Conclusions: This study employing the novel MRS technique of MT did not demonstrate significance between group differences in the kfor of CK but did observe a trend that would require confirmation in a larger study. An exploratory analysis suggested a reduction in depression symptom severity during treatment with high-dose CoEnzyme Q10 for older adults with BPD. Further studies exploring alterations of high-energy phosphate metabolites in geriatric BPD and efficacy studies of CoQ10 in a randomized controlled trial are both warranted.