Harry Rubin-Falcone

Omega-3 polyunsaturated fatty acid supplementation and white matter changes in major depression.

White matter abnormalities are implicated in major depressive disorder (MDD). As omega-3 polyunsaturated fatty acids (PUFAs) are low in MDD and affect myelination, we hypothesized that PUFA supplementation may alleviate depression through improving white matter integrity. Acutely depressed MDD patients (n = 16) and healthy volunteers (HV, n = 12) had 25-direction diffusion tensor imaging before and after 6 weeks of fish oil supplementation. Plasma phospholipid omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and omega-6 PUFA arachidonic acid (AA) levels were determined before and after supplementation using high-throughput extraction and gas chromatography and expressed as a percentage of total phospholipids (PUFA%). Fractional anisotropy (FA) was computed using a least-squares-fit diffusion tensor with non-linear optimization. Regression analyses were performed with changes in PUFA levels or Hamilton Depression Rating Scale scores as predictors, voxel-wise difference maps of FA as outcome, covariates age and sex, with family-wise correction for multiple comparisons. Increases in plasma phospholipid DHA% (but not EPA% or AA%) after fish oil predicted increases in FA in MDD but not HV, in a cluster including genu and body of the corpus callosum, and anterior corona radiata and cingulum (cluster-level p < 0.001, peak t-score = 8.10, p = 0.002). There was a trend for greater change in FA in MDD responders over nonresponders (t = -1.874, df = 13.56, p = 0.08). Decreased depression severity predicted increased FA in left corticospinal tract and superior longitudinal fasciculus (cluster-level p < 0.001, peak t-score = 5.04, p = 0.0001). Increased FA correlated with increased DHA% and decreased depression severity after fish oil supplementation suggests therapeutic effects of omega-3 PUFAs may be related to improvements in white matter integrity.

White matter correlates of impaired attention control in major depressive disorder and healthy volunteers

BACKGROUND Major depressive disorder (MDD) is associated with impaired attention control and alterations in frontal-subcortical connectivity. We hypothesized that attention control as assessed by Stroop task interference depends on white matter integrity in fronto-cingulate regions and assessed this relationship using diffusion tensor imaging (DTI) in MDD and healthy volunteers (HV). METHODS DTI images and Stroop task were acquired in 29 unmedicated MDD patients and 16 HVs, aged 18-65 years. The relationship between Stroop interference and fractional anisotropy (FA) was examined using region-of-interest (ROI) and tract-based spatial statistics (TBSS) analyses. RESULTS ROI analysis revealed that Stroop interference correlated positively with FA in left caudal anterior cingulate cortex (cACC) in HVs (r = 0.62, p = 0.01), but not in MDD (r = -0.05, p= 0.79) even after controlling for depression severity. The left cACC was among 4 ROIs in fronto-cingulate network where FA was lower in MDD relative to HVs (F(1,41) = 8.87, p = 0.005). Additionally, TBSS showed the same group interaction of differences and correlations, although only at a statistical trend level. LIMITATIONS The modest sample size limits the generalizability of the findings. CONCLUSIONS Structural connectivity of white matter network of cACC correlated with magnitude of Stroop interference in HVs, but not MDD. The cACC-frontal network, sub-serving attention control, may be disrupted in MDD. Less cognitive control may include enhanced effects of salience in HVs, or less effective response inhibition in MDD. Further studies of salience and inhibition components of executive function may better elucidate the relationship between brain white matter changes and executive dysfunction in MDD.

Pattern Recognition Of Magnetic Resonance Imaging-Based Gray Matter Volume Measurements Classifies Bipolar Disorder And Major Depressive Disorder

BACKGROUND Bipolar Disorder (BD) cannot be reliably distinguished from Major Depressive Disorder (MDD) until the first manic or hypomanic episode. Consequently, many patients with BD are treated with antidepressants without mood stabilizers, a strategy that is often ineffective and carries a risk of inducing a manic episode. We previously reported reduced cortical thickness in right precuneus, right caudal middle-frontal cortex and left inferior parietal cortex in BD compared with MDD. METHODS This study extends our previous work by performing individual level classification of BD or MDD in an expanded, currently unmedicated, cohort using gray matter volume (GMV) based on Magnetic Resonance Imaging and a Support Vector Machine. All patients were in a Major Depressive Episode and a leave-two-out analysis was performed. RESULTS Nineteen out of 26 BD subjects and 20 out of 26 MDD subjects were correctly identified, for a combined accuracy of 75%. The three brain regions contributing to the classification were higher GMV in bilateral supramarginal gyrus and occipital cortex indicating MDD, and higher GMV in right dorsolateral prefrontal cortex indicating BD. LIMITATIONS This analysis included scans performed with two different headcoils and scan sequences, which limited the interpretability of results in an independent cohort analysis. CONCLUSIONS Our results add to previously published data which suggest that regional gray matter volume should be investigated further as a clinical diagnostic tool to predict BD before the appearance of a manic or hypomanic episode.

Longitudinal effects of cognitive behavioral therapy for depression on the neural correlates of emotion regulation

Cognitive behavioral therapy (CBT) is effective for a substantial minority of patients suffering from major depressive disorder (MDD), but its mechanism of action at the neural level is not known. As core techniques of CBT seek to enhance emotion regulation, we scanned 31 MDD participants prior to 14 sessions of CBT using functional magnetic resonance imaging (fMRI) and a task in which participants engaged in a voluntary emotion regulation strategy while recalling negative autobiographical memories. Eighteen healthy controls were also scanned. Twenty-three MDD participants completed post-treatment fMRI scanning, and 12 healthy volunteers completed repeat scanning without intervention. Better treatment outcome was associated with longitudinal enhancement of the emotion regulation-dependent BOLD contrast within subgenual anterior cingulate, medial prefrontal cortex, and lingual gyrus. Baseline emotion regulation-dependent BOLD contrast did not predict treatment outcome or differ between MDD and control groups. CBT response may be mediated by enhanced downregulation of neural activity during emotion regulation; brain regions identified overlap with those found using a similar task in a normative sample, and include regions related to self-referential and emotion processing. Future studies should seek to determine specificity of this downregulation to CBT, and evaluate it as a treatment target in MDD.

In vivo evaluation of [18F]FECIMBI-36, an agonist 5-HT2A/2C receptor PET radioligand in nonhuman primate

We recently reported the radiosynthesis and in vitro evaluation of [18F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([18F]FECIMBI-36) or ([18F]1), an agonist radioligand for 5HT2A/2C receptors in postmortem samples of human brain. Herein we describe the in vivo evaluation of [18F]FECIMBI-36 in vervet/African green monkeys by PET imaging. PET images show that [18F]FECIMBI-36 penetrates the blood-brain barrier and a low retention of radioactivity is observed in monkey brain. Although the time activity curves indicate a somehow heterogeneous distribution of the radioligand in the brain, the low level of [18F]FECIMBI-36 in brain may limit the use of this tracer for quantification of 5-HT2A/2C receptors by PET.

Lack of association between the serotonin transporter and serotonin 1A receptor: an in vivo PET imaging study in healthy adults.

The serotonin neurotransmitter system is modulated in part by the uptake of synaptically released serotonin (5-HT) by the serotonin transporter (5-HTT), and by specific serotonin autoreceptors such as the somatodendritic 5-HT1A receptor, which can limit serotonin neuron depolarization. However, little is known about how 5-HTT and 5-HT1A are related in vivo. To study this question, we reanalyzed positron emission tomography (PET) data obtained earlier in 40 healthy participants (21 females) using [(11)C]WAY-100635 for quantification of 5-HT1A binding and [(11)C](+)-McN-5652 for quantification of 5-HTT binding. We hypothesized negative correlations between 5-HT1A binding in the raphe nuclei (RN) and 5-HTT binding in RN terminal field regions. Controlling for sex, no significant correlations were found (all p>0.05). Similarly, an exploratory analysis correlating whole-brain voxel-wise 5-HTT binding with 5-HT1A binding in RN identified no significant clusters meeting our a priori statistical threshold. The lack of correlation between 5-HT1A and 5-HTT binding observed in the current study may be due to the different temporal responsiveness of regulatory processes controlling the somatodendritic 5-HT1A receptor and 5-HTT in response to changing availability of intrasynaptic serotonin.

Utility of Molecular and Structural Brain Imaging to Predict Progression from Mild Cognitive Impairment to Dementia

This project compares three neuroimaging biomarkers to predict progression to dementia in subjects with mild cognitive impairment (MCI). Eighty-eight subjects with MCI and 40 healthy controls (HCs) were recruited. Subjects had a 3T magnetic resonance imaging (MRI) scan, and two positron emission tomography (PET) scans, one with Pittsburgh compound B ([11C]PIB) and one with fluorodeoxyglucose ([18F]FDG). MCI subjects were followed for up to 4 y and progression to dementia was assessed on an annual basis. MCI subjects had higher [11C]PIB binding potential (BPND) than HCs in multiple brain regions, and lower hippocampus volumes. [11C]PIB BPND, [18F]FDG standard uptake value ratio (SUVR), and hippocampus volume were associated with time to progression to dementia using a Cox proportional hazards model. [18F]FDG SUVR demonstrated the most statistically significant association with progression, followed by [11C]PIB BPND and then hippocampus volume. [11C]PIB BPND and [18F]FDG SUVR were independently predictive, suggesting that combining these measures is useful to increase accuracy in the prediction of progression to dementia. Hippocampus volume also had independent predictive properties to [11C]PIB BPND, but did not add predictive power when combined with the [18F]FDG SUVR data. This work suggests that PET imaging with both [11C]PIB and [18F]FDG may help to determine which MCI subjects are likely to progress to AD, possibly directing future treatment options.

White matter tract integrity is associated with antidepressant response to lurasidone in bipolar depression

Patients with bipolar disorder spend the most time in the depressed phase, and that phase is associated with the most morbidity and mortality. Treatment of bipolar depression lacks a test to determine who will respond to treatment. White matter disruptions have been found in bipolar disorder. Previous reports suggest that white matter disruptions may be associated with resistance to antidepressant medication, but this has never been investigated in a prospective study using a Food and Drug Administration (FDA)‐approved medication.

Radiosynthesis and In Vivo Evaluation of [11C]A1070722, a High Affinity GSK-3 PET Tracer in Primate Brain

Dysfunction of glycogen synthase kinase 3 (GSK-3) is implicated in the etiology of Alzheimers disease, Parkinsons disease, diabetes, pain, and cancer. A radiotracer for functional positron emission tomography (PET) imaging could be used to study the kinase in brain disorders and to facilitate the development of small molecule inhibitors of GSK-3 for treatment. At present, there is no target-specific or validated PET tracer available for the in vivo monitoring of GSK-3. We radiolabeled the small molecule inhibitor [11C]1-(7-methoxy- quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea ([11C]A1070722) with high affinity to GSK-3 (Ki = 0.6 nM) in excellent radiochemical yield. PET imaging experiments in anesthetized vervet/African green monkey exhibited that [11C]A1070722 penetrated the blood-brain barrier (BBB) and accumulated in brain regions, with highest radioactivity binding in frontal cortex followed by parietal cortex and anterior cingulate, and with the lowest bindings found in caudate, putamen, and thalamus, similarly to the known distribution of GSK-3 in human brain. Our studies suggest that [11C]A1070722 can be a potential PET radiotracer for the in vivo quantification of GSK-3 in brain.

Kappa opioid receptor binding in major depression: A pilot study

Endogenous kappa opioids mediate pathological responses to stress in animal models. However, the relationship of the kappa opioid receptor (KOR) to life stress and to psychopathology in humans is not well described. This pilot study sought, for the first time, to quantify KOR in major depressive disorder (MDD) in vivo in humans using positron emission tomography (PET). KOR binding was quantified in vivo by PET imaging with the [11C]GR103545 radiotracer in 13 healthy volunteers and 10 participants with current MDD. We examined the relationship between regional [11C]GR103545 total volume of distribution (VT) and diagnosis, childhood trauma, recent life stress, and, in a subsample, salivary cortisol levels during a modified Trier Social Stress Test (mTSST), amygdala, hippocampus, ventral striatum and raphe nuclei. Whole‐brain voxel‐wise analyses were also performed. [11C]GR103545 VT did not differ significantly between MDD participants and healthy volunteers in the four a priori ROIs (p = 0.50). [11C]GR103545 VT was unrelated to reported childhood adversity (p = 0.17) or recent life stress (p = 0.56). A trend‐level inverse correlation was observed between [11C]GR103545 VT and cortisol area‐under‐the curve with respect to ground during the mTSST (p = 0.081). No whole‐brain voxel‐wise contrasts were significant. Regional [11C]GR103545 VT, a measure of in vivo KOR binding, does not differentiate MDD from healthy volunteers in this pilot sample. Future studies may examine KOR binding in subgroups of depressed individuals at increased risk for KOR abnormalities, including co‐occurring mood and substance use disorders, as well as depression with psychotic features.