Sabin Khadka

Is Aberrant Functional Connectivity A Psychosis Endophenotype? A Resting State Functional Magnetic Resonance Imaging Study

BACKGROUND Schizophrenia and bipolar disorder share overlapping symptoms and risk genes. Shared aberrant functional connectivity is hypothesized in both disorders and in relatives. METHODS We investigated resting state functional magnetic resonance imaging in 70 schizophrenia and 64 psychotic bipolar probands, their respective first-degree relatives (n = 70 and 52), and 118 healthy subjects. We used independent component analysis to identify components representing various resting state networks and assessed spatial aspects of functional connectivity within all networks. We first investigated group differences using five-level, one-way analysis of covariance (ANCOVA), followed by post hoc t tests within regions displaying ANCOVA group differences and correlation of such functional connectivity measures with symptom ratings to examine clinical relationships. RESULTS Seven networks revealed abnormalities (five-level one-way ANCOVA, family-wise error correction p < .05): A) fronto-occipital, B) midbrain/cerebellum, C) frontal/thalamic/basal ganglia, D) meso/paralimbic, E) posterior default mode network, F) fronto-temporal/paralimbic and G) sensorimotor networks. Abnormalities in networks B and F were unique to schizophrenia probands. Furthermore, abnormalities in networks D and E were common to both patient groups. Finally, networks A, C, and G showed abnormalities shared by probands and their relative groups. Negative correlation with Positive and Negative Syndrome Scale negative and positive scores were found in regions within network C and F respectively, and positive correlation with Positive and Negative Syndrome Scale negative scores was found in regions in network D among schizophrenia probands only. CONCLUSIONS Schizophrenia, psychotic bipolar probands, and their relatives share both unique and overlapping within-network brain connectivity abnormalities, revealing potential psychosis endophenotypes.

Functional magnetic resonance imaging (fMRI) response to alcohol pictures predicts subsequent transition to heavy drinking in college students

BACKGROUND AND AIMS Young adults show the highest rates of escalating drinking, yet the neural risk mechanisms remain unclear. Heavy drinkers show variant functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to alcohol cues, which may presage increasing drinking. In this longitudinal study, we ascertained whether BOLD response to alcohol pictures predicted subsequent heavy drinking among college students. METHODS Participants were 43 18-21-year-olds in the United States who underwent BOLD scanning and completed monthly substance use surveys over the following year. Participants were categorized according to baseline and follow-up drinking into 13 continuously moderate drinkers, 16 continuously heavy drinkers and 14 transitioners who drank moderately at baseline but heavily by follow-up. During fMRI scanning at baseline, participants viewed alcohol and matched non-alcohol beverage images. RESULTS We observed group differences in alcohol cue-elicited BOLD response in bilateral caudate, orbitofrontal cortex, medial frontal cortex/anterior cingulate and left insula (clusters > 2619 ml, voxelwise F(2,40)  > 3.23, P < 0.05, whole-brain corrected P < 0.05), where transitioners hyperactivated compared with moderate and heavy drinkers (all Tukey P < 0.05). Exploratory factor analysis revealed a single brain network differentiating those who subsequently increased drinking. Exploratory regressions showed that, compared with other risk factors (e.g., alcoholism family history, impulsivity), BOLD response best predicted escalating drinking amount and alcohol-related problems. CONCLUSIONS Neural response to pictures of alcohol is substantially enhanced among United States college students who subsequently escalate drinking. Greater cue-reactivity is associated with larger increases in drinking and alcohol-related problems, regardless of other baseline factors. Thus, neural cue-reactivity could uniquely facilitate identifying individuals at greatest risk for future problematic drinking.

A preliminary prospective study of an escalation in 'maximum daily drinks', fronto-parietal circuitry and impulsivity-related domains in young adult drinkers

Excessive alcohol use in young adults is associated with greater impulsivity and neurobiological alterations in executive control systems. The maximum number of drinks consumed during drinking occasions (‘MaxDrinks’) represents a phenotype linked to vulnerability of alcohol use disorders, and an increase, or ‘escalation’, in MaxDrinks may be indicative of greater risk for problematic drinking. Thirty-six young adult drinkers performed a Go/No-Go task during fMRI, completed impulsivity-related assessments, and provided monthly reports of alcohol use during a 12-month follow-up period. Participants were characterized by MaxDrinks at baseline and after follow-up, identifying 18 escalating drinkers and 18 constant drinkers. Independent component analysis was used to investigate functional brain networks associated with response inhibition, and relationships with principal component analysis derived impulsivity-related domains were examined. Greater baseline MaxDrinks was associated with an average reduction in the engagement of a right-lateralized fronto-parietal functional network, while an escalation in MaxDrinks was associated with a greater difference in fronto-parietal engagement between successful inhibitions and error trials. Escalating drinkers displayed greater impulsivity/compulsivity-related domain scores that were positively associated with fronto-parietal network engagement and change in MaxDrinks during follow-up. In young adults, an escalating MaxDrinks trajectory was prospectively associated with altered fronto-parietal control mechanisms and greater impulsivity/compulsivity scores. Continued longitudinal studies of MaxDrinks trajectories, functional network activity, and impulsivity/compulsivity-related features may lend further insight into an intermediate phenotype vulnerable for alcohol use and addictive disorders.

Genetic association of impulsivity in young adults: a multivariate study

Impulsivity is a heritable, multifaceted construct with clinically relevant links to multiple psychopathologies. We assessed impulsivity in young adult (N~2100) participants in a longitudinal study, using self-report questionnaires and computer-based behavioral tasks. Analysis was restricted to the subset (N=426) who underwent genotyping. Multivariate association between impulsivity measures and single-nucleotide polymorphism data was implemented using parallel independent component analysis (Para-ICA). Pathways associated with multiple genes in components that correlated significantly with impulsivity phenotypes were then identified using a pathway enrichment analysis. Para-ICA revealed two significantly correlated genotype–phenotype component pairs. One impulsivity component included the reward responsiveness subscale and behavioral inhibition scale of the Behavioral-Inhibition System/Behavioral-Activation System scale, and the second impulsivity component included the non-planning subscale of the Barratt Impulsiveness Scale and the Experiential Discounting Task. Pathway analysis identified processes related to neurogenesis, nervous system signal generation/amplification, neurotransmission and immune response. We identified various genes and gene regulatory pathways associated with empirically derived impulsivity components. Our study suggests that gene networks implicated previously in brain development, neurotransmission and immune response are related to impulsive tendencies and behaviors.

Joint Coupling of Awake EEG Frequency Activity and MRI Gray Matter Volumes in the Psychosis Dimension: A BSNIP Study

Background Many studies have examined either electroencephalogram (EEG) frequency activity or gray matter volumes (GMV) in various psychoses [including schizophrenia (SZ), schizoaffective (SZA), and psychotic bipolar disorder (PBP)]. Prior work demonstrated similar EEG and gray matter abnormalities in both SZ and PBP. Integrating EEG and GMV and jointly analyzing the combined data fully elucidates the linkage between the two and may provide better biomarker- or endophenotype-specificity for a particular illness. Joint exploratory investigations of EEG and GMV are scarce in the literature and the relationship between the two in psychosis is even less explored. We investigated a joint multivariate model to test whether the linear relationship or linkage between awake EEG (AEEG) frequency activity and GMV is abnormal across the psychosis dimension and if such effects are also present in first-degree relatives. Methods We assessed 607 subjects comprising 264 probands [105 SZ, 72 SZA, and 87 PBP], 233 of their first degree relatives [82 SZ relatives (SZR), 71 SZA relatives (SZAR), and 80 PBP relatives (PBPR)], and 110 healthy comparison subjects (HC). All subjects underwent structural MRI (sMRI) and EEG scans. Frequency activity and voxel-based morphometric GMV were derived from EEG and sMRI data, respectively. Seven AEEG frequency and gray matter components were extracted using Joint independent component analysis (jICA). The loading coefficients (LC) were examined for group differences using analysis of covariance. Further, the LCs were correlated with psychopathology scores to identify relationship with clinical symptoms. Results Joint ICA revealed a single component differentiating SZ from HC (p < 0.006), comprising increased posterior alpha activity associated with decreased volume in inferior parietal lobe, supramarginal, parahippocampal gyrus, middle frontal, inferior temporal gyri, and increased volume of uncus and culmen. No components were aberrant in either PBP or SZA or any relative group. No significant association was identified with clinical symptom measures. Conclusion Our data suggest that a joint EEG and GMV model yielded a biomarker specific to SZ, not abnormal in PBP or SZA. Alpha activity was related to both increased and decreased volume in different cortical structures. Additionally, the joint model failed to identify endophenotypes across psychotic disorders.

The relationship of impulsivity and cortical thickness in depressed and non-depressed adolescents

Major Depressive Disorder (MDD) is recognized to be heterogeneous in terms of brain structure abnormality findings across studies, which might reflect previously unstudied traits that confer variability to neuroimaging measurements. The purpose of this study was to examine the relationships between different types of trait impulsivity and MDD diagnosis on adolescent brain structure. We predicted that adolescents with depression who were high on trait impulsivity would have more abnormal cortical structure than depressed patients or non-MDD who were low on impulsivity. We recruited 58 subjects, including 29 adolescents (ages 12–19) with a primary DSM-IV diagnosis of MDD and a history of suicide attempt and 29 demographically-matched healthy control participants. Our GLM-based analyses sought to describe differences in the linear relationships between cortical thickness and impulsivity trait levels. As hypothesized, we found significant moderation effects in rostral middle frontal gyrus and right paracentral lobule cortical thickness for different subscales of the Barratt Impulsiveness Scale. However, although these brain-behavior relationships differed between diagnostic study groups, they were not simple additive effects as we had predicted. For the middle frontal gyrus, non-MDD participants showed a strong positive association between cortical thickness and BIS-11 Motor scores, while MDD-diagnosed participants showed a negative association. For Non-Planning Impulsiveness, paracentral lobule cortical thickness was observed with greater impulsivity in MDD, but no association was found for controls. In conclusion, the findings confirm that dimensions of impulsivity have discrete neural correlates, and show that relationships between impulsivity and brain structure are expressed differently in adolescents with MDD compared to non-MDD.

Multivariate Imaging Genetics Study of MRI Gray Matter Volume and SNPs Reveals Biological Pathways Correlated with Brain Structural Differences in Attention Deficit Hyperactivity Disorder

Background Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder affecting children, adolescents, and adults. Its etiology is not well understood, but it is increasingly believed to result from diverse pathophysiologies that affect the structure and function of specific brain circuits. Although one of the best-studied neurobiological abnormalities in ADHD is reduced fronto-striatal-cerebellar gray matter (GM) volume, its specific genetic correlates are largely unknown. Methods In this study, T1-weighted MR images of brain structure were collected from 198 adolescents (63 ADHD-diagnosed). A multivariate parallel independent component analysis (Para-ICA) technique-identified imaging genetic relationships between regional GM volume and single nucleotide polymorphism data. Results Para-ICA analyses extracted 14 components from genetic data and 9 from MR data. An iterative cross-validation using randomly chosen subsamples indicated acceptable stability of these ICA solutions. A series of partial correlation analyses controlling for age, sex, and ethnicity revealed two genotype–phenotype component pairs significantly differed between ADHD and non-ADHD groups, after a Bonferroni correction for multiple comparisons. The brain phenotype component not only included structures frequently found to have abnormally low volume in previous ADHD studies but was also significantly associated with ADHD differences in symptom severity and performance on cognitive tests frequently found to be impaired in patients diagnosed with the disorder. Pathway analysis of the genotype component identified several different biological pathways linked to these structural abnormalities in ADHD. Conclusion Some of these pathways implicate well-known dopaminergic neurotransmission and neurodevelopment hypothesized to be abnormal in ADHD. Other more recently implicated pathways included glutamatergic and GABA-eric physiological systems; others might reflect sources of shared liability to disturbances commonly found in ADHD, such as sleep abnormalities.

fMRI response to alcohol pictures predicts subsequent transition to heavy drinking in college students

BACKGROUND AND AIMS Young adults show the highest rates of escalating drinking, yet the neural risk mechanisms remain unclear. Heavy drinkers show variant functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to alcohol cues, which may presage increasing drinking. In this longitudinal study, we ascertained whether BOLD response to alcohol pictures predicted subsequent heavy drinking among college students. METHODS Participants were 43 18-21-year-olds in the United States who underwent BOLD scanning and completed monthly substance use surveys over the following year. Participants were categorized according to baseline and follow-up drinking into 13 continuously moderate drinkers, 16 continuously heavy drinkers and 14 transitioners who drank moderately at baseline but heavily by follow-up. During fMRI scanning at baseline, participants viewed alcohol and matched non-alcohol beverage images. RESULTS We observed group differences in alcohol cue-elicited BOLD response in bilateral caudate, orbitofrontal cortex, medial frontal cortex/anterior cingulate and left insula (clusters > 2619 ml, voxelwise F(2,40)  > 3.23, P < 0.05, whole-brain corrected P < 0.05), where transitioners hyperactivated compared with moderate and heavy drinkers (all Tukey P < 0.05). Exploratory factor analysis revealed a single brain network differentiating those who subsequently increased drinking. Exploratory regressions showed that, compared with other risk factors (e.g., alcoholism family history, impulsivity), BOLD response best predicted escalating drinking amount and alcohol-related problems. CONCLUSIONS Neural response to pictures of alcohol is substantially enhanced among United States college students who subsequently escalate drinking. Greater cue-reactivity is associated with larger increases in drinking and alcohol-related problems, regardless of other baseline factors. Thus, neural cue-reactivity could uniquely facilitate identifying individuals at greatest risk for future problematic drinking.

Altered Functional Connectivity in Sickle Cell Disease Exists at Rest and During Acute Pain Challenge

Objectives: Sickle cell disease (SCD) is a chronic pain disorder in which abnormally shaped red blood cells obstruct microcirculation causing ischemia and pain. The lack of SCD responsiveness to analgesics has led many to propose that nociceptive neural systems engaged when detecting pain become sensitized, resulting in an enhancement of pain response. Methods: Individuals with SCD and non-SCD controls were exposed to a painful stimuli of varying intensity using a pressure algometer and underwent several neuroimaging tasks. Results: This study identified and characterized the neural correlates of possible central sensitization in SCD. We found functional connectivity abnormalities in individuals with SCD in the brain’s somatosensory network, salience network, and default mode network during both an unstructured resting state and paradigm involving acute pain challenge. Discussion: There was evidence for both increased and decreased connectivity which is consistent with findings in other chronic pain disorders. Preliminary evidence was found that subcortical brain regions might contribute to neurodevelopmental abnormalities in chronic pain. The results support a model in which SCD pain sensitization involves abnormally low functional integration of brain regions that make use of nociceptive information to plan movements, and hyperconnectivity of various frontal and parietal lobe regions that direct attention to or represent higher-order abstractions within circuits involved with either nocioceptive processing or detection of abnormally salient environmental stimuli.

The effect of age and smoking on the hippocampus and memory in late middle age

From middle age the hippocampus atrophies at an accelerating rate. Factors that further this acceleration may hasten memory decline and the onset of memory disorder. We studied associations between smoking history, age, ApoE e4 genotype, vascular risk factors, hippocampal volume, and cognition in 67 middle‐aged subjects (mean age = 56 years) who were offspring of parents with dementia. Subjects underwent isotropic T1‐weighted 3 T MRI brain scanning with FreeSurfer volumetric data extraction for the hippocampus, a neuropsychological assessment battery, extensive medical data collection, and ApoE genotyping. ApoE e4, vascular risk variables, and alcohol history were unrelated to hippocampal volume. Hippocampal volume correlated negatively with age and positively with memory performance, but not with global cognition. Aging diminished hippocampal volume by 0.52% per year. Female subjects (only two males smoked) with a heavy smoking history (≥ 9.5 pack‐years; n = 11) exhibited hippocampal volumes that were 7.4% smaller than the volumes of females (n = 37) with a light or no smoking history. In our sample by late middle age, a history of moderate to heavy smoking is associated with hippocampal atrophy equivalent to 12 years of aging. Since only a small number of subjects within the sample have a smoking history, validation of this finding in larger samples is desirable.