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K. Luan Phan

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14 papers
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14

YNIMG Journal 2023 Journal Article

Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium

  • Xi Zhu
  • Yoojean Kim
  • Orren Ravid
  • Xiaofu He
  • Benjamin Suarez-Jimenez
  • Sigal Zilcha-Mano
  • Amit Lazarov
  • Seonjoo Lee

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

YNIMG Journal 2022 Journal Article

A comparison of methods to harmonize cortical thickness measurements across scanners and sites

  • Delin Sun
  • Gopalkumar Rakesh
  • Courtney C. Haswell
  • Mark Logue
  • C. Lexi Baird
  • Erin N. O'Leary
  • Andrew S. Cotton
  • Hong Xie

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1, 340 cases with posttraumatic stress disorder (PTSD) (6. 2–81. 8 years old) and 2, 057 trauma-exposed controls without PTSD (6. 3–85. 2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ 2(3) = 63. 704, p < 0. 001) as well as case-control differences in age-related cortical thinning (Χ 2(3) = 12. 082, p = 0. 007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ 2(3) = 9. 114, p = 0. 028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0. 001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0. 001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0. 001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0. 001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0. 001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

YNIMG Journal 2019 Journal Article

Altered dynamic electroencephalography connectome phase-space features of emotion regulation in social anxiety

  • Mengqi Xing
  • Hyekyoung Lee
  • Zachery Morrissey
  • Moo K. Chung
  • K. Luan Phan
  • Heide Klumpp
  • Alex Leow
  • Olusola Ajilore

Emotion regulation deficits are commonly observed in social anxiety disorder (SAD). We used manifold-learning to learn the phase-space connectome manifold of EEG brain dynamics in twenty SAD participants and twenty healthy controls. The purpose of the present study was to utilize manifold-learning to understand EEG brain dynamics associated with emotion regulation processes. Our emotion regulation task (ERT) contains three conditions: Neutral, Maintain and Reappraise. For all conditions and subjects, EEG connectivity data was converted into series of temporally-consecutive connectomes and aggregated to yield this phase-space manifold. As manifold geodesic distances encode intrinsic geometry, we visualized this space using its geodesic-informed minimum spanning tree and compared neurophysiological dynamics across conditions and groups using the corresponding trajectory length. Results showed that SAD participants had significantly longer trajectory lengths during Neutral and Maintain. Further, trajectory lengths during Reappraise were significantly associated with the habitual use of reappraisal strategies, while Maintain trajectory lengths were significantly associated with the negative affective state during Maintain. In sum, an unsupervised connectome manifold-learning approach can reveal emotion regulation associated phase-space features of brain dynamics.

YNIMG Journal 2019 Journal Article

Neural correlates of inhibition and reward are negatively associated

  • Jessica Weafer
  • Natania A. Crane
  • Stephanie M. Gorka
  • K. Luan Phan
  • Harriet de Wit

Individuals with impulsive and addictive disorders, including drug addiction, binge eating/obesity, and problem gambling, exhibit both impaired control over behavior and heightened sensitivity to reward. However, it is not known whether such deviation in inhibitory and reward circuitry among clinical populations is a cause or consequence of the disorders. Recent evidence suggests that these constructs may be related at the neural level, and together, increase risk for engaging in maladaptive behaviors. The current study examined the degree to which brain function during inhibition relates to brain function during receipt of reward in healthy young adults who have not yet developed problem behaviors. Participants completed the stop signal task to assess inhibitory control and the doors task to assess reactivity to monetary reward (win vs loss) during functional magnetic resonance imaging (fMRI). Brain activation during response inhibition was negatively correlated with brain activation during reward. Specifically, less brain activation in right prefrontal regions during inhibition, including the right inferior frontal gyrus, middle frontal gyrus, and supplementary motor area, was associated with greater brain activation in left ventral striatum during receipt of monetary reward. Moreover, these associations were stronger in binge drinkers compared to non-binge drinkers. These findings suggest that the systems are related even before the onset of impulsive or addictive disorders. As such, it is possible that the association between inhibitory and reward circuitry may be a prospective marker of risk.

YNICL Journal 2019 Journal Article

Neural response during emotion regulation in monozygotic twins at high familial risk of affective disorders

  • Iselin Meluken
  • Ninja Meinhard Ottesen
  • K. Luan Phan
  • Phillipe R. Goldin
  • Martina Di Simplicio
  • Julian Macoveanu
  • Hartwig Roman Siebner
  • Lars Vedel Kessing

PURPOSE: We investigated the neural correlates of emotion regulation and -reactivity in adult unaffected monozygotic twins with a co-twin history of unipolar or bipolar disorder (high-risk), remitted or partially remitted twins with a personal history of unipolar or bipolar disorder (affected) and twins with no personal or first-degree family history of unipolar or bipolar disorder (low-risk). METHODS: We assessed 37 high-risk, 56 affected and 28 low-risk participants. Participants viewed unpleasant and neutral pictures during functional magnetic resonance imaging and were instructed to down-regulate their emotional response through reappraisal or mental imagery, as well as to maintain the elicited emotion. RESULTS: After adjusting for subsyndromal depressive symptoms, bilateral supplementary motor areas, posterior dorsal anterior cingulate cortices and the left frontal eye field showed less activity during reappraisal of unpleasant pictures in high-risk than low-risk participants. Notably, affected participants did not differ from high-risk or low-risk participants in neural response during reappraisal. There were no group differences in ventrolateral prefrontal cortex seed based functional connectivity during reappraisal or neural response during mental imagery or emotional reactivity. CONCLUSION: Lesser response in dorsal midline areas might reflect familial risk related abnormalities during down regulation of emotional reactivity through reappraisal.

YNICL Journal 2017 Journal Article

Predicting cognitive behavioral therapy response in social anxiety disorder with anterior cingulate cortex and amygdala during emotion regulation

  • Heide Klumpp
  • Jacklynn M. Fitzgerald
  • Kerry L. Kinney
  • Amy E. Kennedy
  • Stewart A. Shankman
  • Scott A. Langenecker
  • K. Luan Phan

BACKGROUND: Cognitive Behavioral Therapy (CBT) for social anxiety disorder (SAD) and other internalizing conditions attempts to improve emotion regulation. Accumulating data indicate anterior cingulate cortex (ACC), and to a lesser extent amygdala, activation in various tasks predicts treatment outcome. However, little is known about ACC and amygdala activation to emotion regulation in predicting clinical improvement following CBT in SAD. METHODS: Before treatment, 38 SAD patients completed implicit and explicit emotion regulation paradigms during fMRI. Implicit regulation involved attentional control over negative distractors. Explicit regulation comprised cognitive reappraisal to negative images. Pre-CBT brain activity was circumscribed to anatomical-based ACC sub-regions (rostral, dorsal) and amygdala masks, which were submitted to ROC curves to examine predictive validity as well as correlational analysis to evaluate prognostic change in symptom severity. RESULTS: More rostral (rACC) activity in implicit regulation and less rACC activity during explicit regulation distinguished responders (34%) from non-responders. Greater amygdala response in implicit regulation also foretold responder status. Baseline rACC and amygdala activity during attentional control correlated with pre-to-post CBT change in symptom severity such that more activation was related to greater decline in symptoms. No significant correlations were observed for explicit regulation. CONCLUSIONS: Across forms of regulation, rACC activity predicted responder status whereas amygdala as a neuromarker was limited to implicit regulation. While the direction of effects (enhanced vs. reduced) in rACC activity was task-dependent, results suggest SAD patients with deficient regulation benefited more from CBT. Findings support previous studies involving patients with depression and suggest the rACC may be a viable marker of clinical improvement in SAD.

YNICL Journal 2017 Journal Article

Resting-state theta band connectivity and graph analysis in generalized social anxiety disorder

  • Mengqi Xing
  • Reza Tadayonnejad
  • Annmarie MacNamara
  • Olusola Ajilore
  • Julia DiGangi
  • K. Luan Phan
  • Alex Leow
  • Heide Klumpp

BACKGROUND: Functional magnetic resonance imaging (fMRI) resting-state studies show generalized social anxiety disorder (gSAD) is associated with disturbances in networks involved in emotion regulation, emotion processing, and perceptual functions, suggesting a network framework is integral to elucidating the pathophysiology of gSAD. However, fMRI does not measure the fast dynamic interconnections of functional networks. Therefore, we examined whole-brain functional connectomics with electroencephalogram (EEG) during resting-state. METHODS: Resting-state EEG data was recorded for 32 patients with gSAD and 32 demographically-matched healthy controls (HC). Sensor-level connectivity analysis was applied on EEG data by using Weighted Phase Lag Index (WPLI) and graph analysis based on WPLI was used to determine clustering coefficient and characteristic path length to estimate local integration and global segregation of networks. RESULTS: WPLI results showed increased oscillatory midline coherence in the theta frequency band indicating higher connectivity in the gSAD relative to HC group during rest. Additionally, WPLI values positively correlated with state anxiety levels within the gSAD group but not the HC group. Our graph theory based connectomics analysis demonstrated increased clustering coefficient and decreased characteristic path length in theta-based whole brain functional organization in subjects with gSAD compared to HC. CONCLUSIONS: Theta-dependent interconnectivity was associated with state anxiety in gSAD and an increase in information processing efficiency in gSAD (compared to controls). Results may represent enhanced baseline self-focused attention, which is consistent with cognitive models of gSAD and fMRI studies implicating emotion dysregulation and disturbances in task negative networks (e.g., default mode network) in gSAD.

YNICL Journal 2017 Journal Article

Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder

  • Janna Marie Bas-Hoogendam
  • Henk van Steenbergen
  • J. Nienke Pannekoek
  • Jean-Paul Fouche
  • Christine Lochner
  • Coenraad J. Hattingh
  • Henk R. Cremers
  • Tomas Furmark

Social anxiety disorder (SAD) is a prevalent and disabling mental disorder, associated with significant psychiatric co-morbidity. Previous research on structural brain alterations associated with SAD has yielded inconsistent results concerning the direction of the changes in gray matter (GM) in various brain regions, as well as on the relationship between brain structure and SAD-symptomatology. These heterogeneous findings are possibly due to limited sample sizes. Multi-site imaging offers new opportunities to investigate SAD-related alterations in brain structure in larger samples. An international multi-center mega-analysis on the largest database of SAD structural T1-weighted 3T MRI scans to date was performed to compare GM volume of SAD-patients (n =174) and healthy control (HC)-participants (n =213) using voxel-based morphometry. A hypothesis-driven region of interest (ROI) approach was used, focusing on the basal ganglia, the amygdala-hippocampal complex, the prefrontal cortex, and the parietal cortex. SAD-patients had larger GM volume in the dorsal striatum when compared to HC-participants. This increase correlated positively with the severity of self-reported social anxiety symptoms. No SAD-related differences in GM volume were present in the other ROIs. Thereby, the results of this mega-analysis suggest a role for the dorsal striatum in SAD, but previously reported SAD-related changes in GM in the amygdala, hippocampus, precuneus, prefrontal cortex and parietal regions were not replicated. Our findings emphasize the importance of large sample imaging studies and the need for meta-analyses like those performed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium.

YNIMG Journal 2014 Journal Article

Volitional regulation of emotions produces distributed alterations in connectivity between visual, attention control, and default networks

  • Chandra Sripada
  • Michael Angstadt
  • Daniel Kessler
  • K. Luan Phan
  • Israel Liberzon
  • Gary W. Evans
  • Robert C. Welsh
  • Pilyoung Kim

The ability to volitionally regulate emotions is critical to health and well-being. While patterns of neural activation during emotion regulation have been well characterized, patterns of connectivity between regions remain less explored. It is increasingly recognized that the human brain is organized into large-scale intrinsic connectivity networks (ICNs) whose interrelationships are altered in characteristic ways during psychological tasks. In this fMRI study of 54 healthy individuals, we investigated alterations in connectivity within and between ICNs produced by the emotion regulation strategy of reappraisal. In order to gain a comprehensive picture of connectivity changes, we utilized connectomic psychophysiological interactions (PPI), a whole-brain generalization of standard single-seed PPI methods. In particular, we quantified PPI connectivity pair-wise across 837 ROIs placed throughout the cortex. We found that compared to maintaining one's emotional responses, engaging in reappraisal produced robust and distributed alterations in functional connections involving visual, dorsal attention, frontoparietal, and default networks. Visual network in particular increased connectivity with multiple ICNs including dorsal attention and default networks. We interpret these findings in terms of the role of these networks in mediating critical constituent processes in emotion regulation, including visual processing, stimulus salience, attention control, and interpretation and contextualization of stimuli. Our results add a new network perspective to our understanding of the neural underpinnings of emotion regulation, and highlight that connectomic methods can play a valuable role in comprehensively investigating modulation of connectivity across task conditions.

YNIMG Journal 2013 Journal Article

Distributed effects of methylphenidate on the network structure of the resting brain: A connectomic pattern classification analysis

  • Chandra Sekhar Sripada
  • Daniel Kessler
  • Robert Welsh
  • Michael Angstadt
  • Israel Liberzon
  • K. Luan Phan
  • Clayton Scott

Methylphenidate is a psychostimulant medication that produces improvements in functions associated with multiple neurocognitive systems. To investigate the potentially distributed effects of methylphenidate on the brain's intrinsic network architecture, we coupled resting state imaging with multivariate pattern classification. In a within-subject, double-blind, placebo-controlled, randomized, counterbalanced, cross-over design, 32 healthy human volunteers received either methylphenidate or placebo prior to two fMRI resting state scans separated by approximately one week. Resting state connectomes were generated by placing regions of interest at regular intervals throughout the brain, and these connectomes were submitted for support vector machine analysis. We found that methylphenidate produces a distributed, reliably detected, multivariate neural signature. Methylphenidate effects were evident across multiple resting state networks, especially visual, somatomotor, and default networks. Methylphenidate reduced coupling within visual and somatomotor networks. In addition, default network exhibited decoupling with several task positive networks, consistent with methylphenidate modulation of the competitive relationship between these networks. These results suggest that connectivity changes within and between large-scale networks are potentially involved in the mechanisms by which methylphenidate improves attention functioning.

YNIMG Journal 2011 Journal Article

Effects of alcohol on brain responses to social signals of threat in humans

  • Chandra Sekhar Sripada
  • Mike Angstadt
  • Patrick McNamara
  • Andrea C. King
  • K. Luan Phan

Alcohol is a known exogenous modulator of negative affect (anxiety, tension) in both animals and humans. It has been proposed that the anxiolytic effects of alcohol are mediated via the amygdala, an area critical to fear perception and responding. However, little is known about the acute effects of alcohol on amygdala reactivity to threatening information in humans. We used functional magnetic resonance imaging and a validated task to probe amygdala responses to social signals of threat in 12 healthy, social drinkers after a double-blind crossover administration of alcohol or placebo. We found that alcohol significantly reduced amygdala reactivity to threat signals. The current findings fit well with the notion that alcohol may attenuate threat-based responding and provide a potential brain-based mechanism for the link between alcohol and anxiety and/or social threat perception.

YNIMG Journal 2009 Journal Article

Medial prefrontal cortex and right insula activity predict plasma ACTH response to trauma recall

  • Anthony P. King
  • James L. Abelson
  • Jennifer C. Britton
  • K. Luan Phan
  • Stephan F. Taylor
  • Israel Liberzon

Neural substrates underlying psychological activation of the limbic–hypothalamic–pituitary–adrenal (LHPA) axis are not well understood in humans. Trauma recall (using autobiographical script-driven imagery) may provide a model to study neural circuitry involved in LHPA axis activation to personally threatening psychological stimuli. This study sought to identify brain activation patterns that differentiated combat veterans who mounted an LHPA response to trauma recall from those who did not. Twenty-five Vietnam combat veterans (14 with current PTSD, 11 with no PTSD history) experienced autobiographic script-driven imagery in an [15O] H2O positron emission tomography (PET) paradigm with recurrent blood sampling. Trauma recall elicited acute ACTH responses in some but not all veterans, regardless of the PTSD status and independent of emotional responses. ACTH responders (mean ACTH increase of 24±7 pg/ml, n =13) were compared to non-responders (mean decrease of −0. 6±0. 6 pg/ml, n =12) in regional cerebral blood flow (rCBF). Both groups activated right insula (BA13) in response to trauma recall. However, ACTH responders deactivated rostral mPFC (BA10)/rostral ACC (BA32), whereas non-responders activated this same mPFC region, and deactivated amygdala, hippocampus, and temporal pole. In group contrasts comparing ACTH responders to non-responders, the responders had significantly higher rCBF in right insula and right temporal pole, whereas non-responders had higher rCBF in rostral mPFC and dorsal ACC. These results support the hypotheses that right insula is involved in psychological activation of the LHPA axis and that rostral mPFC may negatively modulate LHPA axis responses.

YNIMG Journal 2006 Journal Article

Beyond threat: Amygdala reactivity across multiple expressions of facial affect

  • Daniel A. Fitzgerald
  • Mike Angstadt
  • Laura M. Jelsone
  • Pradeep J. Nathan
  • K. Luan Phan

The amygdala has been consistently isolated as a key neural substrate for processing facial displays of affect. Recent evidence from human lesion and functional neuroimaging studies have begun to challenge the notion that the amygdala is reserved for signals of threat (fear/anger). We performed a 4 T fMRI study in which 20 subjects viewed a contemporary set of photographs displaying 6 different facial expressions (fearful, disgusted, angry, sad, neutral, happy) while performing a task with minimal cognitive demand. Across subjects, the left amygdala was activated by each face condition separately, and its response was not selective for any particular emotion category. These results challenge the notion that the amygdala has a specialized role in processing certain emotions and suggest that the amygdala may have a more general-purpose function in processing salient information from faces.

YNIMG Journal 2006 Journal Article

Neural correlates of social and nonsocial emotions: An fMRI study

  • Jennifer C. Britton
  • K. Luan Phan
  • Stephan F. Taylor
  • Robert C. Welsh
  • Kent C. Berridge
  • I. Liberzon

Common theories of emotion emphasize valence and arousal dimensions or alternatively, specific emotions, and the search for the underlying neurocircuitry is underway. However, it is likely that other important dimensions for emotional neurocircuitry exist, and one of them is sociality. A social dimension may code whether emotions are addressing an individual's biological/visceral need versus more remote social goals involving semantic meaning or intentionality. Thus, for practical purposes, social emotions may be distinguished from nonsocial emotions based in part on the presence of human forms. In the current fMRI study, we aimed to compare regional coding of the sociality dimension of emotion (nonsocial versus social) versus the valence dimension of emotion (positive versus negative). Using a novel fMRI paradigm, film and picture stimuli were combined to induce and maintain four emotions varying along social and valence dimensions. Nonsocial emotions of positively valenced appetite and negatively valenced disgust and social emotions of positively valenced joy/amusement and negatively valenced sadness were studied. All conditions activated the thalamus. Appetite and disgust activated posterior insula and visual cortex, whereas joy/amusement and sadness activated extended amygdala, superior temporal gyrus, hippocampus, and posterior cingulate. Activations within the anterior cingulate, nucleus accumbens, orbitofrontal cortex, and amygdala were modulated by both social and valence dimensions. Overall, these findings highlight that sociality has a key role in processing emotional valence, which may have implications for patient populations with social and emotional deficits.