Xue Zhang

All Publications

• Adaptive cognitive control circuit changes associated with problem-solving ability and depression symptom outcomes over 24 months. Science translational medicine Zhang, X., Pines, A., Stetz, P., Goldstein-Piekarski, A. N., Xiao, L., Lv, N., Tozzi, L., Lavori, P. W., Snowden, M. B., Venditti, E. M., Smyth, J. M., Suppes, T., Ajilore, O., Ma, J., Williams, L. M. 2024; 16 (763): eadh3172

  Abstract

  Mechanistically targeted behavioral interventions are a much-needed strategy for improving outcomes in depression, especially for vulnerable populations with comorbidities such as obesity. Such interventions may change behavior and outcome by changing underlying neural circuit function. However, it is unknown how these circuit-level modifications unfold over intervention and how individual differences in early circuit-level modifications may explain the heterogeneity of treatment effects. We addressed this need within a clinical trial of problem-solving therapy for participants with depression symptoms and comorbid obesity, focusing on the cognitive control circuit as a putative neural mechanism of action. Functional magnetic resonance imaging was applied to measure the cognitive control circuit activity at five time points over 24 months. Compared with participants who received usual care, those receiving problem-solving therapy showed that attenuations in cognitive control circuit activity were associated with enhanced problem-solving ability, which suggests that this circuit plays a key role in the mechanisms of problem-solving therapy. Attenuations in circuit activity were also associated with improved depression symptoms. Changes in cognitive control circuit activity at 2 months better predicted changes in problem-solving ability and depression symptoms at 6, 12, and 24 months, with predictive improvements ranging from 17.8 to 104.0%, exceeding baseline demographic and symptom characteristics. Our findings suggest that targeting the circuit mechanism of action could enhance the prediction of treatment outcomes, warranting future model refinement and improvement to pave the way for its clinical application.

  View details for DOI 10.1126/scitranslmed.adh3172

  View details for PubMedID 39231241

• Psychiatric Symptoms, Cognition, and Symptom Severity in Children. JAMA psychiatry Pines, A., Tozzi, L., Bertrand, C., Keller, A. S., Zhang, X., Whitfield-Gabrieli, S., Hastie, T., Larsen, B., Leikauf, J., Williams, L. M. 2024

  Abstract

  Mental illnesses are a leading cause of disability globally, and functional disability is often in part caused by cognitive impairments across psychiatric disorders. However, studies have consistently reported seemingly opposite findings regarding the association between cognition and psychiatric symptoms.To determine if the association between general cognition and mental health symptoms diverges at different symptom severities in children.A total of 5175 children with complete data at 2 time points assessed 2 years apart (aged 9 to 11 years at the first assessment) from the ongoing Adolescent Brain and Cognitive Development (ABCD) study were evaluated for a general cognition factor and mental health symptoms from September 2016 to August 2020 at 21 sites across the US. Polynomial and generalized additive models afforded derivation of continuous associations between cognition and psychiatric symptoms across different ranges of symptom severity. Data were analyzed from December 2022 to April 2024.Aggregate cognitive test scores (general cognition) were primarily evaluated in relation to total and subscale-specific symptoms reported from the Child Behavioral Checklist.The sample included 5175 children (2713 male [52.4%] and 2462 female [47.6%]; mean [SD] age, 10.9 [1.18] years). Previously reported mixed findings regarding the association between general cognition and symptoms may consist of several underlying, opposed associations that depend on the class and severity of symptoms. Linear models recovered differing associations between general cognition and mental health symptoms, depending on the range of symptom severities queried. Nonlinear models confirm that internalizing symptoms were significantly positively associated with cognition at low symptom burdens higher cognition = more symptoms) and significantly negatively associated with cognition at high symptom burdens.The association between mental health symptoms and general cognition in this study was nonlinear. Internalizing symptoms were both positively and negatively associated with general cognition at a significant level, depending on the range of symptom severities queried in the analysis sample. These results appear to reconcile mixed findings in prior studies, which implicitly assume that symptom severity tracks linearly with cognitive ability across the entire spectrum of mental health. As the association between cognition and symptoms may be opposite in low vs high symptom severity samples, these results reveal the necessity of clinical enrichment in studies of cognitive impairment.

  View details for DOI 10.1001/jamapsychiatry.2024.2399

  View details for PubMedID 39196567

• Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety. Nature medicine Tozzi, L., Zhang, X., Pines, A., Olmsted, A. M., Zhai, E. S., Anene, E. T., Chesnut, M., Holt-Gosselin, B., Chang, S., Stetz, P. C., Ramirez, C. A., Hack, L. M., Korgaonkar, M. S., Wintermark, M., Gotlib, I. H., Ma, J., Williams, L. M. 2024

  Abstract

  There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.

  View details for DOI 10.1038/s41591-024-03057-9

  View details for PubMedID 38886626

  View details for PubMedCentralID 7653736

• Ketamine's acute effects on negative brain states are mediated through distinct altered states of consciousness in humans. Nature communications Hack, L. M., Zhang, X., Heifets, B. D., Suppes, T., van Roessel, P. J., Yesavage, J. A., Gray, N. J., Hilton, R., Bertrand, C., Rodriguez, C. I., Deisseroth, K., Knutson, B., Williams, L. M. 2023; 14 (1): 6631

  Abstract

  Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain's affective circuits during acute ketamine-induced ASCs within a randomized, multi-modal, placebo-controlled design examining placebo, 0.05 mg/kg ketamine, and 0.5 mg/kg ketamine in nonclinical adult participants (NCT03475277). Licensed clinicians monitored infusions for safety. Linear mixed effects models, analysis of variance, t-tests, and mediation models were used for statistical analyses. Our design enabled us to test our pre-specified primary and secondary endpoints, which were met: effects of ketamine across dose conditions on (1) emotional task-evoked brain activity, and (2) sub-components of dissociation and other ASCs. With this design, we also could disentangle which ketamine-induced affective brain states are dependent upon specific aspects of ASCs. Differently valenced ketamine-induced ASCs mediated opposing effects on right anterior insula activity. Participants experiencing relatively higher depersonalization induced by 0.5 mg/kg of ketamine showed relief from negative brain states (reduced task-evoked right anterior insula activity, 0.39 SD). In contrast, participants experiencing dissociative amnesia showed an exacerbation of insula activity (0.32 SD). These results in nonclinical participants may shed light on the mechanisms by which specific dissociative states predict response to ketamine in depressed individuals.

  View details for DOI 10.1038/s41467-023-42141-5

  View details for PubMedID 37857620

  View details for PubMedCentralID 5126726

• Effects of Levodopa Therapy on Cerebral Arteries and Perfusion in Parkinson's Disease Patients. Journal of magnetic resonance imaging : JMRI Xiong, Y., Ji, L., He, L., Chen, L., Zhang, X., Chen, Z., Li, X., Zhao, H., Shirakawa, M., Yuan, C., Ma, Y., Guo, H. 2021

  Abstract

  BACKGROUND: Levodopa is the most-commonly used therapy for Parkinson's Disease (PD). Imaging findings show increased cerebral blood flow (CBF) response to levodopa, but the artery morphological change is less studied.PURPOSE: To investigate the effect of levodopa on cerebral arteries and CBF.STUDY TYPE: Prospective.POPULATION: 57 PD patients (56±10years, 26 males) and 17 age-matched healthy controls (AMC, 57±9years, 9 males) were scanned at baseline (OFF). Patients were rescanned 50minutes after taking levodopa (ON).FIELD STRENGTH AND SEQUENCE: 3T; Simultaneous noncontrast angiography intraplaque imaging (SNAP) based on turbo field echo; Pseudo-continuous arterial spin labeling (PCASL) based on echo-planner imaging.ASSESSMENT: The Unified Parkinson's Disease Rating Scale (UPDRS-III) was used to assess the disease severity. Length and radius of arteries were measured from SNAP images. CBF was calculated from PCASL images globally and regionally.STATISTICAL TESTS: Mann Whitney U tests were conducted in comparing PD vs. AMC. Wilcoxon matched-pairs signed rank tests were used in comparing OFF vs. ON, and the more-affected vs. the less-affected hemisphere in PD. Linear regressions were performed to test the correlations of neuroimaging findings with behavioral changes. Significance threshold was P<0.05 with Bonferroni correction.RESULTS: PD patients were identified with significantly lower CBF (PD OFF Mean=40.15±5.99, AMC Mean=43.48±6.21mL/100g/min) and shortened total artery length (PD OFF Mean=5851.07±1393.45, AMC Mean=7479.16±1335.93mm). Levodopa elevated CBF of PD brains (PD ON Mean=41.48±6.32mL/100g/min) and expanded radius of proximal arteries. Artery radius change significantly correlated with CBF change in corresponding territories (r=0.559 for Internal Carotid Arteries, r=0.448 for Basilar Artery, and r=0.464 for Middle Cerebral Artery M1). Global CBF significantly related to UPDRS-III (r=-0.391) post-levodopa.DATA CONCLUSION: Levodopa can increase CBF by dilating proximal arteries.LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 4.

  View details for DOI 10.1002/jmri.27903

  View details for PubMedID 34477268

• Activation of Cognitive Control Network During Inhibition Processing Dynamically Predicts Symptom Outcomes for Depression: A 24-month Longitudinal Study Zhang, X., Stetz, P., Goldstein-Piekarski, A. N., Xiao, L., Lv, N., Rosas, L. G., Lavori, P. W., Snowden, M. B., Venditti, E. M., Simmons, J. M., Smyth, J. M., Suppes, T., Lewis, M. A., Ajilore, O., Ma, J., Williams, L. M. ELSEVIER SCIENCE INC. 2021: S98

  View details for Web of Science ID 000645683800234

• Striato-Cortical Neuroimaging Markers in the Reward Network Distinguish Melancholic Depression and Response to Treatment: An iSPOT-D Report Hack, L. M., Zhang, X., Williams, L. M. ELSEVIER SCIENCE INC. 2021: S270

  View details for Web of Science ID 000645683800648

• Reduced functional connectivity of default mode network subsystems in depression: Meta-analytic evidence and relationship with trait rumination. NeuroImage. Clinical Tozzi, L. n., Zhang, X. n., Chesnut, M. n., Holt-Gosselin, B. n., Ramirez, C. A., Williams, L. M. 2021; 30: 102570

  Abstract

  Resting-state functional connectivity changes in the default mode network (DMN) of patients with major depressive disorder (MDD) have been linked to rumination. The DMN is divided into three subsystems: a midline Core, a dorsal medial prefrontal cortex (DMPFC) subsystem, and a medial temporal lobe (MTL) subsystem. We examined resting-state functional connectivity within and between DMN subsystems in MDD and its association with rumination. First, we conducted a meta-analysis on a large multi-site dataset of 618 MDD and 683 controls to quantify the differences in DMN subsystem functional connectivity between MDD and controls. Second, we tested the association of DMN subsystem functional connectivity and rumination in a sample of 115 unmedicated participants with symptoms of anxiety/depression and 48 controls. In our meta-analysis, only functional connectivity in the DMN Core was significantly reduced in MDD compared to controls (g = -0.246, CI = [-0.417; -0.074], pFDR = 0.048). Functional connectivity in the DMPFC subsystem and between the Core and DMPFC subsystems was slightly reduced but not significantly (g = -0.162, CI = [-0.310; -0.013], pFDR = 0.096; g = -0.249, CI = [-0.464; -0.034], pFDR = 0.084). Results were heterogeneous across sites for connectivity in the Core and between Core and DMPFC (I2 = 0.348 and I2 = 0.576 respectively). Prediction intervals consistently encompassed 0. In the independent sample we collected, functional connectivity within the DMN Core, DMPFC and between Core and DMPFC was not reduced in MDD compared to controls (all pFDR > 0.05). Trait rumination did not predict connectivity within and between DMN subsystems (all pFDR > 0.05). We conclude that MDD as a diagnostic category shows slightly reduced functional connectivity within the DMN Core, independent of illness duration, treatment, symptoms and trait rumination. However, this effect is small, highly variable and heterogeneous across samples, so that we could only detect it at the meta-analytic level, with a sample size of several hundreds. Our results indicate that reduced Core DMN connectivity has significant limitations as a potential clinical or prognostic marker for the diagnosis of MDD and might be more relevant to consider as a characteristic distinguishing a subgroup of individuals within this diagnostic category.

  View details for DOI 10.1016/j.nicl.2021.102570

  View details for PubMedID 33540370

• Deep learning-based MR fingerprinting ASL ReconStruction (DeepMARS) MAGNETIC RESONANCE IN MEDICINE Zhang, Q., Su, P., Chen, Z., Liao, Y., Chen, S., Guo, R., Qi, H., Li, X., Zhang, X., Hu, Z., Lu, H., Chen, H. 2020; 84 (2): 1024–34

  Abstract

  To develop a reproducible and fast method to reconstruct MR fingerprinting arterial spin labeling (MRF-ASL) perfusion maps using deep learning.A fully connected neural network, denoted as DeepMARS, was trained using simulation data and added Gaussian noise. Two MRF-ASL models were used to generate the simulation data, specifically a single-compartment model with 4 unknowns parameters and a two-compartment model with 7 unknown parameters. The DeepMARS method was evaluated using MRF-ASL data from healthy subjects (N = 7) and patients with Moymoya disease (N = 3). Computation time, coefficient of determination (R2 ), and intraclass correlation coefficient (ICC) were compared between DeepMARS and conventional dictionary matching (DM). The relationship between DeepMARS and Look-Locker PASL was evaluated by a linear mixed model.Computation time per voxel was <0.5 ms for DeepMARS and >4 seconds for DM in the single-compartment model. Compared with DM, the DeepMARS showed higher R2 and significantly improved ICC for single-compartment derived bolus arrival time (BAT) and two-compartment derived cerebral blood flow (CBF) and higher or similar R2 /ICC for other parameters. In addition, the DeepMARS was significantly correlated with Look-Locker PASL for BAT (single-compartment) and CBF (two-compartment). Moreover, for Moyamoya patients, the location of diminished CBF and prolonged BAT shown in DeepMARS was consistent with the position of occluded arteries shown in time-of-flight MR angiography.Reconstruction of MRF-ASL with DeepMARS is faster and more reproducible than DM.

  View details for DOI 10.1002/mrm.28166

  View details for Web of Science ID 000510713500001

  View details for PubMedID 32017236

• Dynamic changes in thalamic connectivity following stress and its association with future depression severity BRAIN AND BEHAVIOR Zhang, X., Li, X., Steffens, D. C., Guo, H., Wang, L. 2019; 9 (12): e01445

  Abstract

  Tracking stress-induced brain activity and connectivity dynamically and examining activity/connectivity-associated recovery ability after stress might be an effective way of detecting stress vulnerability.Using two widely used stress paradigms, a speech task (social stress) and a mathematical calculation task (mental loading stress), we examined common changes in regional homogeneity (ReHo) and functional connectivity (FC) before, during, and after the two stressful tasks in thirty-nine college students. A counting breath relaxation task was employed as a contrast task. ReHo and FC were compared between subjects with higher versus lower depression symptoms (assessed by the Beck Depression Inventory, BDI). We developed a recovery index (RI) based on dynamic changes of ReHo/FC to evaluate individuals' ability to recover from a stressful state. To assess RI's usefulness in predicting future depression severity, BDI was also measured at one-year follow-up.Our results revealed a ReHo decrease after both stressful tasks and a ReHo increase after the relaxation task in bilateral thalamus. The ReHo decrease after both stressful tasks was more significant in the higher BDI than the lower BDI group. Higher ReHo RI of the right thalamus in the higher BDI groups was significantly correlated with lower BDI severity at one-year follow-up. Bilateral thalamus also showed increased FC with the default mode network and decreased FC with the executive control network after the stressful tasks.These findings highlight the importance of tracking resting activity and connectivity of thalamus dynamically for detecting stress vulnerability.

  View details for DOI 10.1002/brb3.1445

  View details for Web of Science ID 000492395500001

  View details for PubMedID 31651099

  View details for PubMedCentralID PMC6908855

• Downward cross-modal plasticity in single-sided deafness NEUROIMAGE Qiao, Y., Li, X., Shen, H., Zhang, X., Sun, Y., Hao, W., Guo, B., Ni, D., Gao, Z., Guo, H., Shang, Y. 2019; 197: 608–17

  Abstract

  The auditory cortex has been shown to participate in visual processing in individuals with complete auditory deprivation. However, it remains unclear whether partial hearing deprivation like single-sided deafness (SSD) leads to similar cross-modal plasticity. To investigate this, we enrolled individuals with long-term SSD, into functional MRI scans under resting-state and a visuo-spatial working memory task. Contrary to previous findings in bilateral deafness, our study revealed decreased activation in the auditory cortex in both left (LSSD) and right (RSSD) single-sided deafness compared to normal hearing controls, with statistical significance in RSSD. The degree of involvement was correlated with residual hearing ability in RSSD. These observations suggest that SSD can lead to a downward cross-modal plasticity: the more hearing ability lost, the fewer brain resources in the auditory cortex can be applied to visual tasks. In addition, the fronto-parietal cortex was observed to be less activated during the visual task in RSSD while the resting-state fMRI revealed increased functional connectivity between the fronto-parietal cortex and the auditory cortex, suggesting fronto-parietal resources may be recruited less by vision but more by hearing. The LSSD showed a similar alteration trend with RSSD, but without statistical significance. Together these findings may indicate that when hearing is partially deprived in SSD, there may be redistribution for brain resources between hearing and vision, and vision tends to allocate less resources. Our findings in this pilot study of unilateral auditory-deprived individuals enrich the understanding of cross-modal plasticity in the brain.

  View details for DOI 10.1016/j.neuroimage.2019.05.031

  View details for Web of Science ID 000472161500056

  View details for PubMedID 31091475

• Exploring common changes after acute mental stress and acute tryptophan depletion: Resting-state fMRI studies JOURNAL OF PSYCHIATRIC RESEARCH Zhang, X., Huettel, S. A., Mullette-Gillman, O. A., Guo, H., Wang, L. 2019; 113: 172–80

  Abstract

  Stress and low serotonin levels are important biological factors in depression and anxiety etiologies. Although studies indicate that low serotonin levels, stress, and other factors may interact in depression/anxiety psychopathology, few studies have investigated the potentially shared neural substrates. We conducted resting-state fMRI scans pre- and post-stress task, and under control and tryptophan depletion condition, to explore the common changes induced by acute mental stress (AMS) and acute tryptophan depletion (ATD). The present study targeted regions within core brain networks - default mode network, salience network, executive control network, and emotion network - reported altered in AMS and ATD, and used regional homogeneity (ReHo) and functional connectivity (FC) analyses to explore their overlapped effects. We additionally examined the relationships among core neural networks - operationalized as an index of resource allocation bias that quantifies the shift from internal to external modes of processing. We found both manipulations induced increased ReHo of the amygdala and decreased ReHo of the posterior cingulate cortex (PCC). The PCC-amygdala FC was negatively correlated with the change of negative affect, whereas the right dorsolateral prefrontal cortex and right anterior insula FC was positively associated with anxiety level. In addition, we found that a greater shift to an external mode was correlated with higher anxiety level under both conditions. Common changes induced by acute mental stress and acute tryptophan depletion confirmed our hypothesis that AMS and ATD induce changes in common neural pathways, which in turn might mark vulnerability to depression and anxiety.

  View details for DOI 10.1016/j.jpsychires.2019.03.025

  View details for Web of Science ID 000467670000025

  View details for PubMedID 30959228

• Physical exercise increases involvement of motor networks as a compensatory mechanism during a cognitively challenging task INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Ji, L., Pearlson, G. D., Zhang, X., Steffens, D. C., Ji, X., Guo, H., Wang, L. 2018; 33 (8): 1153–59

  Abstract

  Neuroimaging studies suggest that older adults may compensate for declines in cognitive function through neural compensation and reorganization of neural resources. While neural compensation as a key component of cognitive reserve is an important factor that mediates cognitive decline, the field lacks a quantitative measure of neural compensatory ability, and little is known about factors that may modify compensation, such as physical exercise.Twenty-five healthy older adults participated in a 6-week dance training exercise program. Gait speed, cognitive function, and functional magnetic resonance imaging during a challenging memory task were measured before and after the exercise program. In this study, we used a newly proposed data-driven independent component analysis approach to measure neural compensatory ability and tested the effect of physical exercise on neural compensation through a longitudinal study.After the exercise program, participants showed significantly improved memory performance in Logical Memory Test (WMS(LM)) (P < .001) and Rey Auditory Verbal Learning Test (P = .001) and increased gait speed measured by the 6-minute walking test (P = .01). Among all identified neural networks, only the motor cortices and cerebellum showed greater involvement during the memory task after exercise. Importantly, subjects who activated the motor network only after exercise (but not before exercise) showed WMS(LM) increases.We conclude that physical exercise improved gait speed, cognitive function, and compensatory ability through increased involvement of motor-related networks.

  View details for DOI 10.1002/gps.4909

  View details for Web of Science ID 000438028900019

  View details for PubMedID 29851152

• Dual-TRACER: High resolution fMRI with constrained evolution reconstruction NEUROIMAGE Li, X., Ma, X., Li, L., Zhang, Z., Zhang, X., Tong, Y., Wang, L., Song, S., Guo, H. 2018; 164: 172–82

  Abstract

  fMRI with high spatial resolution is beneficial for studies in psychology and neuroscience, but is limited by various factors such as prolonged imaging time, low signal to noise ratio and scarcity of advanced facilities. Compressed Sensing (CS) based methods for accelerating fMRI data acquisition are promising. Other advanced algorithms like k-t FOCUSS or PICCS have been developed to improve performance. This study aims to investigate a new method, Dual-TRACER, based on Temporal Resolution Acceleration with Constrained Evolution Reconstruction (TRACER), for accelerating fMRI acquisitions using golden angle variable density spiral. Both numerical simulations and in vivo experiments at 3T were conducted to evaluate and characterize this method. Results show that Dual-TRACER can provide functional images with a high spatial resolution (1×1mm2) under an acceleration factor of 20 while maintaining hemodynamic signals well. Compared with other investigated methods, dual-TRACER provides a better signal recovery, higher fMRI sensitivity and more reliable activation detection.

  View details for DOI 10.1016/j.neuroimage.2017.02.087

  View details for Web of Science ID 000417972000016

  View details for PubMedID 28263924