John A. Sweeney

YNICL Journal 2024 Journal Article

Altered brain complexity in first-episode antipsychotic-naïve patients with schizophrenia: A whole-brain voxel-wise study

• Naici Liu
• Rebekka Lencer
• Christina Andreou
• Mihai Avram
• Heinz Handels
• Wenjing Zhang
• Sun Hui
• Chengmin Yang

BACKGROUND: Measures of cortical topology are believed to characterize large-scale cortical networks. Previous studies used region of interest (ROI)-based approaches with predefined templates that limit analyses to linear pair-wise interactions between regions. As cortical topology is inherently complex, a non-linear dynamic model that measures the brain complexity at the voxel level is suggested to characterize topological complexities of brain regions and cortical folding. METHODS: T1-weighted brain images of 150 first-episode antipsychotic-naïve schizophrenia (FES) patients and 161 healthy comparison participants (HC) were examined. The Chaos analysis approach was applied to detect alterations in brain structural complexity using the largest Lyapunov exponent (Lambda) as the key measure. Then, the Lambda spatial series was mapped in the frequency domain using the correlation of the Morlet wavelet to reflect cortical folding complexity. RESULTS: A widespread voxel-wise decrease in Lambda values in space and frequency domains was observed in FES, especially in frontal, parietal, temporal, limbic, basal ganglia, thalamic, and cerebellar regions. The widespread decrease indicates a general loss of brain topological complexity and cortical folding. An additional pattern of increased Lambda values in certain regions highlights the redistribution of complexity measures in schizophrenia at an early stage with potential progression as the illness advances. Strong correlations were found between the duration of untreated psychosis and Lambda values related to the cerebellum, temporal, and occipital gyri. CONCLUSIONS: Our findings support the notion that defining brain complexity by non-linear dynamic analyses offers a novel approach for identifying structural brain alterations related to the early stages of schizophrenia.

YNIMG Journal 2022 Journal Article

Brain-wide neural co-activations in resting human

• Lei Ding
• Guofa Shou
• Yoon-Hee Cha
• John A. Sweeney
• Han Yuan

Spontaneous neural activity in human as assessed with resting-state functional magnetic resonance imaging (fMRI) exhibits brain-wide coordinated patterns in the frequency of < 0.1 Hz. However, understanding of fast brain-wide networks at the timescales of neuronal events (milliseconds to sub-seconds) and their spatial, spectral, and transitional characteristics remain limited due to the temporal constraints of hemodynamic signals. With milli-second resolution and whole-head coverage, scalp-based electroencephalography (EEG) provides a unique window into brain-wide networks with neuronal-timescale dynamics, shedding light on the organizing principles of brain functions. Using the state-of-the-art signal processing techniques, we reconstructed cortical neural tomography from resting-state EEG and extracted component-based co-activation patterns (cCAPs). These cCAPs revealed brain-wide intrinsic networks and their dynamics, indicating the configuration/reconfiguration of resting human brains into recurring and transitional functional states, which are featured with the prominent spatial phenomena of global patterns and anti-state pairs of co-(de)activations. Rich oscillational structures across a wide frequency band (i.e., 0.6 Hz, 5 Hz, and 10 Hz) were embedded in the nonstationary dynamics of these functional states. We further identified a superstructure that regulated between-state immediate and long-range transitions involving the entire set of identified cCAPs and governed a significant aspect of brain-wide network dynamics. These findings demonstrated how resting-state EEG data can be functionally decomposed using cCAPs to reveal rich dynamic structures of brain-wide human neural activations.

YNICL Journal 2020 Journal Article

Resting state auditory-language cortex connectivity is associated with hallucinations in clinical and biological subtypes of psychotic disorders

• Victoria T. Okuneye
• Shashwath Meda
• Godfrey D. Pearlson
• Brett A. Clementz
• Matcheri S. Keshavan
• Carol A. Tamminga
• Elena Ivleva
• John A. Sweeney

BACKGROUND: Auditory hallucinations are prevalent across the major psychotic disorders, but their underlying mechanism is poorly understood. Limited prior work supports a hypothesis of altered auditory/language brain systems. To more definitively assess this, we examined whether alterations in resting state connectivity of auditory and language cortices are associated with hallucination severity in a large sample of individuals in the schizo-bipolar spectrum. METHODS: Whole brain resting state connectivity of auditory and language cortex (primary auditory cortex, unimodal auditory association cortex, Wernicke's area [speech and heteromodal association cortex] and Broca's area [speech production motor]) was evaluated for 243 subjects with schizophrenia, schizoaffective, or bipolar disorder with psychosis and 186 healthy controls from the Bipolar Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Regression analyses were conducted to evaluate whether resting state connectivity of auditory and language cortex was a significant predictor of current overall hallucination severity (information about specific modality of hallucinations experienced was not available). RESULTS: Increased connectivity between lower and higher order regions of left temporal-parietal auditory/language processing cortex was associated with worse hallucination severity for all psychosis patients. Additionally, within bipolar subjects, increased interhemispheric connectivity between higher order temporal-parietal auditory/language regions was related to greater hallucination severity. When patients were categorized by B-SNIP biomarker-based Biotype groups, interhemispheric connectivity between left auditory association cortex and right core auditory cortex was related to greater hallucination severity for Biotype 1 patients. Exploratory analyses resulted in different patterns of connectivity of auditory/language cortex in patients and controls, unrelated to current hallucination severity. CONCLUSIONS: Although the findings cannot be precisely attributed to auditory hallucination severity or possible differences in such experiences between groups, increased connectivity among the left hemisphere auditory and receptive language cortex may represent a significant factor contributing to hallucination severity across psychotic disorders, and additional subgroup specific connectivity alterations may also be present.

YNIMG Journal 2019 Journal Article

Network analysis reveals disrupted functional brain circuitry in drug-naive social anxiety disorder

• Xun Yang
• Jin Liu
• Yajing Meng
• Mingrui Xia
• Zaixu Cui
• Xi Wu
• Xinyu Hu
• Wei Zhang

Social anxiety disorder (SAD) is a common and disabling condition characterized by excessive fear and avoidance of public scrutiny. Psychoradiology studies have suggested that the emotional and behavior deficits in SAD are associated with abnormalities in regional brain function and functional connectivity. However, little is known about whether intrinsic functional brain networks in patients with SAD are topologically disrupted. Here, we collected resting-state fMRI data from 33 drug-naive patients with SAD and 32 healthy controls (HC), constructed functional networks with 34 predefined regions based on previous meta-analytic research with task-based fMRI in SAD, and performed network-based statistic and graph-theory analyses. The network-based statistic analysis revealed a single connected abnormal circuitry including the frontolimbic circuit (termed the “fear circuit”, including the dorsolateral prefrontal cortex, ventral medial prefrontal cortex and insula) and posterior cingulate/occipital areas supporting perceptual processing. In this single altered network, patients with SAD had higher functional connectivity than HC. At the global level, graph-theory analysis revealed that the patients exhibited a lower normalized characteristic path length than HC, which suggests a disorder-related shift of network topology toward randomized configurations. SAD-related deficits in nodal degree, efficiency and participation coefficient were detected in the parahippocampal gyrus, posterior cingulate cortex, dorsolateral prefrontal cortex, insula and the calcarine sulcus. Aspects of abnormal connectivity were associated with anxiety symptoms. These findings highlight the aberrant topological organization of functional brain network organization in SAD, which provides insights into the neural mechanisms underlying excessive fear and avoidance of social interactions in patients with debilitating social anxiety.

YNICL Journal 2018 Journal Article

Abnormal dynamic functional connectivity between speech and auditory areas in schizophrenia patients with auditory hallucinations

• Wenjing Zhang
• Siyi Li
• Xiuli Wang
• Yao Gong
• Li Yao
• Yuan Xiao
• Jieke Liu
• Sarah K. Keedy

Purpose: Auditory hallucinations (AH), typically hearing voices, are a core symptom in schizophrenia. They may result from deficits in dynamic functional connectivity (FC) between cortical regions supporting speech production and language perception that interfere with the ability to recognize self-generated speech as not coming from external sources. We tested this hypothesis by investigating dynamic connectivity between the frontal cortex region related to language production and the temporal cortex region related to auditory processing. Methods: Resting-state fMRI scans were acquired from 18 schizophrenia patients with AH (AH+), 17 schizophrenia patients without AH (AH-) and 22 healthy controls. A multiband sequence with TR = 427 ms was adopted to provide relatively high temporal resolution data for characterizing dynamic FC. Analysis focused on connectivity between speech production and language comprehension areas, eloquent language cortex in the left hemisphere. Two frequency bands of brain oscillatory activity were evaluated (0.01-0.027 Hz, 0.027-0.08 Hz) in which differential alterations that have been previously linked to schizophrenia. Conventional static FC maps of these seeds were also calculated. Results: Dynamic connectivity analysis indicated that AH+ patients showed not only less temporal variability but transient lower strength in connectivity between speech and auditory areas than healthy controls, while AH- patients not. These findings were restricted to 0.027-0.08 Hz activity. In static connectivity analysis, no significant differences were observed in connectivity between speech production and language comprehension areas in either frequency band. Conclusions: Reduced temporal variability and connectivity strength between key regions of eloquent language cortex may represent a mechanism for AH in schizophrenia.

YNICL Journal 2018 Journal Article

Disrupted grey matter network morphology in pediatric posttraumatic stress disorder

• Running Niu
• Du Lei
• Fuqin Chen
• Ying Chen
• Xueling Suo
• Lingjiang Li
• Su Lui
• Xiaoqi Huang

Introduction: Disrupted topological organization of brain functional networks has been widely observed in posttraumatic stress disorder (PTSD). However, the topological organization of the brain grey matter (GM) network has not yet been investigated in pediatric PTSD who was more vulnerable to develop PTSD when exposed to stress. Materials and methods: Twenty two pediatric PTSD patients and 22 matched trauma-exposed controls who survived a massive earthquake (8.0 magnitude on Richter scale) in Sichuan Province of western China in 2008 underwent structural brain imaging with MRI 8-15 months after the earthquake. Brain networks were constructed based on the morphological similarity of GM across regions, and analyzed using graph theory approaches. Nonparametric permutation testing was performed to assess group differences in each topological metric. Results: Compared with controls, brain networks of PTSD patients were characterized by decreased characteristic path length (P = 0.0060) and increased clustering coefficient (P = 0.0227), global efficiency (P = 0.0085) and local efficiency (P = 0.0024). Locally, patients with PTSD exhibited increased centrality in nodes of the default-mode (DMN), central executive (CEN) and salience networks (SN), involving medial prefrontal (mPFC), parietal, anterior cingulate (ACC), occipital and olfactory cortex and hippocampus. Conclusions: Our analyses of topological brain networks in children with PTSD indicate a significantly more segregated and integrated organization. The associations and disassociations between these grey matter findings and white matter (WM) and functional changes previously reported in this sample may be important for diagnostic purposes and understanding the brain maturational effects of pediatric PTSD.

YNICL Journal 2018 Journal Article

Volume alteration of hippocampal subfields in first-episode antipsychotic-naïve schizophrenia patients before and after acute antipsychotic treatment

• Wenbin Li
• Kaiming Li
• Pujun Guan
• Ying Chen
• Yuan Xiao
• Su Lui
• John A. Sweeney
• Qiyong Gong

The nature of hippocampal changes in schizophrenia before first treatment, and whether hippocampal subfields are affected by antipsychotic treatment are important questions for schizophrenia research. Forty-one first-episode antipsychotic-naïve acutely ill schizophrenia inpatients had MRI scans before and six weeks after antipsychotic treatment. Thirty-nine matched healthy controls were also scanned, twenty-two of which were scanned a second time six weeks later. Volumes of hippocampal subfields were measured via FreeSurfer v6.0 using a longitudinal analysis pipeline. Before treatment, schizophrenia patients had no significant changes in total hippocampal volume but exhibited significantly greater subfield volumes than controls in bilateral molecular layers of the hippocampus (ML), bilateral granular cell layers of the dentate gyrus (GC-DG), and bilateral cornu ammonis area 4 (CA4). After six weeks of antipsychotic treatment, patients showed volume reductions compared with pretreatment scans in total hippocampus bilaterally, with subfield volume reduction noted in previously enlarged subfields (i.e., bilateral ML, GC-DG and CA4) and in bilateral hippocampal tails, left CA1, CA3, and fimbria. Subfields with volume increases before treatment were reduced to the level of healthy controls (bilateral ML and GC-DG) or near to it (bilateral CA4) after treatment. These results indicate subfield-specific hippocampal hypertrophy prior to treatment, and that these abnormalities were reduced after acute antipsychotic therapy in a dose-related manner together with volume reductions in other areas that were not hypertrophic before treatment.

YNIMG Journal 2014 Journal Article

Action planning and predictive coding when speaking

• Jun Wang
• Daniel H. Mathalon
• Brian J. Roach
• James Reilly
• Sarah K. Keedy
• John A. Sweeney
• Judith M. Ford

Across the animal kingdom, sensations resulting from an animal's own actions are processed differently from sensations resulting from external sources, with self-generated sensations being suppressed. A forward model has been proposed to explain this process across sensorimotor domains. During vocalization, reduced processing of one's own speech is believed to result from a comparison of speech sounds to corollary discharges of intended speech production generated from efference copies of commands to speak. Until now, anatomical and functional evidence validating this model in humans has been indirect. Using EEG with anatomical MRI to facilitate source localization, we demonstrate that inferior frontal gyrus activity during the 300ms before speaking was associated with suppressed processing of speech sounds in auditory cortex around 100ms after speech onset (N1). These findings indicate that an efference copy from speech areas in prefrontal cortex is transmitted to auditory cortex, where it is used to suppress processing of anticipated speech sounds. About 100ms after N1, a subsequent auditory cortical component (P2) was not suppressed during talking. The combined N1 and P2 effects suggest that although sensory processing is suppressed as reflected in N1, perceptual gaps may be filled as reflected in the lack of P2 suppression, explaining the discrepancy between sensory suppression and preserved sensory experiences. These findings, coupled with the coherence between relevant brain regions before and during speech, provide new mechanistic understanding of the complex interactions between action planning and sensory processing that provide for differentiated tagging and monitoring of one's own speech, processes disrupted in neuropsychiatric disorders.

YNIMG Journal 2011 Journal Article

Gray matter loss in young relatives at risk for schizophrenia: Relation with prodromal psychopathology

• Tejas S. Bhojraj
• John A. Sweeney
• Konasale M. Prasad
• Shaun M. Eack
• Alan N. Francis
• Jean M. Miewald
• Debra M. Montrose
• Matcheri S. Keshavan

The maturation of neocortical regions mediating social cognition during adolescence and young adulthood in relatives of schizophrenia patients may be vulnerable to heritable alterations of neurodevelopment. Prodromal psychotic symptoms, commonly emerging during this period in relatives, have been hypothesized to result from alterations in brain regions mediating social cognition. We hypothesized these regions to show longitudinal alterations and these alterations to predict prodromal symptoms in adolescent and young adult relatives of schizophrenia patients. 27 Healthy controls and 23 relatives were assessed at baseline and one-year follow-up using scale of prodromal symptoms and gray matter volumes of hypothesized regions from T1-MRI images. Regional volumes showing deficits on ANCOVA and repeated-measures ANCOVAs (controlling intra cranial volume, age and gender) were correlated with prodromal symptoms. At baseline, bilateral amygdalae, bilateral pars triangulares, left lateral orbitofrontal, right frontal pole, angular and supramarginal gyrii were smaller in relatives compared to controls. Relatives declined but controls increased or remained stable on bilateral lateral orbitofrontal, left rostral anterior cingulate, left medial prefrontal, right inferior frontal gyrus and left temporal pole volumes at follow-up relative to baseline. Smaller volumes predicted greater severity of prodromal symptoms at both cross-sectional assessments. Longitudinally, smaller baseline volumes predicted greater prodromal symptoms at follow-up; greater longitudinal decreases in volumes predicted worsening (increase) of prodromal symptoms over time. These preliminary findings suggest that abnormal longitudinal gray matter loss may occur in regions mediating social cognition and may convey risk for prodromal symptoms during adolescence and early adulthood in individuals with a familial diathesis for schizophrenia.

YNIMG Journal 2011 Journal Article

Human reversal learning under conditions of certain versus uncertain outcomes

• Anna-Maria D'Cruz
• Michael E. Ragozzino
• Matthew W. Mosconi
• Mani N. Pavuluri
• John A. Sweeney

Reversal learning tasks assess behavioral flexibility by requiring subjects to switch from one learned response choice to a different response choice when task contingencies change. This requires both the processing of negative feedback once a learned response is no longer reinforced, and the capacity for flexible response selection. In 2-choice reversal learning tasks, subjects switch between only two responses. Multiple choice reversal learning is qualitatively different in that at reversal, it requires subjects to respond to non-reinforcement of a learned response by selecting a new response from among several alternatives that have uncertain consequences. While activity in brain regions responsible for processing unexpected negative feedback is known to increase in relation to the hedonic value of the reward itself, it is not known whether the uncertainty of reinforcement for future response choices also modulates these responses. In an fMRI study, 15 participants performed 2- and 4-choice reversal learning tasks. Upon reversal in both tasks, activation was observed in brain regions associated with processing changing reinforcement contingencies (midbrain, ventral striatum, insula), as well as in neocortical regions that support cognitive control and behavioral planning (prefrontal, premotor, posterior parietal, and anterior cingulate cortices). Activation in both systems was greater in the 4- than in the 2-choice task. Therefore, reinforcement uncertainty for future responses enhanced activity in brain systems that process performance feedback, as well as in areas supporting behavioral planning of future response choices. A mutually facilitative integration of responses in motivational and cognitive brain systems might enhance behavioral flexibility and decision making in conditions for which outcomes for future response choices are uncertain.

YNIMG Journal 2007 Journal Article

fMRI studies of eye movement control: Investigating the interaction of cognitive and sensorimotor brain systems

• John A. Sweeney
• Beatriz Luna
• Sarah K. Keedy
• Jennifer E. McDowell
• Brett A. Clementz

Functional neuroimaging studies of eye movement control have been a useful approach for investigating the interaction of cognitive and sensorimotor brain systems. Building on unit recording studies of behaving nonhuman primates and clinical studies of patients with a focal brain lesion, functional neuroimaging studies have elucidated a pattern of hierarchical organization through which prefrontal and premotor systems interact with sensorimotor systems to support context-dependent adaptive behavior. Studies of antisaccades, memory-guided saccades, and predictive saccades have helped clarify how cognitive brain systems support contextually guided and internally generated action. The use of cognitive and sensorimotor eye movement paradigms is being used to develop a better understanding of life span changes in neurocognitive systems from childhood to late life, and about behavioral and systems-level brain abnormalities in neuropsychiatric disorders.

YNIMG Journal 2004 Journal Article

Estimation and classification of fMRI hemodynamic response patterns

• Robert D. Gibbons
• Nicole A. Lazar
• Dulal K. Bhaumik
• Stanley L. Sclove
• Hua Yun Chen
• Keith R. Thulborn
• John A. Sweeney
• Kwan Hur

In this paper, we propose an approach to modeling functional magnetic resonance imaging (fMRI) data that combines hierarchical polynomial models, Bayes estimation, and clustering. A cubic polynomial is used to fit the voxel time courses of event-related design experiments. The coefficients of the polynomials are estimated by Bayes estimation, in a two-level hierarchical model, which allows us to borrow strength from all voxels. The voxel-specific Bayes polynomial coefficients are then transformed to the times and magnitudes of the minimum and maximum points on the hemodynamic response curve, which are in turn used to classify the voxels as being activated or not. The procedure is demonstrated on real data from an event-related design experiment of visually guided saccades and shown to be an effective alternative to existing methods.

YNIMG Journal 2002 Journal Article

Combining Brains: A Survey of Methods for Statistical Pooling of Information

• Nicole A. Lazar
• Beatriz Luna
• John A. Sweeney
• William F. Eddy

More than one subject is scanned in a typical functional brain imaging experiment. How can the scientist make best use of the acquired data to map the specific areas of the brain that become active during the performance of different tasks? It is clear that we can gain both scientific and statistical power by pooling the images from multiple subjects; furthermore, for the comparison of groups of subjects (clinical patients vs healthy controls, children of different ages, left-handed people vs right-handed people, as just some examples), it is essential to have a “group map” to represent each population and to form the basis of a statistical test. While the importance of combining images for these purposes has been recognized, there has not been an organized attempt on the part of neuroscientists to understand the different statistical approaches to this problem, which have various strengths and weaknesses. In this paper we review some popular methods for combining information, and demonstrate the surveyed techniques on a sample data set. Given a combination of brain images, the researcher needs to interpret the result and decide on areas of activation; the question of thresholding is critical here and is also explored.

YNIMG Journal 2001 Journal Article

Maturation of Widely Distributed Brain Function Subserves Cognitive Development

• Beatriz Luna
• Keith R. Thulborn
• Douglas P. Munoz
• Elisha P. Merriam
• Krista E. Garver
• Nancy J. Minshew
• Matcheri S. Keshavan
• Christopher R. Genovese

Cognitive and brain maturational changes continue throughout late childhood and adolescence. During this time, increasing cognitive control over behavior enhances the voluntary suppression of reflexive/impulsive response tendencies. Recently, with the advent of functional MRI, it has become possible to characterize changes in brain activity during cognitive development. In order to investigate the cognitive and brain maturation subserving the ability to voluntarily suppress context-inappropriate behavior, we tested 8–30 year olds in an oculomotor response–suppression task. Behavioral results indicated that adult-like ability to inhibit prepotent responses matured gradually through childhood and adolescence. Functional MRI results indicated that brain activation in frontal, parietal, striatal, and thalamic regions increased progressively from childhood to adulthood. Prefrontal cortex was more active in adolescents than in children or adults; adults demonstrated greater activation in the lateral cerebellum than younger subjects. These results suggest that efficient top-down modulation of reflexive acts may not be fully developed until adulthood and provide evidence that maturation of function across widely distributed brain regions lays the groundwork for enhanced voluntary control of behavior during cognitive development.

YNIMG Journal 2001 Journal Article

Stimulus–Response Incompatibility Activates Cortex Proximate to Three Eye Fields

• Elisha P. Merriam
• Carol L. Colby
• Keith R. Thulborn
• Beatriz Luna
• Carl R. Olson
• John A. Sweeney

We used functional magnetic resonance imaging (fMRI) to investigate cortical activation during the performance of three oculomotor tasks that impose increasing levels of cognitive demand. (1) In a visually guided saccade (VGS) task, subjects made saccades to flashed targets. (2) In a compatible task, subjects made leftward and rightward saccades in response to foveal presentation of the uppercase words “LEFT” or “RIGHT. ” (3) In a mixed task, subjects made rightward saccades in response to the lowercase word “left” and leftward saccades in response to the lowercase word “right” on incompatible trials (60%). The remaining 40% of trials required compatible responses to uppercase words. The VGS and compatible tasks, when compared to fixation, activated the three cortical eye fields: the supplementary eye field (SEF), the frontal eye field (FEF), and the parietal eye field (PEF). The mixed task, when compared to the compatible task, activated three additional cortical regions proximate to the three eye fields: (1) rostral to the SEF in medial frontal cortex; (2) rostral to the FEF in dorsolateral prefrontal cortex (DLPFC); (3) rostral and lateral to the PEF in posterior parietal cortex. These areas may contribute to the suppression of prepotent responses and in holding novel visuomotor associations in working memory.

YNIMG Journal 1996 Journal Article

Clinical fMRI: Implementation and Experience

• Keith R. Thulborn
• Denise Davis
• Patricia Erb
• Magda Strojwas
• John A. Sweeney