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Randy L. Gollub

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YNIMG Journal 2021 Journal Article

Perturbing fMRI brain dynamics using transcranial direct current stimulation

  • Yiheng Tu
  • Jin Cao
  • Seyhmus Guler
  • Thalia Chai-Zhang
  • Joan A. Camprodon
  • Mark Vangel
  • Randy L. Gollub
  • Darin D. Dougherty

The dynamic nature of resting-state functional magnetic resonance imaging (fMRI) brain activity and connectivity has drawn great interest in the past decade. Specific temporal properties of fMRI brain dynamics, including metrics such as occurrence rate and transitions, have been associated with cognition and behaviors, indicating the existence of mechanism distruption in neuropsychiatric disorders. The development of new methods to manipulate fMRI brain dynamics will advance our understanding of these pathophysiological mechanisms from native observation to experimental mechanistic manipulation. In the present study, we applied repeated transcranial direct current stimulation (tDCS) to the right dorsolateral prefrontal cortex (rDLPFC) and the left orbitofrontal cortex (lOFC), during multiple simultaneous tDCS-fMRI sessions from 81 healthy participants to assess the modulatory effects of stimulating target brain regions on fMRI brain dynamics. Using the rDLPFC and the lOFC as seeds, respectively, we first identified two reoccurring co-activation patterns (CAPs) and calculated their temporal properties (e.g., occurrence rate and transitions) before administering tDCS. The spatial maps of CAPs were associated with different cognitive and disease domains using meta-analytical decoding analysis. We then investigated how active tDCS compared to sham tDCS in the modulation of the occurrence rates of these different CAPs and perturbations of transitions between CAPs. We found that by enhancing neuronal excitability of the rDLPFC and the lOFC, the occurrence rate of one CAP was significantly decreased while that of another CAP was significantly increased during the first 6 min of stimulation. Furthermore, these tDCS-associated changes persisted over subsequent testing sessions (both during and before/after tDCS) across three consecutive days. Active tDCS could perturb transitions between CAPs and a non-CAP state (when the rDLPFC and the lOFC were not activated), but not the transitions within CAPs. These results demonstrate the feasibility of modulating fMRI brain dynamics, and open new possibilities for discovering stimulation targets and dynamic connectivity patterns that can ensure the propagation of tDCS-induced neuronal excitability, which may facilitate the development of new treatments for disorders with altered dynamics.

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YNICL Journal 2020 Journal Article

Corrigendum to “Multivariate resting-state functional connectivity predicts responses to real and sham acupuncture treatment in chronic low back pain” [Neuroimage Clinical 23 (2019) 101885]

  • Yiheng Tu
  • Ana Ortiz
  • Randy L. Gollub
  • Jin Cao
  • Jessica Gerber
  • Courtney Lang
  • Joel Park
  • Georgia Wilson

The authors regret to find several errors that do not influence the main findings or conclusions.Specifically, we have found that the values of pre-and post-treatment clinical sub-scores for 'physical function' and 'sleep' in Fig. 4 contain errors.The corrected Fig. 4 is shown below: As a result, the Results section 3.3 (Page 6, right column): "Real and sham acupuncture significantly reduced PROMIS sub-scores in

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YNIMG Journal 2020 Journal Article

Impaired mesocorticolimbic connectivity underlies increased pain sensitivity in chronic low back pain

  • Siyi Yu
  • Wen Li
  • Wei Shen
  • Robert R. Edwards
  • Randy L. Gollub
  • Georgia Wilson
  • Joel Park
  • Ana Ortiz

Chronic low back pain (cLBP) is a prevalent disorder. A growing body of evidence linking the pathology of the reward network to chronic pain suggests that pain sensitization may contribute to cLBP chronification via disruptions of mesocortical and mesolimbic circuits in the reward system. Resting-state (RS) functional magnetic resonance imaging (fMRI) data was acquired from 90 patients with cLBP and 74 matched pain-free controls (HCs) at baseline and after a manipulation for back pain intensification. The ventral tegmental area (VTA) was chosen as a seed region to perform RS functional connectivity (FC) analysis. Baseline rsFC of both the mesocortical (between the VTA and bilateral rostral anterior cingulate cortex (rACC)/and medial prefrontal cortex (mPFC)) and mesolimbic (between the VTA and bilateral hippocampus/parahippocampus) pathways was reduced in patients with cLBP (vs. HCs). In addition, patients exhibiting higher back pain intensity (compared to the relatively lower back pain intensity condition) also showed increases in both mesocortical and mesolimbic connectivity, implicating these pathways in pain downregulation in cLBP. Mediation analysis further isolated the mesolimbic (VTA-hippocampus/parahippocampus) dysconnectivity as a neural mechanism mediating the association between mechanical pain sensitivity (indexed by P40 pressure) and cLBP severity. In sum, the current study demonstrates deficient mesocorticolimbic connectivity in cLBP, with mesolimbic dysconnectivity potentially mediating the contribution of pain sensitization to pain chronification. These reward network dysfunctions and purportedly, dopaminergic dysregulations, may help us to identify key brain targets of neuromodulation in the treatment of cLBP.

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YNIMG Journal 2020 Journal Article

Reduced tactile acuity in chronic low back pain is linked with structural neuroplasticity in primary somatosensory cortex and is modulated by acupuncture therapy

  • Hyungjun Kim
  • Ishtiaq Mawla
  • Jeungchan Lee
  • Jessica Gerber
  • Kathryn Walker
  • Jieun Kim
  • Ana Ortiz
  • Suk-Tak Chan

Prior studies have shown that patients suffering from chronic Low Back Pain (cLBP) have impaired somatosensory processing including reduced tactile acuity, i. e. reduced ability to resolve fine spatial details with the perception of touch. The central mechanism(s) underlying reduced tactile acuity are unknown but may include changes in specific brain circuitries (e. g. neuroplasticity in the primary somatosensory cortex, S1). Furthermore, little is known about the linkage between changes in tactile acuity and the amelioration of cLBP by somatically-directed therapeutic interventions, such as acupuncture. In this longitudinal neuroimaging study, we evaluated healthy control adults (HC, N ​= ​50) and a large sample of cLBP patients (N ​= ​102) with structural brain imaging (T1-weighted MRI for Voxel-Based Morphometry, VBM; Diffusion Tensor Imaging, DTI) and tactile acuity testing using two-point discrimination threshold (2PDT) over the lower back (site of pain) and finger (control) locations. Patients were evaluated at baseline and following a 4-week course of acupuncture, with patients randomized to either verum acupuncture, two different forms of sham acupuncture (designed with or without somatosensory afference), or no-intervention usual care control. At baseline, cLBP patients demonstrated reduced acuity (greater 2PDT, P ​= ​0. 01) over the low back, but not finger (P ​= ​0. 29) locations compared to HC, suggesting that chronic pain affects tactile acuity specifically at body regions encoding the experience of clinical pain. At baseline, Gray Matter Volume (GMV) was elevated and Fractional Anisotropy (FA) was reduced, respectively, in the S1-back region of cLBP patients compared to controls (P ​< ​0. 05). GMV in cLBP correlated with greater 2PDT-back scores (ρ ​= ​0. 27, P ​= ​0. 02). Following verum acupuncture, tactile acuity over the back was improved (reduced 2PDT) and greater improvements were associated with reduced S1-back GMV (ρ ​= ​0. 52, P ​= ​0. 03) and increased S1-back adjacent white matter FA (ρ ​= ​−0. 56, P ​= ​0. 01). These associations were not seen for non-verum control interventions. Thus, S1 neuroplasticity in cLBP is linked with deficits in tactile acuity and, following acupuncture therapy, may represent early mechanistic changes in somatosensory processing that track with improved tactile acuity.

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YNICL Journal 2019 Journal Article

Corrigendum to ‘Multivariate resting-state functional connectivity predicts responses to real and sham acupuncture treatment in chronic low back pain’ Neuroimage Clinical, 23, 2019, 101885

  • Yiheng Tu
  • Ana Ortiz
  • Randy L. Gollub
  • Jin Cao
  • Jessica Gerber
  • Courtney Lang
  • Joel Park
  • Georgia Wilson

The authors regret to find several errors that do not influence the main findings or conclusions.Specifically, we have found that the values of pre-and post-treatment clinical sub-scores for 'physical function' and 'sleep' in Fig. 4 contain errors.The corrected Fig. 4 is shown below: As a result, the Results section 3.3 (Page 6, right column): "Real and sham acupuncture significantly reduced PROMIS sub-scores in

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YNICL Journal 2019 Journal Article

Multivariate resting-state functional connectivity predicts responses to real and sham acupuncture treatment in chronic low back pain

  • Yiheng Tu
  • Ana Ortiz
  • Randy L. Gollub
  • Jin Cao
  • Jessica Gerber
  • Courtney Lang
  • Joel Park
  • Georgia Wilson

Despite the high prevalence and socioeconomic impact of chronic low back pain (cLBP), treatments for cLBP are often unsatisfactory, and effectiveness varies widely across patients. Recent neuroimaging studies have demonstrated abnormal resting-state functional connectivity (rsFC) of the default mode, salience, central executive, and sensorimotor networks in chronic pain patients, but their role as predictors of treatment responsiveness has not yet been explored. In this study, we used machine learning approaches to test if pre-treatment rsFC can predict responses to both real and sham acupuncture treatments in cLBP patients. Fifty cLBP patients participated in 4 weeks of either real (N = 24, age = 39.0 ± 12.6, 16 females) or sham acupuncture (N = 26, age = 40.0 ± 13.7, 15 females) treatment in a single-blinded trial, and a resting-state fMRI scan prior to treatment was used in data analysis. Both real and sham acupuncture can produce significant pain reduction, with those receiving real treatment experiencing greater pain relief than those receiving sham treatment. We found that pre-treatment rsFC could predict symptom changes with up to 34% and 29% variances for real and sham treatment, respectively, and the rsFC characteristics that were significantly predictive for real and sham treatment differed. These results suggest a potential way to predict treatment responses and may facilitate the development of treatment plans that optimize time, cost, and available resources.

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YNICL Journal 2019 Journal Article

Visual network alterations in brain functional connectivity in chronic low back pain: A resting state functional connectivity and machine learning study

  • Wei Shen
  • Yiheng Tu
  • Randy L. Gollub
  • Ana Ortiz
  • Vitaly Napadow
  • Siyi Yu
  • Georgia Wilson
  • Joel Park

Chronic low back pain (cLBP) is associated with widespread functional and structural changes in the brain. This study aims to investigate the resting state functional connectivity (rsFC) changes of visual networks in cLBP patients and the feasibility of distinguishing cLBP patients from healthy controls using machine learning methods. cLBP (n = 90) and control individuals (n = 74) were enrolled and underwent resting-state BOLD fMRI scans. Primary, dorsal, and ventral visual networks derived from independent component analysis were used as regions of interest to compare resting state functional connectivity changes between the cLBP patients and healthy controls. We then applied a support vector machine classifier to distinguish the cLBP patients and control individuals. These results were further verified in a new cohort of subjects. We found that the functional connectivity between the primary visual network and the somatosensory/motor areas were significantly enhanced in cLBP patients. The rsFC between the primary visual network and S1 was negatively associated with duration of cLBP. In addition, we found that the rsFC of the visual network could achieve a classification accuracy of 79.3% in distinguishing cLBP patients from HCs, and these results were further validated in an independent cohort of subjects (accuracy = 66.7%). Our results demonstrate significant changes in the rsFC of the visual networks in cLBP patients. We speculate these alterations may represent an adaptation/self-adjustment mechanism and cross-model interaction between the visual, somatosensory, motor, attention, and salient networks in response to cLBP. Elucidating the role of the visual networks in cLBP may shed light on the pathophysiology and development of the disorder.

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YNICL Journal 2018 Journal Article

Basal ganglia involvement in ARX patients: The reason for ARX patients very specific grasping?

  • Aurore Curie
  • Gaëlle Friocourt
  • Vincent des Portes
  • Alice Roy
  • Tatjana Nazir
  • Amandine Brun
  • Anne Cheylus
  • Pascale Marcorelles

The ARX (Aristaless Related homeoboX) gene was identified in 2002 as responsible for XLAG syndrome, a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons, and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in the ARX gene, a duplication of 24 base pairs (c. 429_452dup24) in exon 2, results in a recognizable syndrome in which patients present ID without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip, described as developmental Limb Kinetic Apraxia (LKA). In this study, we first present ARX expression during human fetal brain development showing that it is strongly expressed in GABAergic neuronal progenitors during the second and third trimester of pregnancy. We show that although ARX expression strongly decreases towards the end of gestation, it is still present after birth in some neurons of the basal ganglia, thalamus and cerebral cortex, suggesting that ARX also plays a role in more mature neuron functioning. Then, using morphometric brain MRI in 13 ARX patients carrying c. 429_452dup24 mutation and in 13 sex- and age-matched healthy controls, we show that ARX patients have a significantly decreased volume of several brain structures including the striatum (and more specifically the caudate nucleus), hippocampus and thalamus as well as decreased precentral gyrus cortical thickness. We observe a significant correlation between caudate nucleus volume reduction and motor impairment severity quantified by kinematic parameter of precision grip. As basal ganglia are known to regulate sensorimotor processing and are involved in the control of precision gripping, the combined decrease in cortical thickness of primary motor cortex and basal ganglia volume in ARX dup24 patients is very likely the anatomical substrate of this developmental form of LKA.

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YNICL Journal 2018 Journal Article

Enhancing treatment of osteoarthritis knee pain by boosting expectancy: A functional neuroimaging study

  • Jian Kong
  • Zengjian Wang
  • Jaclyn Leiser
  • Domenic Minicucci
  • Robert Edwards
  • Irving Kirsch
  • Ajay D. Wasan
  • Courtney Lang

Objectives: Expectation can significantly modulate pain and treatment effects. This study aims to investigate if boosting patients' expectancy can enhance the treatment of knee osteoarthritis (KOA), and its underlying brain mechanism. Methods: Seventy-four KOA patients were recruited and randomized to three groups: boosted acupuncture (with a manipulation to enhance expectation), standard acupuncture, or treatment as usual (TAU). Each patient underwent six treatments before being debriefed, and four additional treatments after being debriefed. The fMRI scans were applied during the first and sixth treatment sessions. Results: We found significantly decreased knee pain in the boosted acupuncture group compared to the standard acupuncture or TAU groups after both six and ten treatments. Resting state functional connectivity (rsFC) analyses using the nucleus accumbens (NAc) as the seed showed rsFC increases between the NAc and the medial prefrontal cortex (MPFC)/rostral anterior cingulate cortex (rACC) and dorsolateral prefrontal cortex in the boosted group as compared to the standard acupuncture group after multiple treatments. Expectancy scores after the first treatment were significantly associated with increased NAc-rACC/MPFC rsFC and decreased knee pain following treatment. Conclusions: Our study provides a novel method and mechanism for boosting the treatment of pain in patients with KOA. Our findings may shed light on enhancing outcomes of pharmacological and integrative medicines in clinical settings.

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YNIMG Journal 2018 Journal Article

Maturation trajectories of cortical resting-state networks depend on the mediating frequency band

  • Sheraz Khan
  • Javeria A. Hashmi
  • Fahimeh Mamashli
  • Konstantinos Michmizos
  • Manfred G. Kitzbichler
  • Hari Bharadwaj
  • Yousra Bekhti
  • Santosh Ganesan

The functional significance of resting state networks and their abnormal manifestations in psychiatric disorders are firmly established, as is the importance of the cortical rhythms in mediating these networks. Resting state networks are known to undergo substantial reorganization from childhood to adulthood, but whether distinct cortical rhythms, which are generated by separable neural mechanisms and are often manifested abnormally in psychiatric conditions, mediate maturation differentially, remains unknown. Using magnetoencephalography (MEG) to map frequency band specific maturation of resting state networks from age 7 to 29 in 162 participants (31 independent), we found significant changes with age in networks mediated by the beta (13–30 Hz) and gamma (31–80 Hz) bands. More specifically, gamma band mediated networks followed an expected asymptotic trajectory, but beta band mediated networks followed a linear trajectory. Network integration increased with age in gamma band mediated networks, while local segregation increased with age in beta band mediated networks. Spatially, the hubs that changed in importance with age in the beta band mediated networks had relatively little overlap with those that showed the greatest changes in the gamma band mediated networks. These findings are relevant for our understanding of the neural mechanisms of cortical maturation, in both typical and atypical development.

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YNIMG Journal 2015 Journal Article

Brain extraction in pediatric ADC maps, toward characterizing neuro-development in multi-platform and multi-institution clinical images

  • Yangming Ou
  • Randy L. Gollub
  • Kallirroi Retzepi
  • Nathaniel Reynolds
  • Rudolph Pienaar
  • Steve Pieper
  • Shawn N. Murphy
  • P. Ellen Grant

Apparent Diffusion Coefficient (ADC) maps can be used to characterize myelination and to detect abnormalities in the developing brain. However, given the normal variation in regional ADC with myelination, detection of abnormalities is difficult when based on visual assessment. Quantitative and automated analysis of pediatric ADC maps is thus desired but requires accurate brain extraction as the first step. Currently, most existing brain extraction methods are optimized for structural T1-weighted MR images of fully myelinated brains. Due to differences in age and image contrast, these approaches do not translate well to pediatric ADC maps. To address this problem, we present a multi-atlas brain extraction framework that has 1) specificity: designed and optimized specifically for pediatric ADC maps; 2) generality: applicable to multi-platform and multi-institution data, and to subjects at various neuro-developmental stages across the first 6years of life; 3) accuracy: highly accurate compared to expert annotations; and 4) consistency: consistently accurate regardless of sources of data and ages of subjects. We show how we achieve these goals, via optimizing major components in a multi-atlas brain extraction framework, and via developing and evaluating new criteria for its atlas ranking component. Moreover, we demonstrate that these goals can be achieved with a fixed set of atlases and a fixed set of parameters, which opens doors for our optimized framework to be used in large-scale and multi-institution neuro-developmental and clinical studies. In a pilot study, we use this framework in a dataset containing scanner-generated ADC maps from 308 pediatric patients collected during the course of routine clinical care. Our framework leads to successful quantifications of the changes in whole-brain volumes and mean ADC values across the first 6years of life.

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YNIMG Journal 2015 Journal Article

Distinct neural representations of placebo and nocebo effects

  • Sonya Freeman
  • Rongjun Yu
  • Natalia Egorova
  • Xiaoyan Chen
  • Irving Kirsch
  • Brian Claggett
  • Ted J. Kaptchuk
  • Randy L. Gollub

Expectations shape the way we experience the world. In this study, we used fMRI to investigate how positive and negative expectation can change pain experiences in the same cohort of subjects. We first manipulated subjects' treatment expectation of the effectiveness of three inert creams, with one cream labeled “Lidocaine” (positive expectancy), one labeled “Capsaicin” (negative expectancy) and one labeled “Neutral” by surreptitiously decreasing, increasing, or not changing respectively, the intensity of the noxious stimuli administered following cream application. We then used fMRI to investigate the signal changes associated with administration of identical pain stimuli before and after the treatment and control creams. Twenty-four healthy adults completed the study. Results showed that expectancy significantly modulated subjective pain ratings. After controlling for changes in the neutral condition, the subjective pain rating changes evoked by positive and negative expectancies were significantly associated. fMRI results showed that the expectation of an increase in pain induced significant fMRI signal changes in the insula, orbitofrontal cortex, and periaqueductal gray, whereas the expectation of pain relief evoked significant fMRI signal changes in the striatum. No brain regions were identified as common to both “Capsaicin” and “Lidocaine” conditioning. There was also no significant association between the brain response to identical noxious stimuli in the pain matrix evoked by positive and negative expectancies. Our findings suggest that positive and negative expectancies engage different brain networks to modulate our pain experiences, but, overall, these distinct patterns of neural activation result in a correlated placebo and nocebo behavioral response.

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YNICL Journal 2015 Journal Article

Repeated verum but not placebo acupuncture normalizes connectivity in brain regions dysregulated in chronic pain

  • Natalia Egorova
  • Randy L. Gollub
  • Jian Kong

Acupuncture, an ancient East Asian therapy, is aimed at rectifying the imbalance within the body caused by disease. Studies evaluating the efficacy of acupuncture with neuroimaging tend to concentrate on brain regions within the pain matrix, associated with acute pain. We, however, focused on the effect of repeated acupuncture treatment specifically on brain regions known to support functions dysregulated in chronic pain disorders. Transition to chronic pain is associated with increased attention to pain, emotional rumination, nociceptive memory and avoidance learning, resulting in brain connectivity changes, specifically affecting the periaqueductal gray (PAG), medial frontal cortex (MFC) and bilateral hippocampus (Hpc). We demonstrate that the PAG-MFC and PAG-Hpc connectivity in patients with chronic pain due to knee osteoarthritis indeed correlates with clinical severity scores and further show that verum acupuncture-induced improvement in pain scores (compared to sham) is related to the modulation of PAG-MFC and PAG-Hpc connectivity in the predicted direction. This study shows that repeated verum acupuncture might act by restoring the balance in the connectivity of the key pain brain regions, altering pain-related attention and memory.

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YNICL Journal 2014 Journal Article

Disrupted functional connectivity of the periaqueductal gray in chronic low back pain

  • Rongjun Yu
  • Randy L. Gollub
  • Rosa Spaeth
  • Vitaly Napadow
  • Ajay Wasan
  • Jian Kong

Chronic low back pain is a common neurological disorder. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. In this study, we investigated brain resting state PAG functional connectivity (FC) differences between patients with chronic low back pain (cLBP) in low pain or high pain condition and matched healthy controls (HCs). PAG seed based functional connectivity (FC) analysis of the functional MR imaging data was performed to investigate the difference among the connectivity maps in the cLBP in the low or high pain condition and HC groups as well as within the cLBP at differing endogenous back pain intensities. Results showed that FC between the PAG and the ventral medial prefrontal cortex (vmPFC)/rostral anterior cingulate cortex (rACC) increased in cLBP patients compared to matched controls. In addition, we also found significant negative correlations between pain ratings and PAG-vmPFC/rACC FC in cLBP patients after pain-inducing maneuver. The duration of cLBP was negatively correlated with PAG-insula and PAG-amygdala FC before pain-inducing maneuver in the patient group. These findings are in line with the impairments of the descending pain modulation reported in patients with cLBP. Our results provide evidence showing that cLBP patients have abnormal FC in PAG centered pain modulation network during rest.

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YNIMG Journal 2014 Journal Article

Simultaneous fMRI–PET of the opioidergic pain system in human brain

  • Hsiao-Ying Wey
  • Ciprian Catana
  • Jacob M. Hooker
  • Darin D. Dougherty
  • Gitte M. Knudsen
  • Danny J.J. Wang
  • Daniel B. Chonde
  • Bruce R. Rosen

MRI and PET provide complementary information for studying brain function. While the potential use of simultaneous MRI/PET for clinical diagnostic and disease staging has been demonstrated recently; the biological relevance of concurrent functional MRI–PET brain imaging to dissect neurochemically distinct components of the blood oxygenation level dependent (BOLD) fMRI signal has not yet been shown. We obtained sixteen fMRI–PET data sets from eight healthy volunteers. Each subject participated in randomized order in a pain scan and a control (nonpainful pressure) scan on the same day. Dynamic PET data were acquired with an opioid radioligand, [11C]diprenorphine, to detect endogenous opioid releases in response to pain. BOLD fMRI data were collected at the same time to capture hemodynamic responses. In this simultaneous human fMRI–PET imaging study, we show co-localized responses in thalamus and striatum related to pain processing, while modality specific brain networks were also found. Co-localized fMRI and PET signal changes in the thalamus were positively correlated suggesting that pain-induced changes in opioid neurotransmission contribute a significant component of the fMRI signal change in this region. Simultaneous fMRI–PET provides unique opportunities allowing us to relate specific neurochemical events to functional hemodynamic activation and to investigate the impacts of neurotransmission on neurovascular coupling of the human brain in vivo.

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YNIMG Journal 2011 Journal Article

DISC1 is associated with cortical thickness and neural efficiency

  • Stefan Brauns
  • Randy L. Gollub
  • Joshua L. Roffman
  • Anastasia Yendiki
  • Beng-Choon Ho
  • Thomas H. Wassink
  • Andreas Heinz
  • Stefan Ehrlich

Background Disrupted in schizophrenia 1 (DISC1) is known to play a major role during brain development and is a candidate gene for schizophrenia. Cortical thickness is highly heritable and several MRI studies have shown widespread reductions of cortical thickness in patients with schizophrenia. Here, we investigated the effects of variation in DISC1 on cortical thickness. In a subsequent analysis we tested whether the identified DISC1 risk variant is also associated with neural activity during working memory functioning. Methods We acquired structural MRI (sMRI), functional MRI (fMRI) and genotype data from 96 healthy volunteers. Separate cortical statistical maps for five single nucleotide polymorphisms (SNP) of DISC1 were generated to detect differences of cortical thickness in genotype groups across the entire cortical surface. Working-memory related load-dependent activation was measured during the Sternberg Item Recognition Paradigm and analyzed using a region-of-interest approach. Results Phe allele carriers of the DISC1 SNP Leu607Phe had significantly reduced cortical thickness in the left supramarginal gyrus compared to Leu/Leu homozygotes. Neural activity in the left dorsolateral prefrontal cortex (DLPFC) during working memory task was increased in Phe allele carriers, whereas working memory performance did not differ between genotype groups. Conclusions This study provides convergent evidence for the effect of DISC1 risk variants on two independent brain-based intermediate phenotypes of schizophrenia. The same risk variant was associated with cortical thickness reductions and signs of neural inefficiency during a working memory task. Our findings provide further evidence for a neurodevelopmental model of schizophrenia.

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YNIMG Journal 2010 Journal Article

Does function follow form?: Methods to fuse structural and functional brain images show decreased linkage in schizophrenia

  • Andrew M. Michael
  • Stefi A. Baum
  • Tonya White
  • Oguz Demirci
  • Nancy C. Andreasen
  • Judith M. Segall
  • Rex E. Jung
  • Godfrey Pearlson

When both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) data are collected they are typically analyzed separately and the joint information is not examined. Techniques that examine joint information can help to find hidden traits in complex disorders such as schizophrenia. The brain is vastly interconnected, and local brain morphology may influence functional activity at distant regions. In this paper we introduce three methods to identify inter-correlations among sMRI and fMRI voxels within the whole brain. We apply these methods to examine sMRI gray matter data and fMRI data derived from an auditory sensorimotor task from a large study of schizophrenia. In Method 1 the sMRI–fMRI cross-correlation matrix is reduced to a histogram and results show that healthy controls (HC) have stronger correlations than do patients with schizophrenia (SZ). In Method 2 the spatial information of sMRI–fMRI correlations is retained. Structural regions in the cerebellum and frontal regions show more positive and more negative correlations, respectively, with functional regions in HC than in SZ. In Method 3 significant sMRI–fMRI inter-regional links are detected, with regions in the cerebellum showing more significant positive correlations with functional regions in HC relative to SZ. Results from all three methods indicate that the linkage between gray matter and functional activation is stronger in HC than SZ. The methods introduced can be easily extended to comprehensively correlate large data sets.

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YNIMG Journal 2010 Journal Article

Multi-site characterization of an fMRI working memory paradigm: Reliability of activation indices

  • Anastasia Yendiki
  • Douglas N. Greve
  • Stuart Wallace
  • Mark Vangel
  • Jeremy Bockholt
  • Bryon A. Mueller
  • Vince Magnotta
  • Nancy Andreasen

Neuroimaging studies are facilitated significantly when it is possible to recruit subjects and acquire data at multiple sites. However, the use of different scanners and acquisition protocols is a potential source of variability in multi-site data. In this work we present a multi-site study of the reliability of fMRI activation indices, where 10 healthy volunteers were scanned at 4 different sites while performing a working memory paradigm. Our results indicate that, even with different scanner manufacturers and field strengths, activation variability due to site differences is small compared to variability due to subject differences in this cognitive task, provided we choose an appropriate activation measure.

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YNIMG Journal 2010 Journal Article

The COMT Val108/158Met polymorphism and medial temporal lobe volumetry in patients with schizophrenia and healthy adults

  • Stefan Ehrlich
  • Eric M. Morrow
  • Joshua L. Roffman
  • Stuart R. Wallace
  • Melissa Naylor
  • H. Jeremy Bockholt
  • Antonia Lundquist
  • Anastasia Yendiki

Abnormalities of the medial temporal lobe have been consistently demonstrated in schizophrenia. A common functional polymorphism, Val108/158Met, in the putative schizophrenia susceptibility gene, catechol-O-methyltransferase (COMT), has been shown to influence medial temporal lobe function. However, the effects of this polymorphism on volumes of medial temporal lobe structures, particularly in patients with schizophrenia, are less clear. Here we measured the effects of COMT Val108/158Met genotype on the volume of two regions within the medial temporal lobe, the amygdala and hippocampus, in patients with schizophrenia and healthy control subjects. We obtained MRI and genotype data for 98 schizophrenic patients and 114 matched controls. An automated atlas-based segmentation algorithm was used to generate volumetric measures of the amygdala and hippocampus. Regression analyses included COMT met allele load as an additive effect, and also controlled for age, intracranial volume, gender and acquisition site. Across patients and controls, each copy of the COMT met allele was associated on average with a 2. 6% increase in right amygdala volume, a 3. 8% increase in left amygdala volume and a 2. 2% increase in right hippocampus volume. There were no effects of COMT genotype on volumes of the whole brain and prefrontal regions. Thus, the COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism. Taken together with previous work, our data support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures.

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YNIMG Journal 2010 Journal Article

WITHDRAWN: Erratum to “Does function follow form?: Methods to fuse structural and functional brain images show decreased linkage in schizophrenia” [NeuroImage 49 (2010) 2626–2637]

  • Andrew M. Michael
  • Stefi A. Baum
  • Tonya White
  • Oguz Demirci
  • Nancy C. Andreasen
  • Judith M. Segall
  • Rex E. Jung
  • Godfrey Pearlson

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http: //www. elsevier. com/locate/withdrawalpolicy.

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YNIMG Journal 2009 Journal Article

An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment

  • Jian Kong
  • Ted J. Kaptchuk
  • Ginger Polich
  • Irving Kirsch
  • Mark Vangel
  • Carolyn Zyloney
  • Bruce Rosen
  • Randy L. Gollub

It is well established that expectation can significantly modulate pain perception. In this study, we combined an expectancy manipulation model and fMRI to investigate how expectation can modulate acupuncture treatment. Forty-eight subjects completed the study. The analysis on two verum acupuncture groups with different expectancy levels indicates that expectancy can significantly influence acupuncture analgesia for experimental pain. Conditioning positive expectation can amplify acupuncture analgesia as detected by subjective pain sensory rating changes and objective fMRI signal changes in response to calibrated noxious stimuli. Diminished positive expectation appeared to inhibit acupuncture analgesia. This modulation effect is spatially specific, inducing analgesia exclusively in regions of the body where expectation is focused. Thus, expectation should be used as an important covariate in future studies evaluating acupuncture efficacy. In addition, we also observed dissociation between subjective reported analgesia and objective fMRI signal changes to calibrated pain in the analysis across all four groups. We hypothesize that as a peripheral-central modulation, acupuncture needle stimulation may inhibit incoming noxious stimuli; while as a top-down modulation, expectancy (placebo) may work through the emotional circuit.

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YNIMG Journal 2007 Journal Article

Reproducibility of quantitative tractography methods applied to cerebral white matter

  • Setsu Wakana
  • Arvind Caprihan
  • Martina M. Panzenboeck
  • James H. Fallon
  • Michele Perry
  • Randy L. Gollub
  • Kegang Hua
  • Jiangyang Zhang

Tractography based on diffusion tensor imaging (DTI) allows visualization of white matter tracts. In this study, protocols to reconstruct eleven major white matter tracts are described. The protocols were refined by several iterations of intra- and inter-rater measurements and identification of sources of variability. Reproducibility of the established protocols was then tested by raters who did not have previous experience in tractography. The protocols were applied to a DTI database of adult normal subjects to study size, fractional anisotropy (FA), and T 2 of individual white matter tracts. Distinctive features in FA and T 2 were found for the corticospinal tract and callosal fibers. Hemispheric asymmetry was observed for the size of white matter tracts projecting to the temporal lobe. This protocol provides guidelines for reproducible DTI-based tract-specific quantification.

Details DOI

YNIMG Journal 2007 Journal Article

Test–retest study of fMRI signal change evoked by electroacupuncture stimulation

  • Jian Kong
  • Randy L. Gollub
  • J. Megan Webb
  • Jiang-Ti Kong
  • Mark G. Vangel
  • Kenneth Kwong

Recent efforts to use fMRI to investigate the effects of acupuncture needle manipulation on the brain have yielded discrepant results. This study was designed to test the reliability of fMRI signal changes evoked by acupuncture stimulation. Six subjects participated in six identical scanning sessions consisting of four functional scans, one for each of the four conditions: electroacupuncture stimulation (2 Hz) at GB 37, UB 60, non-acupoint (NP), and a control task of the finger tapping. In the group analysis across all subjects and sessions, both the average ratings on a Subjective Acupuncture Sensation Scale and the average fMRI signal changes (increases and decreases) were similar for GB37, UB 60, and NP. Visual inspection of the activation maps from individual sessions and ICC analysis revealed that fMRI signal changes evoked by electroacupuncture stimulation were significantly more variable than those from the control finger-tapping task. The relatively large variability across different sessions within the same subject suggests multiple sessions should be used to accurately capture the activation patterns evoked by acupuncture stimulation at a particular point for a specific subject.

Details DOI
v2026.09.13